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List of investigational aggression drugs

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This is a list of investigational aggression drugs, or drugs that are currently under development for clinical use in the treatment of aggression but are not yet approved. Drugs used to treat aggression may also be known as "serenics".[1]

Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses.

This list was last comprehensively updated in February 2025. It is likely to become outdated with time.

Under development

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Phase 3

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  • Molindone (AFX 2201; EN-1733A; -810; SPN-810M; Zalvari) – antipsychotic (non-selective monoamine receptor modulator) – specifically for aggression in children and adolescents with attention-deficit hyperactivity disorder (ADHD)[2][3][4]

Phase 2

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  • Vafidemstat (ORY-2001) – lysine-specific demethylase 1 (LSD1; KDM1A) and monoamine oxidase B (MAO-B) inhibitor[5]

Preclinical

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  • SRX251 – vasopressin V1A receptor antagonist – no recent development since 2007[6][7]

Not under development

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No development reported

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  • Eltoprazine (DU-28853) – serotonin 5-HT1A and 5-HT1B receptor agonist and serotonin 5-HT2C receptor antagonist[8][1]
  • Zolmitriptan (ML-004) – serotonin 5-HT1B and 5-HT1D receptor agonist[9][10][11]

Development discontinued

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  • Batoprazine – serotonin 5-HT1A and 5-HT1B receptor agonist[12][1]
  • Mibampator (LY-451395) – ionotropic glutamate AMPA receptor positive allosteric modulator[13]
  • Olanzapine intranasal (INP-105; POD™ olanzapine) – atypical antipsychotic (non-selective monoamine receptor modulator)[14]
  • Risperidone extended-release (Risperisphere) – atypical antipsychotic (non-selective monoamine receptor modulator)[15]

Formal development never or not yet started

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Clinically used drugs

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Approved drugs

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  • Olanzapine (Zyprexa) – atypical antipsychotic (non-selective monoamine receptor modulator)[31]
  • Paliperidone (Invega) – atypical antipsychotic (non-selective monoamine receptor modulator)[32]
  • Risperidone (Risperdal) – atypical antipsychotic (non-selective monoamine receptor modulator)[33]

Off-label drugs

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See also

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References

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  1. ^ a b c d Olivier B, van Oorschot R (December 2005). "5-HT1B receptors and aggression: a review". Eur J Pharmacol. 526 (1–3): 207–217. doi:10.1016/j.ejphar.2005.09.066. PMID 16310769. The early serenics (fluprazine, DU28412, DU 27725, eltoprazine, batoprazine: Olivier et al. (1990a,b)) are mixed 5- HT1A/1B receptor agonist, leaving the 5-HT1A receptor still as an option for mediating (part of) the anti-aggressive effect, but more recently synthesized 5-HT1B receptor agonists including, e.g. anpirtoline, CP-94,253 (5-propoxy-3-( 1,2,3,6- tetrahydro4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine) and zolmitriptan, are far more selective for this receptor and showed a similar, highly specific anti-aggressive effect, both in aggressive residential mice and in mice made more aggressive via low-doses of alcohol or social instigation (Fish et al., 1999; de Almeida et al., 2001; De Almeida and Miczek, 2002; Miczek and de Almeida, 2001). [...]
  2. ^ "Molindone - Supernus Pharmaceuticals". AdisInsight. 29 May 2024. Retrieved 24 February 2025.
  3. ^ Robb AS, Schwabe S, Ceresoli-Borroni G, Nasser A, Yu C, Marcus R, Candler SA, Findling RL (March 2019). "A proposed anti-maladaptive aggression agent classification: improving our approach to treating impulsive aggression". Postgrad Med. 131 (2): 129–137. doi:10.1080/00325481.2019.1574401. PMID 30678534.
  4. ^ Balia C, Carucci S, Coghill D, Zuddas A (August 2018). "The pharmacological treatment of aggression in children and adolescents with conduct disorder. Do callous-unemotional traits modulate the efficacy of medication?". Neurosci Biobehav Rev. 91: 218–238. doi:10.1016/j.neubiorev.2017.01.024. PMID 28137460.
  5. ^ "Vafidemstat - Oryzon Genomics". AdisInsight. 6 December 2024. Retrieved 24 February 2025.
  6. ^ "SRX 251". AdisInsight. 3 January 2024. Retrieved 24 February 2025.
  7. ^ Ferris CF, Lu SF, Messenger T, Guillon CD, Heindel N, Miller M, Koppel G, Robert Bruns F, Simon NG (February 2006). "Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior". Pharmacol Biochem Behav. 83 (2): 169–174. doi:10.1016/j.pbb.2006.01.001. PMID 16504276.
  8. ^ "Eltoprazine". AdisInsight. 23 February 2022. Retrieved 24 February 2025.
  9. ^ "ML 004". AdisInsight. 28 December 2024. Retrieved 24 February 2025.
  10. ^ de Almeida RM, Nikulina EM, Faccidomo S, Fish EW, Miczek KA (September 2001). "Zolmitriptan--a 5-HT1B/D agonist, alcohol, and aggression in mice". Psychopharmacology (Berl). 157 (2): 131–141. doi:10.1007/s002130100778. PMID 11594437.
  11. ^ Gowin JL, Swann AC, Moeller FG, Lane SD (July 2010). "Zolmitriptan and human aggression: interaction with alcohol". Psychopharmacology (Berl). 210 (4): 521–531. doi:10.1007/s00213-010-1851-6. PMC 9150756. PMID 20407761.
  12. ^ "Batoprazine". AdisInsight. 13 March 2001. Retrieved 24 February 2025.
  13. ^ "Mibampator". AdisInsight. 2 October 2021. Retrieved 24 February 2025.
  14. ^ "Olanzapine intranasal". AdisInsight. 13 October 2023. Retrieved 24 February 2025.
  15. ^ "Risperidone extended release". AdisInsight. 24 August 2023. Retrieved 24 February 2025.
  16. ^ Volavka J, Citrome L, Huertas D (2006). "Update on the biological treatment of aggression". Actas Esp Psiquiatr. 34 (2): 123–135. PMID 16552640. Along 1993-98, our group conducted a pilot, randomiz-ed, triple-blind, head-to-head, parallel-group clinical trial,to examine the effectiveness and safety of cyproterone against haloperidol in the treatment of aggression associa-ted with Alzheimer's dementia5. Cyproterone proved to be significantly more effective and better tolerated than haloperidol as a specific antiaggressive treatment in this population (report in preparation).
  17. ^ Lavine R (1997). "Psychopharmacological treatment of aggression and violence in the substance using population". J Psychoactive Drugs. 29 (4): 321–329. doi:10.1080/02791072.1997.10400558. PMID 9460025. Several other medications are being used in treatment of aggression, but less commonly than those mentioned above. Medroxyprogesterone is an anti-androgen which lowers testosterone. It is the equivalent of a pharmacological castration and will decrease or eliminate the sex drive in males. [...] The correlation between androgens and violence is not entirely clear; Virkkunen and Linnoila (1993) report, for instance, that testosterone levels are associated with outward-directed aggressiveness and lack of socialization as opposed to impulsiveness. The use of anti-androgens also presents certain ethical questions, such as whether it could be said to be freely chosen when a jail sentence is a potential alternative or whether it should even be offered as an allowable alternative. The treatment is controversial and ethical guidelines have not been established.
  18. ^ Pivovarciova A, Hnilicova S, Ostatnikova D, Mace FC (2014). "Testosterone and explosive aggression in autism spectrum disorders" (PDF). Neuro Endocrinol Lett. 35 (7): 553–559. PMID 25617877. Cyproterone acetate, medroxyprogesterone acetate, leuprolide acetate and spironolactone are anti-androgen drugs used when there are indications of hyperandrogeny. [...] These medications have also been used in the treatment of aggression in various clinical populations: sexual offenders, demented aggressive patients, aggressive patients with brain injuries, children with precocious puberty, and children with ASD (Bradstreet et al. 2007; Caparros-Lefebvre & Dewailly 2005; Huertas et al. 2007; Laue & Cutler 1994; Leschek et al. 1999; O'Connor & Baker 1983). Anti-androgen medication may prove a valuable adjunctive treatment to behavioral interventions and reduce the intensity and duration of aggressive episodes in individuals with explosive aggression and ASD. Although existing evidence for the therapeutic effects of anti-androgen medication is promising, there are no randomized controlled trials with most research involving uncontrolled case studies or open trials conducted mainly in populations others than children with autism. Some reports are anecdotal findings of reduced aggression during primary treatment of other diseases with anti-androgen medication (e.g. precocious puberty) (Laue & Cutler 1994; Leschek et al. 1999). [...] Research investigating hormonal levels in ASD children and objective assessment of aggressive behavior are essential for further potential clinical indications for anti-androgen therapy.
  19. ^ Bolea-Alamanac BM, Davies SJ, Christmas DM, Baxter H, Cullum S, Nutt DJ (January 2011). "Cyproterone to treat aggressivity in dementia: a clinical case and systematic review". J Psychopharmacol. 25 (1): 141–145. doi:10.1177/0269881109353460. PMID 19942637.
  20. ^ Bradford LD, Olivier B, van Dalen D, Schipper J (1984). "Serenics: the pharmacology of fluprazine and DU 28412". Prog Clin Biol Res. 167: 191–207. PMID 6150489.
  21. ^ a b Wang L, Clark EA, Hanratty L, Koblan KS, Foley A, Dedic N, Bristow LJ (December 2024). "TAAR1 and 5-HT1B receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid". Pharmacol Biochem Behav. 245: 173862. doi:10.1016/j.pbb.2024.173862. PMID 39197535.
  22. ^ de Boer SF, Koolhaas JM (December 2005). "5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis". Eur J Pharmacol. 526 (1–3): 125–139. doi:10.1016/j.ejphar.2005.09.065. PMID 16310183. Using such an ethopharmacological approach in either rats or mice, it has recently been claimed that only certain specific 5-HT1A receptor agonists (i.e., alnespirone and S-15535; de Boer et al., 1999, 2000), a mixed 5-HT1A/1B receptor agonist (i.e., eltoprazine; Olivier et al., 1995) and several specific 5-HT1B receptor agonists (i.e., CGS12066b, CP-94,253, anpirtoline, zolmitriptan, sumatriptan; Bell and Hobson, 1994; Fish et al., 1999; De Almeida et al., 2001; Miczek et al., 2004) exert behavioral specific anti-aggressive effects. In particular, it was claimed that agonists acting on the 5-HT1B receptors have more selective anti-aggressive effects in mice than those acting on 5-HT1A receptors (Miczek et al., 2004; Olivier, 2004).
  23. ^ Fish EW, Faccidomo S, Miczek KA (October 1999). "Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT(1B) receptor agonist CP-94,253". Psychopharmacology (Berl). 146 (4): 391–399. doi:10.1007/pl00005484. PMID 10550489.
  24. ^ de Almeida RM, Miczek KA (August 2002). "Aggression escalated by social instigation or by discontinuation of reinforcement ("frustration") in mice: inhibition by anpirtoline: a 5-HT1B receptor agonist". Neuropsychopharmacology. 27 (2): 171–181. doi:10.1016/S0893-133X(02)00291-9. PMID 12093591.
  25. ^ Popova NK, Tsybko AS, Naumenko VS (August 2022). "The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference". Int J Mol Sci. 23 (15): 8814. doi:10.3390/ijms23158814. PMC 9369404. PMID 35955946. There are a few currently available data in support of the antiaggressive role of 5-HT2C receptors: (1) the activation of 5-HT2C receptors enhanced the display of defeat submissive and defensive behavior in golden hamsters [172]. (2) 5-HT2C receptor agonist/alpha 2 receptor antagonist S32212 suppressed aggressive behavior in mice [173]. (3) Mice expressing only the VGV isoform of 5-HT2C receptors displayed a high level of conspecific aggression [174]. (4) The association between Htr2c gene polymorphism and criminal behavior in humans was demonstrated [175]. (5) Recently, a novel 5-HT2C agonist, lorcaserin, has been demonstrated to have antiaggressive properties in human subjects with impulsive aggressive behavior. Lorcaserin attenuated provoked, but not unprovoked, aggression in impulsively aggressive individuals indicating that 5-HT2C receptor may be a putative target for the treatment of impulsive aggressive behavior in human subjects [176].
  26. ^ Desilva, Nilifa; Hollander, Eric (2023). "Impulse Control Disorders: Intermittent Explosive Disorder, Kleptomania, Pyromania". Tasman's Psychiatry. Cham: Springer International Publishing. p. 1–49. doi:10.1007/978-3-030-42825-9_165-1. ISBN 978-3-030-42825-9. Based on evidence from a recent pilot study, lorcaserin, a selective 5-HT2c agonist, was found to have anti-aggressive effects in humans with high levels of impulsive aggression like in those diagnosed with IED.
  27. ^ Tahir T, Wong MM, Maaz M, Naufal R, Tahir R, Naidoo Y (May 2022). "Pharmacotherapy of impulse control disorders: A systematic review". Psychiatry Res. 311: 114499. doi:10.1016/j.psychres.2022.114499. PMID 35305343.
  28. ^ Coccaro EF, Lee RJ (November 2019). "5-HT2c agonist, lorcaserin, reduces aggressive responding in intermittent explosive disorder: A pilot study". Hum Psychopharmacol. 34 (6): e2714. doi:10.1002/hup.2714. PMID 31774584.
  29. ^ Cherek DR, Lane SD (September 2001). "Acute effects of D-fenfluramine on simultaneous measures of aggressive escape and impulsive responses of adult males with and without a history of conduct disorder". Psychopharmacology (Berl). 157 (3): 221–227. doi:10.1007/s002130100812. PMID 11605076.
  30. ^ Zhukov IS, Alnefeesi Y, Krotova NA, Nemets VV, Demin KA, Karpenko MN, Budygin EA, Kanov EV, Kalueff AV, Shabanov PD, Bader M, Alenina N, Gainetdinov RR (2024). "Trace amine-associated receptor 1 agonist reduces aggression in brain serotonin-deficient tryptophan hydroxylase 2 knockout rats". Front Psychiatry. 15: 1484925. doi:10.3389/fpsyt.2024.1484925. PMC 11693706. PMID 39748904.
  31. ^ "Olanzapine - Eli Lilly and Company". AdisInsight. 20 February 2025. Retrieved 24 February 2025.
  32. ^ "Paliperidone - Johnson & Johnson". AdisInsight. 1 July 2020. Retrieved 24 February 2025.
  33. ^ "Risperidone". AdisInsight. 6 December 2023. Retrieved 24 February 2025.
  34. ^ a b c Pringsheim T, Hirsch L, Gardner D, Gorman DA (February 2015). "The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 1: psychostimulants, alpha-2 agonists, and atomoxetine". Can J Psychiatry. 60 (2): 42–51. doi:10.1177/070674371506000202. PMC 4344946. PMID 25886655.
  35. ^ a b c d Castro M, Butler M, Thompson AN, Gee S, Posporelis S (2024). "Effectiveness and Safety of Intravenous Medications for the Management of Acute Disturbance (Agitation and Other Escalating Behaviors): A Systematic Review of Prospective Interventional Studies". J Acad Consult Liaison Psychiatry. 65 (3): 271–286. doi:10.1016/j.jaclp.2024.01.004. PMID 38309683.
  36. ^ a b c d Pringsheim T, Hirsch L, Gardner D, Gorman DA (February 2015). "The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 2: antipsychotics and traditional mood stabilizers". Can J Psychiatry. 60 (2): 52–61. doi:10.1177/070674371506000203. PMC 4344947. PMID 25886656.
  37. ^ a b Rahmani E, Lemelle TM, Samarbafzadeh E, Kablinger AS (2021). "Pharmacological Treatment of Agitation and/or Aggression in Patients With Traumatic Brain Injury: A Systematic Review of Reviews". J Head Trauma Rehabil. 36 (4): E262 – E283. doi:10.1097/HTR.0000000000000656. PMID 33656478.
  38. ^ Romero-Martínez Á, Murciano-Martí S, Moya-Albiol L (May 2019). "Is Sertraline a Good Pharmacological Strategy to Control Anger? Results of a Systematic Review". Behav Sci (Basel). 9 (5): 57. doi:10.3390/bs9050057. PMC 6562745. PMID 31126061.
  39. ^ Kim S, Boylan K (October 2016). "Effectiveness of Antidepressant Medications for Symptoms of Irritability and Disruptive Behaviors in Children and Adolescents". J Child Adolesc Psychopharmacol. 26 (8): 694–704. doi:10.1089/cap.2015.0127. PMID 27482998.
  40. ^ Sharma T, Guski LS, Freund N, Gøtzsche PC (January 2016). "Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports". BMJ. 352: i65. doi:10.1136/bmj.i65. PMC 4729837. PMID 26819231.
  41. ^ a b c "Medication-induced violence others towards". Prescrire Int. 23 (150): 153–155. June 2014. PMID 25121148.
  42. ^ Eikelenboom-Schieveld, Selma J. M.; Fogleman, James C. (2023). "Violence Caused by Prescription Medication". Handbook of Anger, Aggression, and Violence. Cham: Springer International Publishing. pp. 215–241. doi:10.1007/978-3-031-31547-3_24. ISBN 978-3-031-31546-6.
  43. ^ Zaman H, Sampson SJ, Beck AL, Sharma T, Clay FJ, Spyridi S, Zhao S, Gillies D (December 2017). "Benzodiazepines for psychosis-induced aggression or agitation". Cochrane Database Syst Rev. 12 (12): CD003079. doi:10.1002/14651858.CD003079.pub4. PMC 6486117. PMID 29219171.
  44. ^ a b Bak M, Weltens I, Bervoets C, De Fruyt J, Samochowiec J, Fiorillo A, Sampogna G, Bienkowski P, Preuss WU, Misiak B, Frydecka D, Samochowiec A, Bak E, Drukker M, Dom G (April 2019). "The pharmacological management of agitated and aggressive behaviour: A systematic review and meta-analysis" (PDF). Eur Psychiatry. 57: 78–100. doi:10.1016/j.eurpsy.2019.01.014. PMID 30721802.
  45. ^ Dietch JT, Jennings RK (May 1988). "Aggressive dyscontrol in patients treated with benzodiazepines". J Clin Psychiatry. 49 (5): 184–188. PMID 2896665.
  46. ^ Jones KA, Nielsen S, Bruno R, Frei M, Lubman DI (November 2011). "Benzodiazepines - Their role in aggression and why GPs should prescribe with caution". Aust Fam Physician. 40 (11): 862–865. PMID 22059213.
  47. ^ Albrecht B, Staiger PK, Hall K, Miller P, Best D, Lubman DI (December 2014). "Benzodiazepine use and aggressive behaviour: a systematic review". Aust N Z J Psychiatry. 48 (12): 1096–114. doi:10.1177/0004867414548902. PMID 25183003.
  48. ^ a b Fleminger S, Greenwood RJ, Oliver DL (October 2006). "Pharmacological management for agitation and aggression in people with acquired brain injury". Cochrane Database Syst Rev (4): CD003299. doi:10.1002/14651858.CD003299.pub2. PMID 17054165.
  49. ^ Müller-Oerlinghausen B, Lewitzka U (2010). "Lithium reduces pathological aggression and suicidality: a mini-review". Neuropsychobiology. 62 (1): 43–49. doi:10.1159/000314309. PMID 20453534.
  50. ^ Mercer D, Douglass AB, Links PS (April 2009). "Meta-analyses of mood stabilizers, antidepressants and antipsychotics in the treatment of borderline personality disorder: effectiveness for depression and anger symptoms". J Pers Disord. 23 (2): 156–174. doi:10.1521/pedi.2009.23.2.156. PMID 19379093.
  51. ^ Salazar de Pablo G, Pastor Jordá C, Vaquerizo-Serrano J, Moreno C, Cabras A, Arango C, Hernández P, Veenstra-VanderWeele J, Simonoff E, Fusar-Poli P, Santosh P, Cortese S, Parellada M (February 2023). "Systematic Review and Meta-analysis: Efficacy of Pharmacological Interventions for Irritability and Emotional Dysregulation in Autism Spectrum Disorder and Predictors of Response". J Am Acad Child Adolesc Psychiatry. 62 (2): 151–168. doi:10.1016/j.jaac.2022.03.033. PMID 35470032.
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  53. ^ O'Malley KY, Hart CL, Casey S, Downey LA (October 2022). "Methamphetamine, amphetamine, and aggression in humans: A systematic review of drug administration studies". Neurosci Biobehav Rev. 141: 104805. doi:10.1016/j.neubiorev.2022.104805. PMID 35926727.
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