Schizophrenia is a chronic psychiatric disorder affecting major thought processes such as perception, thinking and behavior. It is characterized by three major symptom domains: positive, negative and cognitive. Given these symptoms, schizophrenia has a major impact on the functioning and quality of life of patients, as they cause disruptions to work and school performance as well as to social relationships.

Studies estimate that about 30% of patients will develop treatment-resistant schizophrenia (TRS). The development of the concept of TRS was associated with the introduction of the second-generation antipsychotic drugs in dichotomic terms of response or no response to previous drug (1). The advancement of psychiatry science, using of integrated biopsychosocial approach and a multi-level assessment of treatment response lead to formulate concepts such as remission, much closer to the idea of recovery and functional recovery, based on patients' social functioning level (2). Up to now, TRS is defined as the presence of persisting symptoms despite two or more antipsychotic trials with adequate dose and treatment duration as well as documented medication-adherence (3). One of the defining features of TRS is the persistence of positive symptoms (4), yet cognitive or negative symptoms may also persist (5). Patients with TRS tend to have more severe symptoms, worse cognitive functioning and therefore higher costs to the healthcare providers (6). In addition, it further increases the burden on families and caregivers as they need to spend significant amount of their time and income on patient-care activates, having a negative impact on family life (6–8). It is important to note that TRS affects not only the patient and their family, but also the medical team responsible for their care. Healthcare professionals may develop negative attitudes such as pessimism, therapeutic nihilism, and lack of intellectual curiosity toward these patients (6). These patients come to be perceived and labeled as ‘difficult' (6, 9).

In order to provide clinical guidance on the identification and management of TRS, a research group was launched who developed and published a guideline (6). According to their view, re-evaluation of treatment plan is needed in case of non-response to two different antipsychotic medications including clozapine, consideration of adjunctive treatment with non-pharmacologic therapies and sharing of decision-making process among the treatment team, patient, and family, in order to choose the most adequate treatment plan. Finally, the authors suggest monitoring for potential markers of TRS such as high dose of antipsychotics, frequent hospitalisations, and ineffective polypharmacy.

Obsessive-compulsive symptoms in schizophrenia are clinically significant, may manifest in the prodromal or acute phase of the disorder, and have a prevalence rate of 12 to 20% (10, 11). Clinical studies report that obsessive-compulsive symptoms (OCS) not only increase the severity of symptoms and worsens the prognosis of schizophrenia but also causes the patient to respond poorly to conventional antipsychotic treatment, and generally have worse outcomes in social functioning (10–12).

Aggression is a significant concern in individuals with schizophrenia, and it can manifest in various forms, including auto-aggression as a compulsive symptom. According to recent meta-analysis data, the pooled prevalence of aggression is reported as 33.3% (13). Additionally, the estimated prevalence rates for verbal aggression, property-oriented aggression, auto-aggression, and physical aggression are 42.6, 23.8, 23.5, and 23.7%, respectively. In another cross-sectional study, several associated factors for aggressive behavior among patients with schizophrenia were identified, including male gender, unemployment, previous history of aggression, psychotic symptoms, drug nonadherence, poor social support, and alcohol use (14).

Scientists have discussed if this condition is a pure comorbidity or a subtype of schizophrenia. The term schizo-obsessive disorder refers to a clinical spectrum of disorders with characteristics of schizophrenia and obsessive compulsive disorder (OCD) (11, 12). Some studies have pointed out that schizo-obsessive disorder can be considered a subtype of schizophrenia and not a distinct clinical entity (11). Nevertheless, the OCD with psychotic features and absent insight is distinguished in the diagnostic and statistical manual of mental disorders fifth edition (DSM-5) (15). Similarly, the international classification of diseases 11th version (ICD-11) has specified insight levels for OCD as good to fair insight or poor to absent insight (16). Another aspect of relationships is iatrogenic OCS secondary to atypical antipsychotics, particularly clozapine, which appear to have a role in inducing or exacerbating OCS (11, 12, 17). Currently, there is no consensus on the management of OCS in TRS patients, but this does not mean that the condition cannot be improved, rather that these improvements may take time and experimentation.

Cariprazine is a third-generation antipsychotic with dopamine D₂-D₃ partial agonist with preferential binding to the D₃ receptors (18). The exceptional receptor profile and tolerability is a potential beneficial value of this drug. Cariprazine is effective in the treatment of schizophrenia and may be particularly beneficial for the negative symptoms of this disorder. It is approved for the treatment for schizophrenia by the European Medicines Agency (19) and additionally for the treatment of depressive and manic/mixed episodes associated with bipolar I disorder by the Food and Drug Administration (20). It further showed efficacy in the adjunctive treatment of major depressive disorder (21). In schizophrenia, cariprazine showed statistically significant superiority in the treatment of acute patients (22–24) and in long-term relapse prevention (25) over placebo. Furthermore, it statistically significantly outperformed risperidone in the treatment of patients with persistent, predominant negative symptoms (26).

The present case report describes a TRS patient with auto-aggressive compulsive behavior that was managed successfully with switching to cariprazine.

The disorder manifested in adolescence and retrospectively, a prodromal phase of schizophrenia can be detected with neurosis-like symptoms such as tension, anxiety, decreased energy and agoraphobia. The acute phase start at the age of 23, characterized by auditory hallucinations, thoughts echo, delusion of passivity, obsessive thoughts, tension and aggressive compulsive behavior. Throughout the course of the disorder, the patient developed passive social withdrawal, motor retardation, poor attention, disturbance of volition, poor impulse control and active social avoidance. The patient had 14 readmission to mental hospitals, often because he were discharged before he had adequately recovered, that describe the revolving door phenomenon (31). This highlights the importance of providing comprehensive and effective treatment and support to individuals with mental illness to prevent the revolving door phenomenon from occurring.

Despite receiving continuous pharmacological treatment in the form of both first- and second-generation antipsychotics in various combinations, it exemplifies a “difficult to treat” condition. The treatment response was only partial, and complete remission was not achieved. The case meets the criteria for treatment-resistant schizophrenia (TRS) as per the consensus guidelines of the Treatment Response and Resistance in Psychosis Working Group, given the reasons outlined above (5). The patient had active and persistent symptoms for over 12 weeks with impaired functioning and at least 6 weeks of treatment with an appropriate usage of two antipsychotics from different drug profiles at doses equivalent to over 600 mg chlorpromazine per day, and he was also compliant.

Throughout the course of schizophrenia, different approaches of pharmacological treatment were tried without sufficient improvement. Clozapine is wellknown and defined as the first-line medication for the management of TRS with evidence from several studies (32). For instance, the patient did not response to clozapine 400 mg/day and the up-titration was impossible due to side effects such as sedation, hypersalivation and weight gain. In terms of cariprazine, there is some evidence supporting its effectiveness in TRS patients, however it is only based on case reports (33–35). While both cariprazine and clozapine have affinity for dopamine D2 and D3 receptors, their receptor profiles differ in terms of partial agonism vs. antagonism. Clozapine primarily acts as an antagonist at multiple receptors, including dopamine D1, D2, D3, and D4 receptors, serotonin 5-HT2A, 5-HT2C, 5-HT3 receptors, and histamine H1 receptors (32). Cariprazine, on the other hand, acts as a partial agonist at dopamine D2 and D3 receptors and as an antagonist at serotonin 5-HT2A receptors (18). While clozapine exhibits broader antagonistic effects on serotonin receptors, both medications antagonize 5-HT2A receptors. Similarities in receptor profiles can potentially be associated with comparable treatment efficacy. Another possible explanation for the effectiveness of cariprazine in this case could be attributed to a comparison of dose equivalents between cariprazine 6 mg and clozapine 400 mg, where the dose equivalent for cariprazine is ~1.5 times higher (36).

Unfortunately, the use of clozapine in schizophrenia patients with obsessive-compulsive behavior could lead to the worsening of OCS (11, 12, 17). Indeed, in the present case, such symptoms of the patient did not change significantly during clozapine treatment according to the medical records as monitored by standardized rating scales.

Several studies have provided evidence of aripiprazole efficacy in improving symptoms and achieving remission in patients with TRS (37, 38). Additionally, several case reports demonstrated effective use of aripiprasole in OCD (37). Aripiprazole and cariprazine share similarities in their receptor profiles, particularly in their partial agonist activity at dopamine D2 and D3 receptors. This partial agonism may contribute to their ability to stabilize dopamine activity in the brain. Additionally, both aripiprazole and cariprazine display antagonistic effects on serotonin 5-HT2A receptors, which may further contribute to their overall pharmacological effects.

Although a recent study summarizing evidence from clinical trials and real-world studies recommend cross-titration in case of switching from another antipsychotic to cariprazine (39), in this case the authors decided to switch from amisulpride 400 mg/day to cariprazine 6 mg/day without cross-titration due to the severity of symptoms. This abrupt switching strategy was well tolerated by the patient.

Based on the results, the present case demonstrates the efficacy of cariprazine in the treatment of psychotic, negative symptoms and self-aggressive compulsive behavior in a TRS patient. After 6 months of therapy, 50% of the PANSS reduction. The GAF improvement was detected and indicates adequate day-to-day functioning, which was unimaginable previously. Reviewing the literature, this is also supported by other studies focusing on the efficacy of cariprazine in hostility (40, 41). For instance, a recent post-hoc analysis looked at the pooled data from three randomized, placebo-controlled, phase 2/3 studies with patients who had acute exacerbation of schizophrenia and found that with cariprazine there was a significant improvement in hostility compared to patients treated with placebo as measured by the PANSS-derived Marder hostility subscale (40).

Another important aspect in this case is the prevention of further polypharmacy—the combination of more than one antipsychotics and/or antidepressants—with cariprazine. After the fifth month of cariprazine treatment, the patient stopped any other medication and received only cariprazine as monotherapy.

Since the patient received the highest recommended dose, 6 mg/day, a side-effect in the form of hand tremor was induced which was then compensated with anticholinergic medication. Otherwise, the medication was welltolerated. Another safety aspect in this case was metabolic symptoms. It is a wellknown fact that TRS patients belong to a high-risk group of developing metabolic syndrome due to the widespread use of polypharmacy treatment with second-generation antipsychotics as well as due to general lifestyle (40). Given the fact that cariprazine is metabolically neutral, the patient lost 15 kg body weight and his BMI became close from class obese to only class overweight. Moreover, clozapine and mirtazapine, medications that have high metabolic risk, were discontinued and with the reduction of negative symptoms, the patient changed his lifestyle and became more active. It is important to note that the patient did not change his eating regime or the amount of food intake.

Finally, given the fact that the switch to cariprazine prevented further hospitalization of the patient, this case reduced the healthcare costs of the provider as well.

All in all, this is an example of continuous treatment efforts and maintenance of therapeutic optimism that finally resulted in symptom improvement. Nonetheless, it is crucial to continue to follow up the patient in the future in order to understand further changes in symptoms, control tolerability and social functioning. More evidence is needed regarding the long-term effectiveness of cariprazine in TRS schizophrenia with auto-aggressive compulsive behavior.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the patient to publish this case.

LR and ER contributed to the design and conception of the manuscript and data analysis and revision of subsequent versions. LR wrote the first draft of the manuscript. Both authors contributed to the article and approved the submitted version.