Structural brain abnormalities and aggressive behaviour in schizophrenia: Mega-analysis of data from 2095 patients and 2861 healthy controls via the ENIGMA consortium
Authors: Lamsma Jelle , Raine Adrian , Kia Seyed M. , Cahn Wiepke , Arold Dominic , Banaj Nerisa , Barone Annarita , Brosch Katharina , Brouwer Rachel , Brunetti Arturo , Calhoun Vince D. , Chew Qian H. , Choi Sunah , Chung Young-Chul , Ciccarelli Mariateresa , Cobia Derin , Cocozza Sirio , Dannlowski Udo , Dazzan Paola , de Bartolomeis Andrea , Forti Marta Di , Dumais Alexandre , Edmond Jesse T. , Ehrlich Stefan , Evermann Ulrika , Flinkenflügel Kira , Georgiadis Foivos , Glahn David C. , Goltermann Janik , Green Melissa J. , Grotegerd Dominik , Guerrero-Pedraza Amalia , Ha Minji , Hong Elliot L. , Pol Hilleke Hulshoff , Iasevoli Felice , Kaiser Stefan , Kaleda Vasily , Karuk Andriana , Kim Minah , Kircher Tilo , Kirschner Matthias , Kochunov Peter , Kwon Jun Soo , Lebedeva Irina , Lencer Rebekka , Marques Tiago R. , Meinert Susanne , Murray Robin , Nenadić Igor , Nguyen Dana , Pearlson Godfrey , Piras Fabrizio , Pomarol-Clotet Edith , Pontillo Giuseppe , Potvin Stéphane , Preda Adrian , Quidé Yann , Rodrigue Amanda , Rootes-Murdy Kelly , Salvador Raymond , Skoch Antonin , Sim Kang , Spalletta Gianfranco , Spaniel Filip , Stein Frederike , Thomas-Odenthal Florian , Tikàsz Andràs , Tomecek David , Tomyshev Alexander , Tranfa Mario , Tsogt Uyanga , Turner Jessica A. , van Erp Theo G. M. , van Haren Neeltje E. M. , van Os Jim , Vecchio Daniela , Wang Lei , Wroblewski Adrian , Nickl-Jockschat Thomas 
Published: February 2024

Background

Schizophrenia is associated with an increased risk of aggressive behaviour, which may partly be explained by illness-related changes in brain structure. However, previous studies have been limited by group-level analyses, small and selective samples of inpatients and long time lags between exposure and outcome.

Methods

This cross-sectional study pooled data from 20 sites participating in the international ENIGMA-Schizophrenia Working Group. Sites acquired T1-weighted and diffusion-weighted magnetic resonance imaging scans in a total of 2095 patients with schizophrenia and 2861 healthy controls. Measures of grey matter volume and white matter microstructural integrity were extracted from the scans using harmonised protocols. For each measure, normative modelling was used to calculate how much patients deviated (inz-scores) from healthy controls at the individual level. Ordinal regression models were used to estimate the associations of these deviations with concurrent aggressive behaviour (as odds ratios [ORs] with 99% confidence intervals [CIs]). Mediation analyses were performed for positive symptoms (i.e., delusions, hallucinations and disorganised thinking), impulse control and illness insight. Aggression and potential mediators were assessed with the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms or Brief Psychiatric Rating Scale.

Results

Aggressive behaviour was significantly associated with reductions in total cortical volume (OR [99% CI] = 0.88 [0.78, 0.98],p= .003) and global white matter integrity (OR [99% CI] = 0.72 [0.59, 0.88],p= 3.50 × 10−5) and additional reductions in dorsolateral prefrontal cortex volume (OR [99% CI] = 0.85 [0.74, 0.97],p=.002), inferior parietal lobule volume (OR [99% CI] = 0.76 [0.66, 0.87],p= 2.20 × 10−7) and internal capsule integrity (OR [99% CI] = 0.76 [0.63, 0.92],p= 2.90 × 10−4). Except for inferior parietal lobule volume, these associations were largely mediated by increased severity of positive symptoms and reduced impulse control.

Conclusions

This study provides evidence that the co-occurrence of positive symptoms, poor impulse control and aggressive behaviour in schizophrenia has a neurobiological basis, which may inform the development of therapeutic interventions.