Time to Think of Aggression as a Treatment Target Symptom, Independent of Diagnosis

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COMMENTARY

Violence and aggression are not diagnostic features of any psychiatric disorder. Nonetheless, many individuals associate these symptoms with mental illness and they are often the precipitant for emergency presentations and hospitalization.¹ Additionally, society associates severe mental illness with both aggression and violence, a belief that is reinforced by media, politicians, and others.^2,3 Yet, excluding substance use, the rates of aggression and violence by patients with psychiatric disorders are similar to those occurring in the general population.⁴ Despite the fact that aggression has not been identified as a symptom of any specific psychiatric disorder, it is still seen as a consequence of associated disorders. Treatment of aggression is currently constrained within treatment of the associated disorder. However, there are sufficient data to suggest that it is reasonable to view aggression itself as a potential target for treatment.

Pathophysiology of Aggression

Several studies have attempted to discern the physiologic congenators of aggression. While there are many findings, most are probably associations rather than causative. The most reproducible and important of these studies have been associations of polymorphisms of the dopamine D4 receptor with aggression.⁵ DRD4 is the gene that codes for the dopamine D4 receptor. It is found on the short arm of the 11th chromosome. Stimulation of D4 activates the inhibitory G protein second messenger system (Gai) and inhibits cyclic adenosine monophosphate (cAMP) formation.⁶ D4 is expressed in the frontal cortex, where it is much more common than the D2 receptor,⁷ as well as in the thalamus, hypothalamus, and olfactory bulb.⁸ The DRD4 gene has a polymorphic third exon. This part of the gene codes for the third cytoplasmic loop of the protein, which interacts with the Gai second messenger.⁹ The polymorphism presents as variable number of repeats within this 48 base pair section. In the population, the number of repeats varies between 2 and 11 times. A common variant is the seven-repeat allele (7R), which is best known for its association with attention-deficit/hyperactivity disorder.^10-13 But it has also been associated with novelty seeking,^14-17 impulsivity,^15,18 anger,¹⁶ and aggression.¹⁹ This association gains importance when one becomes aware that D4 antagonists with high affinity that exceeds affinity for D2 by the same drug have significant anti-aggression properties.⁵ The Table summarizes the affinities, expressed as dissociation constants (Ki), of several antipsychotics.^20-22 In general, while second-generation antipsychotics have been described to have greater affinity for D4 than D2, that is generally not true.²³ 

Table. The Affinity, Expressed as the Dissociation Constant (Ki) for a Selected Group of Second-Generation Antipsychotics^20-22

The D4/D2 affinity ratio is calculated as the ratio of the inverse of the Ki.

*Note since affinity increases as Ki decreases, the D4/D2 ratio is actually the ratio of (1/Ki/(1/Ki)

Anti-Aggression Agents

The most effective anti-aggression agent available is clozapine.²⁴ This has been repeatedly demonstrated in open studies^25-28 as well as in randomized trials.^29-31 In the blinded, randomized studies, clozapine was superior to risperidone, olanzapine, and haloperidol. Specifically, the likelihood for aggressive behaviors after study entry was significantly lower for clozapine (17.5%) vs olanzapine (23.1%), risperidone 24.4%, and haloperidol (45.9%).²⁹ Measured aggression was significantly less likely to happen with clozapine than haloperidol (physical aggression: odds ration [OR] = 2.04, P < 0.001, aggression against property: OR = 1.85, P < 0.001, and verbal aggression: OR = 1.35, P < 0.001), and olanzapine (physical aggression: OR = 1.33, P < 0.001, and verbal aggression: OR = 1.32, P < 0.001, but not aggression against property: OR = 1.10, P = 0.78) (risperidone not examined in this study).³¹ In this same study, olanzapine was also superior to haloperidol (physical aggression: OR = 1.54, P < 0.001, aggression against property: OR 1.67, P < 0.001, but not verbal aggression: OR = 1.03, P = 0.57).³¹ In a comparative study that examined the hostility items of the Positive and Negative Syndrome Scale (PANNS), clozapine was the only agent that significantly reduced measured hostility vs baseline (P = 0.019) and was superior to risperidone (P = 0.012) and haloperidol (P = 0.021) but not olanzapine.³⁰ More importantly, this effect occurred at therapeutic dosageand was independent of clozapine’s antipsychotic effect or the occurrence of sedation.^25,30,31 Clozapine is also effective in a genetic animal model of a developmental disorder (immediate early gene transcription factor, Egr3, knockout) in which the animals become aggressive.³²

Similarly, asenapine has also demonstrated anti-aggression effects in a prospective study comparing asenapine with treatment as usual (TAU) for 48 patients who were admitted with significant aggression.³³ Asenapine was superior to TAU as measured by the Modified Overt Aggression Scale [MOAS]). There was a significant reduction physical aggression (–8.0 ± 5.06 vs. –0.78 ± 2.40, P < 0.0001), and total (–14.7 ± 11.59 vs. –5.4 ± 10.12, P = 0.045) aggression as measured by the MOAS.33 More recently, a post hoc analysis of hostility in 442 patients with schizophrenia treated with a transdermal formulation of asenapine found that hostility item improved independent of antipsychotic effect and after correcting for covariates, indicating that the antihostility effect is independent of the antipsychotic effect.³⁴ Sublingual asenapine has also demonstrated significant reductions in hostility, irritability, and disruptive behavior vs placebo in participants experiencing acute mania.³⁵ Asenapine may be effective quickly and in a randomized, placebo-controlled study of agitation in a mixed diagnosis sample (schizophrenia, bipolar disorder, major depressive disorder, anxiety, and posttraumatic stress disorder) it significantly reduced the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC).³⁶ Adequate D4 blockade and the anti-aggression effect is likely achieved at 5 mg daily, whereas the minimum antipsychotic dose is 10 mg daily, and it is believed that aggression should improve at 5 mg.⁵

Loxapine is a second-generation antipsychotic agent that was not identified as such prior to the introduction of clozapine.³⁷ It has a long history of treating aggression, hostility, and agitation in patients with bipolar disorder and schizophrenia experiencing acute mania and psychosis with both injectable^38-40 and inhalable formulations.^41-43 Significantly, the effect on reducing aggression in agitated patients appears to occur independent of diagnosis.⁴⁴ Receptor occupancy is generally poorly studied in older medications, but the antipsychotic effect (ie, D2 receptor occupancy of 60% to 80%) probably occurs at 15 to 30 mg daily,⁴⁵ and since the affinity at D4 is 3 times greater than at D2, one would expect that doses as low as 10 mg daily may be effective for aggression control.

Olanzapine and risperidone also have D4 affinities that exceeds D2 affinities (Table).^20-22 The difference is small but similar to asenapine (Table).^20-22 For all 3 agents, it is likely that both receptors are blocked at doses that are frequently used. All these agents are frequently used in aggression because the drugs are approved for use in a wide range of psychiatric disorders. While asenapine has not been compared with clozapine, clozapine appears to be superior to both olanzapine and risperidone. Furthermore, reduction in aggression with olanzapine and risperidone appears to be related to their antipsychotic effect,²⁹ which does not appear to be the case for clozapine.^29-31

Some of these agents have affinity to D4 that exceeds the affinity for D2 (ie, affinity D4/affinity D2 > 1).⁵ Clozapine clearly has the best data and is likely superior to other agents.It is superior to risperidone, olanzapine, and haloperidol. It would appear that when a patient presents with aggression as an important symptom, targeting that symptom may have a greater impact than treating the underlying disease.

Concluding Thoughts

When aggression is the predominant clinical target symptom, agents with greater affinity to the D4 receptor vs the D2 receptor may be preferred. Clozapine, which has the greatest difference between the affinity to these 2 receptors, has been found to be superior in head-to-head studies. Furthermore, it appears that the efficacy of antipsychotic agents for aggression is related to the D4/D2 ratio, although the data are not adequate to be certain of this last point.

Aggression that occurs in patients with psychiatric disorders may frequently fuel psychiatric presentation to either the emergency or inpatient setting. Clinicians tend to choose treatments based on the diagnosis. However, if aggression is a major issue, it may be reasonable to choose a treatment that has demonstrated efficacy to address aggression. The availability of agents that have demonstrated efficacy in aggression should be considered when choosing treatments for patients who present with aggression as a primary symptom.

Dr El-Mallakh is a professor in the department of psychiatry and behavioral sciences and director of the Mood Disorders Research Program at the University of Louisville School of Medicine in Louisville, Kentucky. Dr Aydin is a postdoctoral researcher at the University of Louisville School of Medicine in Louisville, Kentucky.

References

1. Girasek H, Nagy VA, Fekete S, et al. Prevalence and correlates of aggressive behavior in psychiatric inpatient populations. World J Psychiatry. 2022;12(1):1-23.

2. Pescosolido BA, Monahan J, Link BG, et al. The public's view of the competence, dangerousness, and need for legal coercion of persons with mental health problems. Am J Public Health. 1999;89(9):1339-1345.

3. McGinty EE, Kennedy-Hendricks A, Choksy S, Barry CL. Trends in news media coverage of mental illness in the United States: 1995-2014. Health Aff (Millwood). 2016;35(6):1121-1129.

4. Elbogen EB, Johnson SC. The intricate link between violence and mental disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2009;66(2):152-161.

5. El-Mallakh RS, McKenzie CE. The dopamine D4/D2 receptor antagonist affinity ratio as a predictor of anti-aggression medication efficacy. Med Hypoth. 2013;80(5):530-533.

6. Neve KA, Seamans JK, Trantham-Davidson H. Dopamine receptor signaling. J Recept Signal Transduct Res. 2004;24(3):165-205.

7. de Almeida J, Mengod G. D2 and D4 dopamine receptor mRNA distribution in pyramidal neurons and GABAergic subpopulations in monkey prefrontal cortex: implications for schizophrenia treatment. Neuroscience. 2010;170(4):1133-1139.

8. O’Malley KL, Harmon S, Tang L, Todd RD. The rat dopamine D4 receptor: sequence, gene structure, and demonstration of expression in the cardiovascular system. New Biol. 1992;4(2):137-146.

9. Van Tol HH, Wu CM, Guan HC, et al. Multiple dopamine D4 receptor variants in the human population. Nature. 1992;358(6382):149-52.

10. Ding YC, Chi HC, Grady DL, et al. Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci U S A. 2002;99(1):309-314.

11. Grady DL, Chi HC, Ding YC, et al. High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder. Mol Psychiatry. 2003;8(5):536-545.

12. Nikolaidis A, Gray JR. ADHD and the DRD4 exon III 7-repeat polymorphism: an international meta-analysis. Soc Cogn Affect Neurosci. 2010;5(2-3):188-193.

13. Tovo-Rodrigues L, Rohde LA, Roman T, et al. Is there a role for rare variants in DRD4 gene in the susceptibility for ADHD? Searching for an effect of allelic heterogeneity. Mol Psychiatry. 2012;17(5):520-526.

14. Becker K, Laucht M, El-Faddagh M, Schmidt MH. The dopamine D4 receptor gene exon III polymorphism is associated with novelty seeking in 15-year-old males from a high-risk community sample. J Neural Transm. 2005;112(6):847-858.

15. Zalsman G, Frisch A, Lewis R, et al. DRD4 receptor gene exon III polymorphism in inpatient suicidal adolescents. J Neural Transm (Vienna). 2004;111(12):1593-1603.

16. Dmitrieva J, Chen C, Greenberger E, et al. Gender-specific expression of the DRD4 gene on adolescent delinquency, anger and thrill seeking. Soc Cognitive Affective Neurosci. 2011;6(1):82-89.

17. Matthews LJ, Butler PM. Novelty-seeking DRD4 polymorphisms are associated with human migration distance out-of-Africa after controlling for neutral population gene structure. Am J Phys Anthropol. 2011;145(3):382-389.

18. Comings DE, Gonzalez N, Wu S, et al. Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am J Med Genet. 1999;88(4):358-368.

19. Fresan A, Camarena B, Apiquian R, et al. Association study of MAO-A and DRD4 genes in schizophrenic patients with aggressive behavior. Neuropsychobiology. 2007;55(3-4):171-175.

20. Peprah K, Zhu XY, Eyunni SV, et al. Multi-receptor drug design: haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents. Bioorg Med Chem. 2012;20(3):1291-1297.

21. Li P, Snyder GL, Vanover KE. Dopamine targeting drugs for the treatment of schizophrenia: past, present and future. Curr Top Med Chem. 2016;16(29):3385-3403.

22. Singh AN, Barlas C, Singh S, et al. A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes. J Psychiatry Neurosci. 1996;21(1):29-35.

23. Seeman P, Corbett R, Van Tol HH. Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology. 1997;16(2):93-110.

24. Frogley C, Taylor D, Dickens G, Picchioni M. A systematic review of the evidence of clozapine’s anti-aggressive effects. Int J Neuropsychopharmacol. 2012;16(9):1351-1371.

25. Buckley P, Bartell J, Donenwirth K, et al. Violence and schizophrenia: clozapine as a specific antiaggressive agent. Bull Am Acad Psychiatry Law. 1995;23(4):607-611.

26. Wilson WH, Claussen AM. 18-month outcome of clozapine treatment for 100 patients in a state psychiatric hospital. Psychiatr Serv. 1995;46(4):386-398.

27. Rabinowitz J, Avnon M, Rosenberg V. Effect of clozapine on physical and verbal aggression. Schizophr Res. 1996;22(3):249-255.

28. Essock SM, Frisman LK, Covell NH, Hargreaves W. Cost-effectiveness of clozapine compared with conventional antipsychotic medications for patients in state hospitals. Arch Gen Psychiatry. 2000;57(10):987-994.

29. Volavka J, Czobor P, Nolan K, et al. Overt aggression and psychotic symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychopharmacol. 2004;24(2):225-228.

30. Citrome L, Volavka J, Czobor P, et al. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatr Serv. 2001;52(11):1510-1514.

31. Krakowski MI, Czobor P, Citrome L, et al. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2006;63(6):622-629.

32. Gallitano-Mendel A, Wozniak DF, Pehek EA, Millbrandt J. Mice lacking the immediate early gene Egr3 respond to the anti-aggressive effects of clozapine yet are relatively resistant to its sedating effects. Neuropsychopharmacol. 2008;33(6):1266-1275.

33. Amon JS, Johnson SB, El-Mallakh RS. Asenapine for the control of physical aggression: a prospective naturalist pilot study. Psychopharmacol Bull. 2017;47(1):27-32.

34. Citrome L, Komaroff M, Starling B, et al. Efficacy of HP-3070, an asenapine transdermal system, on symptoms of hostility in adults with schizophrenia: a post hoc analysis of a 6-week phase 3 study. J Clin Psychiatry. 2022;83(4):21m14355.

35. Citrome L, Landbloom R, Chang CT, et al. Effects of asenapine on agitation and hostility in adults with acute manic or mixed episodes associated with bipolar I disorder. Neuropsychiatr Dis Treat 2017;13:2955-2963.

36. Pratts M, Citrome L, Grant W, et al. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand. 2014;130(1):61-68.

37. Ferreri F, Drapier D, Baloche E, et al. The in vitro actions of loxapine on dopaminergic and serotonergic receptors. Time to consider atypical classification of this antipsychotic drug? Int J Neuropsychophramcol. 2018;21(4):355-360.

38. Deniker P, Loo H, Cottereau MJ. Parenteral loxapine in severely disturbed schizophrenic patients. J Clin Psychiatry. 1979;41(1):23-26.

39. Feldman HS. Loxapine succinate as initial treatment of hostile and aggressive schizophrenic criminal offenders. J Clin Pharmacol. 1982;22(8-9):366-370.

40. Tuason VB. A comparison of parenteral loxapine and haloperidol in hostile and aggressive acutely schizophrenic patients. J Clin Psychiatry. 1986;47(3):126-129.

41. Allen MH, Feifel D, Lesem MD, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72(10):1313-1321.

42. Lesem MD, Tran-Johson TK, Riesenberg RA, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011;198(1):51-58.

43. Kwentus J, Riesenberg RA, Marandi M, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012;14(1):31-40.

44. Ruch T, Nuss S, Yeruva RR, et al. Inhaled loxapine for acute agitation in a psychiatric emergency service. Ann Clin Psychiatry. 2021;33(3):162-167.

45. Kapur S, Zipursky RB, Jones C, et al. The D2 receptor occupancy profile of loxapine determined using PET. Neuropsychopharmacology. 1996;15(6):562-566.