Grant McQueen

Pre-morbid Conduct Disorder symptoms are associated with cannabis use among individuals with a first episode of psychosis

BACKGROUND Early cannabis use has consistently been associated with an increased risk for the later development of psychosis. Studies suggest that Conduct Disorder (CD) is more common amongst young people who later go on to develop psychosis. CD has been associated with greater and earlier cannabis use in general population samples. Based on this evidence, we hypothesised that among patients experiencing their first episode of psychosis, the presence of CD symptoms prior to age 15 would be associated with cannabis use. METHOD 102 patients experiencing a first episode of psychosis were interviewed to assess CD symptoms prior to age 15 and use of cannabis and other substances. RESULTS The number of CD symptoms was significantly associated with lifetime cannabis use (odds ratio=5.41 (1.76-16.57), p=0.03) and with first use of cannabis before age 14 (odds ratio=1.46 (1.12-1.92), p=0.006), after controlling for stimulant/hallucinogen use and level of education. CONCLUSIONS Among patients experiencing a first episode of psychosis, CD symptoms were significantly associated with use of cannabis and with use by age 14. Among individuals vulnerable for psychosis, CD symptoms may independently increase the likelihood of cannabis use which in turn increases the risk of psychosis.

Effects of antipsychotics on cortisol, interleukin-6 and hippocampal perfusion in healthy volunteers

This randomized within-subject, double blind study aimed to compare the effects of a single dose of two different antipsychotics (haloperidol and aripiprazole) on cortisol, interleukin (IL)-6 and hippocampal regional Cerebral Blood Flow (rCBF) in the same 17 healthy male individuals. Subjects received a single dose of haloperidol (3mg), aripiprazole (10mg) and placebo, in a randomized order on three study appointments. We measured salivary cortisol levels at multiple time points, IL-6 levels from plasma samples, and resting cerebral blood flow (rCBF), using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T). We found significantly lower cortisol levels in the haloperidol condition (F(2,32)=5.78, p=0.007), than in either placebo (p=0.013; CI=0.45, 0.406) or aripiprazole (p=0.037; CI=-0.520, -0.014). Interleukin-6 levels were also lower following haloperidol (F(2,22)=4.19, p=0.048) in comparison with placebo (p=0.02; CI=0.14, 1.8), but not with aripiprazole. Finally, we found a greater rCBF in the right (peak voxel: T=6.47, p<0.0001) and left (peak voxel T=5.17, p<0.01) hippocampus following haloperidol compared with placebo, and at trend level also in the left hippocampus following aripiprazole compared with placebo (T=4.07, p=0.057). These differences in hippocampal rCBF after both antipsychotics were no longer evident (haloperidol) or present at trend level (aripiprazole), after controlling for cortisol and IL-6 levels. Our findings suggest that haloperidol can directly regulate the hypothalamic-pituitary-adrenal (HPA) axis and immune system through a pharmacological action via D2 receptor antagonism. Finally, our data suggest that the increased hippocampal rCBF is a manifestation of the reduction in IL-6 and cortisol which follows the administration of haloperidol.

Effects of aripiprazole and haloperidol on neural activation during the n-back in healthy individuals: A functional MRI study

OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSION 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.

Effects of Antipsychotic Administration on Brain Glutamate in Schizophrenia: A Systematic Review of Longitudinal 1H-MRS Studies

Schizophrenia is associated with brain glutamate dysfunction, but it is currently unclear whether antipsychotic administration can reduce the extent of glutamatergic abnormality. We conducted a systematic review of proton magnetic resonance spectroscopy (1H-MRS) studies examining the effects of antipsychotic treatment on brain glutamate levels in schizophrenia. The Medline database was searched to identify relevant articles published until December 2016. Inclusion required that studies examined longitudinal changes in brain glutamate metabolites in patients with schizophrenia before and after initiation of first antipsychotic treatment or a switch in antipsychotic treatment. The searches identified eight eligible articles, with baseline and follow-up measures in a total of 168 patients. The majority of articles reported a numerical reduction in brain glutamate metabolites with antipsychotic treatment, and the estimated overall mean reduction of 6.5% in Glx (the combined signal from glutamate and glutamine) across brain regions. Significant reductions in glutamate metabolites in at least one brain region were reported in four of the eight studies, and none of the studies reported a significant glutamatergic increase after antipsychotic administration. Relationships between the degree of change in glutamate and the degree of improvement in symptoms have been inconsistent but may provide limited evidence that antipsychotic response may be associated with lower glutamate levels before treatment and a greater extent of glutamatergic reduction during treatment. Further longitudinal, prospective studies of glutamate and antipsychotic response are required to confirm these findings.

O3.7. EFFECT OF N-ACETYLCYSTEINE ON BRAIN GLUTAMATE LEVELS AND RESTING PERFUSION IN SCHIZOPHRENIA

Abstract Background Schizophrenia may be associated with elevations in glutamate levels in the anterior cingulate cortex (ACC), and this may be particularly apparent in patients who have not responded well to conventional antipsychotic treatment (Egerton et al., 2012; Mouchliantis et al., 2016). This suggests that compounds that can decrease ACC glutamate levels may have therapeutic potential for this group. N-acetylcysteine (NAC) is one such compound, currently under investigation as an adjunctive therapy for schizophrenia. The effects of NAC on brain glutamate levels and physiology in schizophrenia have not been previously evaluated. The primary aim of this study was to examine whether a single oral dose of NAC can alter brain glutamate levels in schizophrenia. The secondary aim was to characterise the effects of NAC on regional brain perfusion. Methods In a double-blind placebo-controlled crossover study, twenty patients with a diagnosis of schizophrenia underwent two 3 Tesla MRI scans, performed one week apart, and following administration of a single oral dose of 2400mg NAC or matching placebo. Proton magnetic resonance spectroscopy (1H-MRS) was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling (pCASL) was used to measure the effects of NAC on resting cerebral blood flow (CBF) in the same regions. 1H-MRS spectra were analysed using LCModel version 6.3-0I using a standard basis set. Individual CBF maps were pre-processed in the Automatic Software for ASL Processing (ASAP) toolbox running in SPM-8 in Matlab 6.5. The effects of NAC on 1H-MRS metabolite levels were determined using paired samples t-tests. Changes in rCBF were determined using within-subjects, second-level analysis implemented in SPM-8. Results In the ACC, Glx/Cr was significantly reduced in the NAC compared to placebo condition (t(17) = 2.40; P = .03, d = 0.64). There was no significant effect of condition on Glu/Cr in the ACC, or on Glx/Cr or Glu/Cr in the right caudate nucleus, or on any of the other metabolites quantifiable from the 1H-MRS spectra. There were no significant differences in CBF in the ACC (mean (SD) placebo = 47.22 (8.81); NAC = 46.83 (7.29); t(18) = .349, P = .73) or in the right caudate nucleus (mean (SD) placebo = 37.51 (7.48); NAC = 37.77 (6.71); t(18) -.310, P = .76) in the NAC compared to placebo condition. There was also no significant difference in global CBF between conditions (mean (SD) placebo = 39.64 (10.02); NAC = 40.03 (9.13); t(18) = -.398, P = .70). Discussion These results provide preliminary evidence that NAC may reduce ACC glutamate metabolites in schizophrenia. Future studies will need to determine the extent to which reductions in glutamate metabolites following a single dose of a glutamatergic compound are indicative of longer-term efficacy in improving symptoms.

S146. EFFECT OF CLOZAPINE ON REGIONAL CEREBRAL BLOOD FLOW IN TREATMENT-RESISTANT SCHIZOPHRENIA

Abstract Background Approximately one-third of schizophrenia patients will not respond adequately to conventional antipsychotic treatment; termed treatment-resistant schizophrenia (TRS). The only antipsychotic recommended for this group is clozapine, which may have unique efficacy in improving residual symptoms. The biological mechanisms underlying its efficacy are poorly understood. Previous studies have examined the effects of clozapine on regional cerebral blood flow (rCBF) using radiotracer approaches in relatively small samples of patients, showing, in particular, frontal and limbic perfusion changes1,2,3. In this study, we evaluate the effects of clozapine on rCBF, measured with a non-invasive MRI technique - pulsed continuous arterial spin labelling (pCASL) - which does not require radiotracer injection, as part of an ongoing study to identify neuroimaging predictors and mediators of clozapine response. Methods Participants ≥18 years of age with TRS were recruited at the Institute of Psychiatry, Psychology & Neuroscience, Kings College London (UK). TRS status was ascertained by the documented failure to respond to at least two different antipsychotic trials of adequate length. Participants were either clozapine-naïve or had not taken clozapine for at least three months prior to the baseline MRI scan. After baseline MRI, clozapine was administered as part of routine clinical care for 12 weeks, after which a second MRI scan was performed. Symptomatic response was defined as a reduction of 20% of the Positive and Negative Syndrome Scale (PANSS)4 score and non-response was defined as <20% decrease in PANSS score. pCASL data was acquired on a General Electric 3 Tesla MR-750 MR scanner. Arterial blood was labelled using a long, adiabatic (1.8 seconds) radio frequency pulse. After a post-labelling delay of 2.025s, perfusion images were acquired with a 3D Fast Spin Echo spiral multi-shot readout (TE 32ms/TR = 5500ms; ETL = 64). Cerebral blood flow (CBF) maps were computed with a spatial resolution of 2x2x3mm, in a total acquisition time of less than 6min. CBF maps were pre-processed using the Automatic Software for ASL processing (ASAP) toolbox5. Changes in rCBF after 12 weeks of clozapine were analysed in a full factorial ANOVA design, using SPM 12 (www.fil.ion.ucl.ac.uk/spm). Clusters of significant CBF changes were assessed at p<0.05 after Family-Wise Error correction for cluster extent, using a cluster-forming threshold of T>2.74. Results This is an interim analysis of 24 patients who completed both scans. Contrasts were examined at a whole brain, assumption-free voxel-wise analysis, restricted to grey matter and co-varied for global perfusion. Clozapine administration significantly decreased perfusion in the medial frontal gyrus. There was also a significant response x time interaction, centred in the left posterior cerebellum and extending to the bilateral visual cortex and right precuneus. Discussion These interim results indicate that pCASL may be able to identify brain regions in which activity is modulated by clozapine administration as well as areas that may mediate symptomatic improvement. A key question for future analyses will be the degree to which rCBF may predict symptomatic response to clozapine, as the ability to predict a good likelihood of response could enable earlier clozapine initiation. References 1. Lahti AC et al. Biol Psychiatry 2003; 53: 601–8. 2. Potkin SG et al. Mol Psychiatry 2003; 8: 109–13. 3. Molina V et al. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 948–54. 4. Kay SR et al. Psychiatry Res 1988; 23: 99–110. 5. Mato Abad VM et al. Magn Reson Imaging 2016; 34: 334–44.

Biological Predictors of Clozapine Response: A Systematic Review

Background: Clozapine is the recommended antipsychotic for treatment-resistant schizophrenia (TRS) but there is significant variability between patients in the degree to which clozapine will improve symptoms. The biological basis of this variability is unknown. Although clozapine has efficacy in TRS, it can elicit adverse effects and initiation is often delayed. Identification of predictive biomarkers of clozapine response may aid initiation of clozapine treatment, as well as understanding of its mechanism of action. In this article we systematically review prospective or genetic studies of biological predictors of response to clozapine. Methods: We searched the PubMed database until 20th January 2018 for studies investigating “clozapine” AND (“response” OR “outcome”) AND “schizophrenia.” Inclusion required that studies examined a biological variable in relation to symptomatic response to clozapine. For all studies except genetic-studies, inclusion required that biological variables were measured before clozapine initiation. Results: Ninety-eight studies met the eligibility criteria and were included in the review, including neuroimaging, blood-based, cerebrospinal fluid (CSF)-based, and genetic predictors. The majority (70) are genetic studies, collectively investigating 379 different gene variants, however only three genetic variants (DRD3 Ser9Gly, HTR2A His452Tyr, and C825T GNB3) have independently replicated significant findings. Of the non-genetic variables, the most consistent predictors of a good response to clozapine are higher prefrontal cortical structural integrity and activity, and a lower ratio of the dopamine and serotonin metabolites, homovanillic acid (HVA): 5-hydroxyindoleacetic acid (5-HIAA) in CSF. Conclusions: Recommendations include that future studies should ensure adequate clozapine trial length and clozapine plasma concentrations, and may include multivariate models to increase predictive accuracy.

Effects of aripiprazole and haloperidol on neural activation during a simple motor task in healthy individuals: A functional MRI study

The dopaminergic system plays a key role in motor function and motor abnormalities have been shown to be a specific feature of psychosis. Due to their dopaminergic action, antipsychotic drugs may be expected to modulate motor function, but the precise effects of these drugs on motor function remain unclear. We carried out a within‐subject, double‐blind, randomized study of the effects of aripiprazole, haloperidol and placebo on motor function in 20 healthy men. For each condition, motor performance on an auditory‐paced task was investigated. We entered maps of neural activation into a random effects general linear regression model to investigate motor function main effects. Whole‐brain imaging revealed a significant treatment effect in a distributed network encompassing posterior orbitofrontal/anterior insula cortices, and the inferior temporal and postcentral gyri. Post‐hoc comparison of treatments showed neural activation after aripiprazole did not differ significantly from placebo in either voxel‐wise or region of interest analyses, with the results above driven primarily by haloperidol. We also observed a simple main effect of haloperidol compared with placebo, with increased task‐related recruitment of posterior cingulate and precentral gyri. Furthermore, region of interest analyses revealed greater activation following haloperidol compared with placebo in the precentral and post‐central gyri, and the putamen. These diverse modifications in cortical motor activation may relate to the different pharmacological profiles of haloperidol and aripiprazole, although the specific mechanisms underlying these differences remain unclear. Evaluating healthy individuals can allow investigation of the effects of different antipsychotics on cortical activation, independently of either disease‐related pathology or previous treatment. Hum Brain Mapp 38:1833–1845, 2017.