title: Effects of aripiprazole and haloperidol on neural activation during the n-back in healthy individuals: A functional MRI study.
abstract: Antipsychotic drugs target neurotransmitter systems that play key roles in working memory. Therefore, they may be expected to modulate this cognitive function via their actions at receptors for these neurotransmitters. However, the precise effects of antipsychotic drugs on working memory function remain unclear. Most studies have been carried out in clinical populations, making it difficult to disentangle pharmacological effects from pathology-related brain activation. In this study, we aim to investigate the effects of two antipsychotic compounds on brain activation during working memory in healthy individuals. This would allow elucidation of the effects of current antipsychotic treatments on brain function, independently of either previous antipsychotic use or disease-related pathology.
  
  
  
  We carried out a fully counterbalanced, randomised within-subject, double-blinded and placebo-controlled, cross-over study of the effects of two antipsychotic drugs on working memory function in 17 healthy individuals, using the n-back task. Participants completed the functional MRI task on three separate occasions (in randomised order): following placebo, haloperidol, and aripiprazole. For each condition, working memory ability was investigated, and maps of neural activation were entered into a random effects general linear regression model to investigate main working memory function and linear load. Voxel-wise and region of interest analyses were conducted to attain regions of altered brain activation for each intervention.
  
  
  
  Aripiprazole did not lead to any changes in neural activation compared with placebo. However, reaction time to a correct response was significantly increased following aripiprazole compared to both placebo (p=0.046) and haloperidol (p=0.02). In contrast, compared to placebo, haloperidol dampened activation in parietal (BA 7/40; left: FWE-corr. p=0.005; FWE-corr. right: p=0.007) and frontal (including prefrontal; BA 9/44/46; left: FWE-corr. p=0.009; right: FWE-corr. p=0.014) cortices and the left putamen (FWE-corr. p=0.004). Compared with aripiprazole, haloperidol dampened activation in parietal cortex (BA7/40; left: FWE-corr. p=0.034; right: FWE-corr. p=0.045) and the left putamen (FWE-corr.p=0.015). Haloperidol had no effect on working memory performance compared with placebo.
  
  
  
  Cognitive functions are known to be impaired in schizophrenia and as such are an important target of treatments. Elucidating the mechanisms by which antipsychotic medications alter brain activation underlying cognition is essential to advance pharmacological treatment of this disorder. Studies in healthy individuals can help elucidate some of these mechanisms, whilst limiting the confounding effect of the underlying disease-related pathology. Our study provides evidence for immediate and differential effects of single-dose haloperidol and aripiprazole on brain activation during working memory in healthy individuals. We propose that these differences likely reflect their different receptor affinity profiles, although the precise mechanisms underlying these differences remain unclear.
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK. Electronic address: rhianna.goozee@kcl.ac.uk.
authors.forename: Rhianna
authors.initials: R
authors.lastname: Goozee
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK.
authors.forename: Antje A T S
authors.initials: AATS
authors.lastname: Reinders
authors.affiliation: Bristol-Myers Squibb, UK.
authors.forename: Rowena
authors.initials: R
authors.lastname: Handley
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK.
authors.forename: Tiago
authors.initials: T
authors.lastname: Marques
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Taylor
authors.affiliation: Centre for Neuroimaging Sciences (CNS), King's College London, UK.
authors.forename: Owen
authors.initials: O
authors.lastname: O'Daly
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK.
authors.forename: Grant
authors.initials: G
authors.lastname: McQueen
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hubbard
authors.affiliation: Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK; NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust, King's College London, London, UK.
authors.forename: Valeria
authors.initials: V
authors.lastname: Mondelli
authors.affiliation: Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK; NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust, King's College London, London, UK.
authors.forename: Carmine
authors.initials: C
authors.lastname: Pariante
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK; NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust, King's College London, London, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Dazzan
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology; D001931:Brain Mapping; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole; D006220:Haloperidol; D010100:Oxygen
keywords: Antipsychotic; Functional neuroimaging; Schizophrenia; Working memory; n-back