Aiming to address the broad-spectrum treatment of schizophrenia using the clinical staging framework, the satellite symposium supported by Gedeon Richter and Recordati at the 29^th annual meeting of the European Psychiatric Association included three presentations about the therapeutic needs and considerations of the early, middle and late stages of the disorder. 
 
Professor Agata Szulc, Head of the Department of Psychiatry at the Medical University of Warsaw, chaired the session which also discussed the role of cariprazine, a partial D3/D2 receptor agonist¹ in the different stages of schizophrenia. 
 
The symposium began with the lecture of Professor Stephen Stahl, Adjunct Professor of Psychiatry at University of California, who addressed the early treatment of schizophrenia from a pure pharmacological point of view by explaining the mechanism of action of dopamine partial agonists and how they can alleviate the different symptoms that first episode patients experience. 

Before diving into the therapeutic mechanism of partial agonists at the dopamine D₃ and D₂ receptors for the treatment of the different symptoms of schizophrenia, Professor Stahl started his lecture by providing an overview of the agonist spectrum. Using a rainbow as a metaphor, he showed where agonists, partial agonists, antagonists and inverse agonists lie, as well as how they act at the receptors.² In a nutshell, he stated, agonists are like the naturally occurring neurotransmitters; when released they bind to the receptor and initiate a downstream signaling cascade that leads to a cellular response.² In contrast, antagonists are compounds that bind to the receptor to inhibit a response.² Then, there are the partial agonists that are an in-between, not full agonists neither full antagonists – sometimes initiating, sometimes inhibiting a response depending on the occupancy at the receptor.² Importantly however, receptors also have a so-called constitutive activity, which means that they are a little bit “on” even if there is no compound near.² Drugs that are able to inhibit this constitutive activity are called the inverse agonists.² At last, Professor Stahl showed where aripiprazole, brexpiprazole and cariprazine, three antipsychotic medications with partial agonism lie on the spectrum and on what receptors they act on.²
 
Moving on to the first episode of schizophrenia, Professor Stahl explained that psychosis is defined by the dysregulation of the dopaminergic system in the brain, where positive symptoms are caused by increased levels, and negative symptoms by decreased levels of dopamine.² In the pharmacological treatment of these symptoms, D₂ blockage in the nucleus accumbens is thought to alleviate positive symptoms² and D₃ blockage in the ventral tegmental area, resulting in an increase in dopamine release in the prefrontal cortex, is believed to treat negative symptoms³. Importantly, currently only one agent, cariprazine, has as higher affinity for D₃ receptors then dopamine, emphasised Professor Stahl.⁴
 
Indeed, when looking at the pooled data of cariprazine short term trials focusing on patients with schizophrenia for less than five years, the advantage of cariprazine over placebo in both the total score of the Positive and Negative Syndrome Scale (PANSS) and in the Marder positive and negative factor scores were crystal clear.^5,6,7
 
At last, Professor Stahl explained how the various side effects are related to the different receptor activities and that D₂ blockage is generally associated with motor problems such as extrapyramidal symptoms.⁴ He also showed that cariprazine is associated with a low risk of weight gain⁸ and sedation.⁹ 
 
The key take-away messages of the lecture were that in schizophrenia, positive symptoms are related to the hyperactivity of the dopaminergic system in the striatum and negative symptoms to the hypoactivity in the prefrontal cortex.² By blocking D₂ receptors, one can address the positive symptomatology, nonetheless it will be accompanied by several motor side effects², while the treatment of negative symptoms is associated with the modification of the D₃ receptors.³ In conclusion, Professor Stahl suggested that partial agonists, such as cariprazine can be a good choice for treating first episode patients as it acts on both D₃ and D₂ receptors with low side effect burden thus enhancing compliance and relapse prevention.

During the second lecture of the symposium Professor Stefan Leucht, Head of the Section Evidence Based Medicine in Psychiatry and Psychotherapy at the Technical University of Munich discussed the role of cariprazine in relapse, remission, and recovery – the so-called three Rs. 
 
Starting with relapse, professor Leucht emphasised the importance of relapse prevention as it is associated with several adverse long-term outcomes such as greater use of healthcare resources⁹, progressive decline in brain function¹⁰ and decrease in treatment response.¹¹ Indeed, a cohort study with 130 patients showed that the incidence of 50% response rate at a second episode was much lower than in the first one.¹² The best way to prevent relapse is staying on medication, which was supported by a meta-analysis indicating that the incidence of relapse at 7-12 months was 24% in patients on antipsychotic medication, whereas this number was 61% in patients on placebo.¹³ This was also confirmed by a maintenance of effect study with cariprazine¹⁴, where time to relapse was significantly longer in the cariprazine group than in the placebo group, with total relapse occurring in 21.6% of cariprazine- and 49% of placebo-treated patients.¹ Importantly, patients on cariprazine relapsed in an average of 6-7 weeks after stopping treatment, whereas this was only 1-4 weeks for other antipsychotic medications, indicating that cariprazine protects the patients for a longer period from relapse.¹⁵
 
In the second part of the lecture, Prof. Leucht discussed the concept of remission, which he defined as a state where patients are free of symptoms.¹⁶ He also emphasised that this is different from response, which is more about the improvement of symptoms, and not necessarily the total absence.¹⁶ It is also important to note, he mentioned, that in schizophrenia there are many different cut-offs for defining response (some may consider a 20% reduction in PANSS already a response while others only 50%), which is in contrast to major depressive disorder, where there is a clear criteria for both terms.¹⁷ He then compared at least 20% (minimally better) to at least 50% (much better) reduction in the PANSS means, by using the Clinical Global Improvement (CGI) scale.¹⁷ Before moving to the last R, recovery, he introduced the work of Andreasen et al., who provided a remission criterion based on the symptoms of schizophrenia (DSM-IV) and the PANSS items.¹⁸ According to this criterion, someone is in remission if all eight of their symptoms are mild and for at least 6 months¹⁸, and it has been shown that over 50% of acute patients can actually reach this state after 12 months¹⁹. Prof. Leucht also showed post-hoc analyses from the long-term cariprazine relapse prevention study and stated that cariprazine use was associated with significantly longer sustained remission, higher remission rates, and increased likelihood of sustaining remission for more than 6 consecutive months versus placebo.²⁰
 
In terms of the last R, recovery, Prof. Leucht said that it is an important and a long-term goal as it not only involves remission of symptoms, but also a functional and/or social remission i.e. having a job, being independent etc.¹⁶ Nonetheless, he also noted that there are many courses of schizophrenia – not everyone will develop chronic symptoms and thus there is hope for patients that they can eventually live a meaningful life.^21,22 When looking at the numbers, with very strict recovery criteria (no relapse for at least 2 consecutive years), a meta-analysis found that 13.5% of patients can achieve recovery.²³ Prof. Leucht also added that measuring recovery in clinical trials is not that simple (given that it is a long-term goal), although measuring social functioning or quality of life can shed a light on the drug’s ability to promote recovery.²⁴ Lastly, Prof. Leucht showed that cariprazine treatment of acutely-ill patients is associated with a robust increase in functionality during the stabilisation phase, suggesting that cariprazine can be a good overall option for preventing relapse and promoting remission, and eventually recovery.^14,25

In the final lecture of the symposium, Prof. Peter Falkai, Professor and Chairman at the Ludwig-Maximilians-University Munich looked at how to address the needs of patients in the later stages of schizophrenia. He started his lecture where Prof. Leucht left off – recovery, emphasising that in many patients there is so-called impaired recovery due to residual symptoms such as cognitive dysfunction or negative symptoms²⁶, which should be adequately addressed. 
 
He then presented the cariprazine negative symptom study, where cariprazine was compared to risperidone in a double-blind trial and showed superiority over risperidone from week 14 onwards in alleviating negative symptoms.²⁷ Importantly, cariprazine was not only better in the treatment of negative symptoms, but in improving functioning too, as shown by the results of the Personal and Social Performance (PSP) scale.²⁷
 
Prof. Falkai also stressed that each and every relapse is associated with a deterioration in the course of the illness and increases the chance of not only slower recovery, but also increased frequency of residual symptoms.^14,28 He also presented data from the maintenance of effect cariprazine study to illustrate cariprazine’s ability to prevent relapse and improve remission.¹⁴
 
Finally, Prof. Falkai showed data on the clinical efficacy of cariprazine in treating cognitive symptoms based on the post-hoc analyses of PANSS scores in different trials.^29,30 He emphasised that although there were no studies with cariprazine specifically evaluating cognition, the results of these analyses are quite promising, suggesting that with cariprazine there is a significantly greater improvement in cognition compared to placebo or risperidone.^29,30 
 
At the end of the lecture, Prof. Falkai showed the clinical staging model framework developed by McGorry and colleagues and described the interventions for the last stage³¹. He stressed that the aim of schizophrenia treatment today is recovery, which implies not only the treatment of psychotic symptoms, but also other features such as negative symptoms and cognitive dysfunction, as well as improving resilience and reducing internalised stigma. By tailoring the treatment to the patients’ needs and the stage of the disorder, we have a chance to achieve that, he concluded. 
 
COD 300021/R48. Submitted to AIFA on 20/07/2021