Peter Falkai
Zsófia Borbála Dombi- 1Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
- 2Global Medical Division, Gedeon Richter Plc., Budapest, Hungary
- 3Department of Psychiatry, University of Oxford, Oxford, United Kingdom
Editorial on the Research Topic
Community series in novel antipsychotics within and beyond clinical trials: symptom-based treatment of psychiatric disorders with D3-D2 partial agonists, volume II
Psychiatric disorders are a heterogenous group of conditions characterized by various symptoms and complex underlying pathological mechanisms (1). Aiming to simplify diagnostic and treatment strategies, current definitions of psychiatric disorders are rather categorical, thereby overlooking their inherent complexity (2). To give an example, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (3), schizophrenia is diagnosed based on the presence of two symptoms out of five, meaning that two patients with the same diagnosis can exhibit a completely different symptom profile (2). This leads to the question: how should we treat patients with the same diagnosis but different symptomatology? A solution for this puzzle is a symptom-based treatment which refers to the notion that psychiatrists make their treatment decisions primarily based on the actual symptoms the patient experiences rather than the diagnosis itself (4). This transdiagnostic approach helps to make treatment decisions that are more personalized and therefore might have an increased likelihood of being effective (4).
When it comes to the treatment of psychiatric disorders, the dopaminergic system becomes a key target, as its dysregulation has a major role in the pathophysiology of a wide range of symptoms that are present across various psychiatric disorders, like schizophrenia or bipolar disorder (5). Antipsychotics, a class of drugs that predominantly target dopamine receptors, are key medications utilized in the treatment of these conditions. While dopamine D2 receptors are associated with positive, psychotic, or manic symptoms (6, 7), D3 receptors are thought to be related to negative and depressive symptomatology (8, 9). Partial agonists, a new class of antipsychotic drugs, have the ability to target these receptors according to the actual needs of the patients—they are smart drugs that exhibit agonistic or antagonistic effects depending on the need and the dopamine concentration present (10, 11). The seven articles of the present Research Topic, therefore, aimed to explore how symptoms of psychiatric disorders can be addressed with dopamine D3-D2 partial agonists.
Acute schizophrenia patients are often hospitalized due to the intensity of their positive symptoms such as hallucinations, delusions, or paranoia (12). These patients can also exhibit hostile behavior which further increases the necessity of being hospitalized (13, 14). The primary treatment goal here is to decrease the psychotic symptomatology and hostility so that they can continue their treatment as outpatients and be integrated back into society (12). Usually, these patients need higher doses of antipsychotics (15) or combination treatment (16) to stabilize, which in the long run can be reduced or fine-tuned as needed. A study by Galmes and Rancans involving 14 patients with acute symptoms of schizophrenia and schizoaffective disorder examined the efficacy of high-dose cariprazine in this patient population. The approved dose range of cariprazine is between 1.5 and 6.0 mg/day; however, in the regulatory clinical trials, higher doses were also examined. Patients achieved significant improvement in positive, negative, and hostile symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) over a 2-week hospitalized period with 6.0, 7.5, or 9.0 mg cariprazine per day. Higher doses may be associated with a higher probability of adverse events; however, in this study, only one patient developed severe akathisia and therefore terminated the treatment.
Another core symptom of schizophrenia is the negative symptom domain which is composed of five constructs: anhedonia, avolition, alogia, asociality, and blunted affect (17). Negative-symptom patients can respond remarkably to medications targeting the D3 receptors (18), which has been showcased by three articles in the Research Topic authored by Pappa et al., Ivanova et al., and Vrublevska. Pappa et al. where a 6-month pilot study to evaluate the effectiveness of cariprazine in early psychosis patients (n = 10) with prominent or predominant negative symptoms was conducted. The seven patients who completed the study achieved significant improvement in their negative symptomatology; they had a 53% mean score reduction in the Positive and Negative Syndrome Scale (PANSS) negative subscale. Similarly, Ivanova et al. found cariprazine to be an effective and well-tolerated medication in two patients with early-onset schizophrenia who had predominant negative symptoms. Following these patients for 18 months, the authors reported a 29.8% improvement on the PANSS negative subscale. Finally, Vrublevska published a case report describing a young but severely ill patient who had recurrent relapses of schizophrenia with persistent negative symptoms. Several trials of different antipsychotic combinations were tried without sufficient response and with extrapyramidal side effects. After initiating combination treatment with cariprazine and olanzapine, all symptoms as well as the overall functioning improved. A similar case was described by Schölin et al., whereby a schizophrenia patient with a pronounced functional deficit was successfully treated with cariprazine. The patient had experienced a wide range of symptoms with increasing severity as well as a history of drug abuse. After no success in treating his negative symptoms with first olanzapine and then risperidone, a switch to cariprazine was decided, leading to marked functional improvement and no psychotic symptoms after 6 months of discharge. Although the described patient was not treatment-resistant, this case highlights the difficulty in finding the right treatment strategy for patients with residual schizophrenia symptoms.
Addressing the Research Topic of non-responsivity, Vasiliu (a) reviewed the available evidence regarding the efficacy of third-generation antipsychotics in combination with clozapine in patients with treatment-resistant schizophrenia. Combinations with aripiprazole and cariprazine are most supported and can positively impact not only the positive, negative, and general symptoms but the metabolic profile too. Last, but not least, Vasiliu (b) also submitted a scoping review focusing on the pharmacogenetics of new-generation antipsychotics. The author highlighted why exploring the relationship between clinical efficacy and gene variations is an important aspect of personalized medicine and detailed the available evidence regarding aripiprazole, brexpiprazole, cariprazine, lumateperone, and pimavanserin. One of the main take-away messages of the review is that determining the CYP2D6 metabolizer status can aid the better administration of aripiprazole and brexpiprazole and the CYP3A4 status is relevant for cariprazine, lumateperone, and pimavanserin.
Overall, the present Research Topic underlines how novel antipsychotics offer the opportunity for a more personalized, patient-centered treatment.
Author contributions
PF: Conceptualization, Supervision, Writing—review and editing. ZBD: Data curation, Writing—original draft.
Conflict of interest
ZBD is an employee of Gedeon Richter Plc.
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Moustafa AA, Phillips J, Kéri S, Misiak B, Frydecka D. On the complexity of brain disorders: a symptom-based approach. Front Comput Neurosci. (2016) 10:16. doi: 10.3389/fncom.2016.00016
2. Liu Q, Woo M, Zou X, Champaneria A, Lau C, Mubbashar MI, et al. Symptom-based patient stratification in mental illness using clinical notes. J Biomed Inform. (2019) 98:103274. doi: 10.1016/j.jbi.2019.103274
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DMS-5. 5th ed. American Psychiatric Association (2013).
4. Waszczuk MA, Zimmerman M, Ruggero C, Li K, MacNamara A, Weinberg A, et al. What do clinicians treat: diagnoses or symptoms? The incremental validity of a symptom-based, dimensional characterization of emotional disorders in predicting medication prescription patterns. Compr Psychiatry. (2017) 79:80–8. doi: 10.1016/j.comppsych.2017.04.004
5. Klein MO, Battagello DS, Cardoso AR, Hauser DN, Bittencourt JC, Correa RG. Dopamine: functions, signaling, and association with neurological diseases. Cell Mol Neurobiol. (2019) 39:31–59. doi: 10.1007/s10571-018-0632-3
6. Gomes FV, Grace AA. Beyond dopamine receptor antagonism: new targets for schizophrenia treatment and prevention. Int J Mol Sci. (2021) 22:4467. doi: 10.3390/ijms22094467
7. Lopachev A, Volnova A, Evdokimenko A, Abaimov D, Timoshina Y, Kazanskaya R, et al. Intracerebroventricular injection of ouabain causes mania-like behavior in mice through D2 receptor activation. Sci Rep. (2019) 9:15627. doi: 10.1038/s41598-019-52058-z
8. Calabrese F, Tarazi FI, Racagni G, Riva MA. The role of dopamine D 3 receptors in the mechanism of action of cariprazine. CNS Spectr. (2020) 25:343–51. doi: 10.1017/S109285291900083X
9. Leggio GM, Salomone S, Bucolo C, Platania C, Micale V, Caraci F, et al. Dopamine D3 receptor as a new pharmacological target for the treatment of depression. Eur J Pharmacol. (2013) 719:25–33. doi: 10.1016/j.ejphar.2013.07.022
10. Lambert DG. Drugs and receptors. Contin Educ Anaesth Crit Care Pain. (2004) 4:181–4. doi: 10.1093/bjaceaccp/mkh049
11. Lieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. (2004) 18:251–67. doi: 10.2165/00023210-200418040-00005
12. Keks N, Blashki G. The acutely psychotic patient: assessment and initial management. Aust Fam Physician. (2006) 35:90–4.
13. Pompili M, Fiorillo A. Aggression and impulsivity in schizophrenia. Psychiatric Times. (2015) 32:1–12.
14. Serper MR, Goldberg BR, Herman KG, Richarme D, Chou J, Dill CA, et al. Predictors of aggression on the psychiatric inpatient service. Compr Psychiatry. (2005) 46:121–7. doi: 10.1016/j.comppsych.2004.07.031
15. Takeuchi H, Mackenzie NE, Samaroo D, Agid O, Remington G, Leucht S. Antipsychotic dose in acute schizophrenia: a meta-analysis. Schizophr Bull. (2020) 46:1439–58. doi: 10.1093/schbul/sbaa063
16. Hjorth S. The more, the merrier…? Antipsychotic polypharmacy treatment strategies in schizophrenia from a pharmacology perspective. Front Psychiatry. (2021) 12:760181. doi: 10.3389/fpsyt.2021.760181
17. Correll CU, Schooler NR. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat. (2020) 16:519–34. doi: 10.2147/NDT.S225643
18. Németh G, Laszlovszky I, Czobor P, Szalai E, Szatmári B, Harsányi J, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. (2017) 389:1103–13. doi: 10.1016/S0140-6736(17)30060-0
Keywords: partial agonists, dopamine, symptom-based treatment, real-world evidence, antipsychotic
Citation: Falkai P and Dombi ZB (2023) Editorial: Community series in novel antipsychotics within and beyond clinical trials: symptom-based treatment of psychiatric disorders with D3-D2 partial agonists, volume II. Front. Psychiatry 14:1266566. doi: 10.3389/fpsyt.2023.1266566
Received: 25 July 2023; Accepted: 07 August 2023;
Published: 21 August 2023.
Edited and reviewed by: Chao Deng, University of Wollongong, Australia
Copyright © 2023 Falkai and Dombi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Peter Falkai, peter.falkai@med.uni-muenchen.de; Zsófia Borbála Dombi, dombizsb@richter.hu