Disease Severity in Treatment Resistant Schizophrenia Patients Is Mainly Affected by Negative Symptoms, Which Mediate the Effects of Cognitive Dysfunctions and Neurological Soft Signs

Abstract

This post-hoc study was aimed at assessing whether disease severity was higher in a sample of Treatment Resistant Schizophrenia patients (TRS) compared to schizophrenia patients responsive to antipsychotics (non-TRS). Determinants of disease severity were also investigated in these groups. Eligible patients were screened by standardized diagnostic algorithm to categorize them as TRS or non-TRS. All patients underwent the following assessments: CGI-S; PANSS; DAI; NES; a battery of cognitive tests. Socio-demographic and clinical variables were also recorded. TRS patients exhibited significantly higher disease severity and psychotic symptoms, either as PANSS total score or subscales' scores. A preliminary correlation analysis ruled out clinical and cognitive variables not associated with disease severity in the two groups. Hierarchical linear regression showed that negative symptoms were the clinical variable explaining the highest part of variation in disease severity in TRS, while in non-TRS patients PANSS-General Psychopathology was the variable explaining the highest variation. Mediation analysis showed that negative symptoms mediate the effects of verbal fluency dysfunctions and high-level neurological soft signs (NSS) on TRS' disease severity. These results show that determinants of disease severity sharply differ in TRS and non-TRS patients, and let hypothesize that TRS may stem from cognitive disfunctions and putatively neurodevelopmental aberrations.

Keywords: antipsychotics; clozapine; positive symptoms; psychosis; refractory; response.

Figure 1

Disease severity and psychotic symptoms. In this picture are reported TRS and non-TRS groups' mean scores + standard deviations on the (from left to right): Clinical Global Impression-Severity (CGI-S) scale; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive Symptoms' Subscale (PANSS-P); PANSS Negative Symptoms' Subscale (PANSS-N); PANSS General Psychopathology Subscale (PANSS-GP). Note the different scales on multiple graphics. *p < 0.05 at the Student's t-test. ^#Trend toward significance (p = 0.06).

Figure 2

Graphical rendering of mediation analysis. Panel (A) reports outputs of mediation analysis for the TRS group. Causal variable is on the left and outcome variable on the right. Significantly associated variables are linked by connection lines. Above connection lines are reported standardized beta values from linear regression analyses, along with p values (*p < 0.05; **p < .005). For PANSS Negative connection with CGI-S, we reported uncontrolled, Verbal Fluency controlled (a), and NES controlled (b) standardized betas. Verbal Fluency and NES score were significantly predictive of CGI-S (standardized B = −0.34, p = 0.03; standardized B = 0.438, p = 0.005, respectively), but significance was lost after controlling for PANSS Negative (standardized B = −0.06, p > 0.05; standardized B = 0.218, p > 0.05). For PANSS Positive connection with CGI-s, we reported uncontrolled and VSM controlled (c) standardized betas. VSM was significantly predictive of CGI-S (standardized B = −0.334, p = 0.03), however significance was lost after controlling for PANSS Positive (standardized B = −0.153, p > 0.05). Panel (B) reports outputs of mediation analysis for the non-TRS group. For PANSS General Psychopathology (GP) connection with CGI-S, we reported uncontrolled, PANSS Positive controlled (a), PANSS Negative controlled (b), and age controlled (c) standardized betas. PANSS Positive, PANSS Negative, age, and duration of illness were significantly predictive of CGI-S (standardized B = 0.500, p = 0.004; standardized B = 0.417, p = 0.02; standardized B = −0.382, p = 0.03; standardized B = −0.362, p = 0.04, respectively), but significance was lost after controlling for PANSS-GP (standardized B = 0.225, p > 0.05; standardized B = 0.258, p > 0.05; standardized B = −0.198, p > 0.05, respectively) or PANSS Positive in the case of duration of illness (standardized B = −0.196, p > 0.05).