A Study on the Efficacy of Agomelatine Combined With Antipsychotics to Treat Negative Symptoms in Schizophrenia

Schizophrenia is a group of severe mental disorders of unknown etiology, with significant abnormalities in cognitive, thinking, emotional, behavioral and other aspects of mental activities, and can lead to significant occupational and social function damage. According to the relevant data of the World Health Organization, among 135 diseases or health conditions common to young people (aged 15-44), schizophrenia ranks eighth in the total disease burden, accounting for 2.6% of the total disease burden. Statistics from developed countries show that direct expenditure caused by schizophrenia accounts for 1.4% - 2.8% of total health resource expenditure. At present, there is no relevant medical economic data in China, but it is estimated that nearly 7 million people in China are suffering from schizophrenia, which causes huge medical expenditure every year, and also causes labor loss of patients and their families. Schizophrenia is still the main disease leading to mental disability at present [1].

The clinical manifestations of schizophrenia include five dimensions: positive symptoms, negative symptoms, cognitive symptoms, aggression and hostility, anxiety and depression. The existing antipsychotics (including typical and atypical antipsychotics) have a positive effect on positive symptoms, but have a poor effect on improving symptoms in other dimensions. From the perspective of prognosis, patients with non positive symptoms as the main clinical phase usually have poor prognosis. The existing evidence shows that one of the main reasons for suicide of schizophrenic patients is long-term depressive symptoms, and negative symptoms, depression and cognitive symptoms are important factors affecting the treatment outcome of patients. The treatment of negative symptoms is one of the core problems of schizophrenia at present, which still needs more exploration. At present, the treatment of negative symptoms with second-generation antipsychotics and antidepressants has been supported by some studies. However, due to the heterogeneity of antidepressants, a large number of research results are difficult to reach a unified conclusion with high evidence level. The current clinical experience believes that despite the lack of strong RCT research, the new antidepressants are well tolerated and have less side effects, which supports the use of new antidepressants in the treatment of depressive symptoms of schizophrenics.

The pathogenesis of schizophrenia is very complex. At present, the hypothesis of dopamine dysfunction plays a major role in the neurobiochemical abnormalities of schizophrenia. Carlsson et al put forward the hypothesis of dopamine neurodevelopmental defect, which believes that the core symptoms of schizophrenia are cognitive decline and negative symptoms, which is due to the lack of dopaminergic neurogenesis. In the initial state of the disease, the patients' brain has insufficient dopaminergic nerve function. When the load of the middle cerebral cortex pathway increases (puberty), it shows that the function of the dopaminergic nerve pathway is insufficient, activating the feedback regulation pathway of brain neurotransmitters, Compensatory release of dopamine leads to excessive activation of dopaminergic neural pathway in the midbrain limbic system, causing positive symptoms. With the further extension of the course of the disease and the development of the disease, this dopamine compensation mechanism is still insufficient to compensate for the dopaminergic neural function, which leads to long-term negative symptoms and cognitive dysfunction of patients.

Agomelatine is a new type of antidepressant. Its pharmacological effect is realized by activating melatonin receptor (MT1/MT2) and antagonizing 5-HT2C receptor. Agomelatine antagonizes the 5-HT2C receptor and can specifically increase the concentration of norepinephrine and dopamine in the prefrontal cortex, thereby producing antidepressant, anti anxiety and other effects. At the same time, the activation of melatonin receptor in the brain can resynchronize the circadian rhythm and biological rhythm of patients, and improve sleep rhythm disorder and sleep phase disorder caused by various reasons. At the same time, through the synergistic effect of melatonin receptor activation and 5-HT2C receptor antagonism, it can regulate the steady-state balance of neurotransmitters in the brain, especially between 5-HT and dopamine, and restore neural function. In addition, studies have shown that agomeratine has a certain role in the regeneration of hippocampal neurons and the remodeling of neural circuits [2]. An open and prospective study abroad included 27 schizophrenic patients with depressive symptoms who received a stable dose of antipsychotic drugs combined with agomeratine. The results showed that after 6 weeks of acute treatment, the depressive symptoms of the patients were significantly improved. At the same time, negative symptoms, overall psychopathology and psychosocial performance also improved significantly, while positive symptoms remained stable [3]. Subsequently, the research team further analyzed the data, which showed that after 12 weeks of treatment with agomeratine (6 weeks of acute phase+6 weeks of stable phase), the cognitive function of patients was improved (the changes in MCCB scores were statistically different). However, due to the lack of control in the experimental design, the limitation of sample number and other reasons, the research team believed that the improvement of cognitive function of patients lacked clinical significance, It is suggested to carry out research with reasonable design for further verification. In China, a single center, single blind, controlled study conducted by Jingzhou Mental Health Center in Hubei Province included 102 chronic schizophrenic patients with negative symptoms. They were randomly divided into the treatment group of argomepratin combined with risperidone (52 cases) and the treatment group of risperidone alone (50 cases). The results showed that argomepratin combined with risperidone could significantly improve the negative symptoms of patients after 6 months of treatment, Improve the quality of life of patients [4, 5].

The above clinical studies confirm that antipsychotic drugs combined with agomeratine are safe and feasible for the treatment of schizophrenia. The combined treatment has a positive effect in improving the negative symptoms and depressive symptoms of patients. Long term treatment may have the effect of improving the cognitive function of patients. However, the current clinical research sample size is small, the follow-up period is short, and the selected patients are biased, resulting in a low level of evidence. In addition, existing studies have not studied other events (such as all-cause readmission rate, suicide/self mutilation events, etc.) and the overall medical burden of patients during the treatment process, so it is difficult to form reliable evidence-based medical evidence to promote the development of clinical treatment plans for schizophrenia.

To sum up, it is proposed to carry out this prospective, multicenter, real world study of second-generation antipsychotic drugs combined with agomeratine for schizophrenia patients, aiming to further analyze the overall benefits of the combined agomeratine regimen for schizophrenia patients, and to study in detail the treatment responses of patients in the real world, and specifically analyze the effectiveness and safety of the regimen, Grasp the advantage target population and comprehensive disease burden of the program, accurately judge the application principle and medical social benefits of the program, and ultimately promote the development of clinical treatment program for schizophrenia.