O9.4. RELATIONSHIPS BETWEEN AGE AT ONSET OF PSYCHOTIC SYMPTOMS AND POOR RESPONSE TO ANTIPSYCHOTICS IN A SAMPLE OF TRS/NON-TRS PATIENTS
Authors: Iasevoli Felice , Razzino Eugenio , Altavilla Benedetta , Avagliano Camilla , Barone Annarita , Ciccarelli Mariateresa , D’Ambrosio Luigi , Matrone Marta , Milandri Federica , Notar Francesco Danilo , Pariano Riccardo , Vellucci Licia , de Bartolomeis Andrea 
Published: May 2020

Abstract

Background
Earlier age at schizophrenia onset has been associated with worse prognosis, greater symptom severity, social withdrawal, poorer cognitive performances, however much heterogeneity and inconsistency in findings have been reported in these studies.
Treatment Resistant Schizophrenia (TRS) is defined as the persistence of significant symptoms despite at least two adequate treatment trials, each for a minimum duration and dosage. Patients affected by TRS display worse cognitive functioning, social performances and a greater prevalence of Neurological Soft Signs compared to non-TRS.
To date, no studies have explored whether early onset TRS patients differ in multiple clinical, cognitive, and social outcomes compared to early onset non-TRS patients and to adult onset patients.
The objective of this study is to investigate the relationship of the condition of non-response to antipsychotic agents with age at onset of the first psychotic episode

Methods
We recruited 99 non-affective psychotic patients, that were referred to our academic outpatient unit for supposed resistance to antipsychotics. The diagnosis of TRS was made by a structured diagnostic flowchart, according to published guidelines. Patients underwent a wide set of clinical and cognitive evaluations by trained raters. According to the age of the first episode of psychosis, patients were subdivided in early onset (EO, &lt;20 years) and adult onset (AO, &gt;20 years). Clinical and demographic variables were compared by Student’s t and Chi square tests.
Then, patients were subdivided in EO-TRS, EO-nonTRS, AO-TRS, AO-nonTRS and their clinical outcomes were compared by ANCOVA, using age as a covariate. The 2way ANOVA was used to assess whether significant differences among groups were attributable to Diagnosis (TRS vs. non-TRS), Age at Onset (EO vs. AO), or combined effects.

Results
Compared to AO schizophrenia patients, EO had more relevant cognitive impairments (although limited to discrete domains), more severe neurological soft signs, more severe psychotic symptoms, mostly in the disorganized and autistic trait domains, and exhibited more severe social and functional impairments. The rate of TRS patients was significantly higher in the EO group and the rate of non-TRS was significantly higher in the AO group (X=6.31, df=1, p=0.012).
At the ANCOVA, EO-TRS patients had significantly longer duration of disease, more severe disease, and were under higher antipsychotic doses. Neurological soft signs were more relevant in the group of EO-TRS, while Visuospatial memory and verbal memory were more impaired in this group compared to the others. Also, this subgroup of patients exhibited the highest scores on PANSS total and subscales, and more impaired psychosocial functioning at the PSP, the UPSA, and the SLOF. Notably, in many cases, EO-TRS were more impaired than EO-nonTRS, while significant differences with AO-TRS were less consistent.
2way ANOVA demonstrated that in the majority of the investigated variables the significant differences among groups were attributable to a Diagnosis effect rather than to Age at Onset or combined effects.

Discussion
The study confirmed previous observations in patients subdivided into EO vs. AO ones. However, EO patients were more frequently TRS. The group of EO-TRS had the most severe and impaired outcomes. These results were mostly dependent on the condition of non-response to antipsychotic agents rather than to the earlier age at onset of psychotic symptoms. The neurobiology of TRS may cause both the most severe clinical course and the earlier age at onset of these patients. Heterogeneity in previous reports on EO schizophrenia may stem from fluctuating relative rates of TRS/non-TRS patients included in some studies compared to others.