Diet quality, dietary inflammatory index and body mass index as predictors of response to adjunctive<i>N</i>-acetylcysteine and mitochondrial agents in adults with bipolar disorder: A sub-study of a randomised placebo-controlled trial

S64 characterized the role of MOR on immobility behavior using selective mu 1 (OPRM1) knock out rats. Additionally we demonstrate that selective pharmacologic blockade of the MOR activity abolishes the BUP: SAM antidepressant-like behavioral effect in FST, in Wistar Kyoto (WKY) rats [3]. Female OPRM1 (-/-) knock out rats (SAGE® Labs, Boyertown, PA) and their OPRM1 (+/+) controls were tested in the FST (water: 23 ᵒC, 32 cm depth; 5 min). For pharmacological studies, male WKY rats were employed (n=8/group) as they spontaneously exhibit high levels of immobility in the FST and are insensitive to chronic SSRI treatment [4]. To selectively block MOR activity, cyprodime (0, 3, 10 or 30 mg/kg s.c.) was administered 15 min before the BUP: SAM (0.1: 0.3 mg/kg s.c.) combination. Based on previously published BUP: SAM neurochemical responses [2], depressive-like behaviors were measured initially at 3hrs post-drug treatment, and again 24hr and 1 week later. Finally, to verify the mechanism of BUP: SAM response, we titrated MOR activity by increasing SAM drug exposure. WKY rats were co-administered vehicle or BUP (0.1 mg/kg s.c.) with increasing concentrations of SAM (0, 0.3, 3 or 10 mg/kg) and tested in the FST 3, 24hr and 1 week later. All behavior was video-recorded and scored manually. Data are expressed as mean + SEM and were analyzed as a repeating measures ANOVA, with follow-up post hoc analysis or t-test where appropriate. OPRM1 (-/-) knock out rats showed significantly increased immobility in the FST compared to OPRM1 (+/+) controls. BUP (0.1 mg): SAM (0.3 mg) significantly reduced immobility compared to vehicle-treated controls. This anti-immobility effect was blocked by cyprodime (30 mg/kg) pre-treatment at all time-points. Lower doses of cyprodime did not significantly alter the BUP: SAM response. Similarly, decreasing MOR activity of the combination with a higher concentration of SAM (10 mg/kg) blocked the BUP: SAM anti-immobility response at each time-point tested. Selective knock out of OPRM1 induces a pro-depressivelike phenotype in the FST, indicating that MOR may play a role mediating adaptive responses to learned helplessness. In these studies, modulation of MOR activity with a combination of BUP and SAM produced rapid and sustained antidepressant-like behaviors in WKY rats. This antidepressant-like effect was blocked by selective MOR antagonism. Furthermore, increasing concentrations of SAM in the combination (↓ MOR activity), completely abolished the BUP: SAM-induced anti-immobility effect. Taken together, these results indicate that modulation of MOR activity is required for the efficacy of the BUP: SAM combination in the FST model of depression. Disclosure statement: Employee Alkermes, Inc References [1] Lutz, P.E., Kieffer, B.L., 2013. Opioid receptors: distinct roles in mood disorders. Trends Neurosci 36 (3), 195–206. [2] Cunningham, J.I., Dean III, R.L., Deaver, D.R., Eyerman, D., 2015. The effects of buprenorphine in combination with samidorphan on neurochemical and behavioral measures in Wistar Kyoto rats. In: European Neuropsychopharmacology. Vienna. [3] Willner, P., Belzung, C., 2015. Treatment-resistant depression: are animal models of depression fit for purpose? Psychopharmacology (Berl) 232 (19), 3473–3495. Abstracts [4] Griebel, G., Cohen, C., Perrault, G., Sanger, D.J., 1999. Behavioral effects of acute and chronic fluoxetine in Wistar-Kyoto rats. Physiol Behav 67 (3), 315–320. doi: 10.1016/j.euroneuro.2018.11.1041 P.039 Diet quality, dietary inflammatory index and body composition as predictors of N-acetylcysteine and mitochondrial agents efficacy in bipolar disorder M. Ashton 1,2,3,∗, O.M. Dean 1,4,3, W. Marx 1,5, M. Mohebi 6, M. Berk 1,3,4,7, G.S. Malhi 8,9,10, C. Ng 2, S.M. Cotton 6,7, S. Dodd 1,6, J. Sarris 2,11, M. Hopwood 4,12, C. Voigt 13, K. Faye-Chauhan 1, Y. Kim 1, S.R. Dash 11, F.N. Jacka 1,14,15, N. Shivappa 16,17,18, J. Hebert 16,17,18, A. Turner 1 1 Deakin University, IMPACT SRC- School of Medicine, Geelong, Australia 2 University of Melbourne, Department of psychiatry- The Melbourne Clinic, Richmond, Australia 3 University of Melbourne, The Florey Institute of Neuroscience and Mental Health, Parkville, Australia 4 University of Melbourne, Department of Psychiatry, Parkville, Australia 5 Deakin University, Biostatistics unit- Faculty of Health, Geelong, Australia 6 Centre of Youth Mental Health, University of Melbourne, Parkville, Australia 7 Orygen Youth Research Centre, Parkville, Australia 8 Academic Department of Psychiatry, Northern Sydney Local Health District, St Leonards 9 Department of Psychiatry- Sydney Medical School, Faculty of Medicine, University of Sydney 10 CADE Clinic Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards 11 NICM, Health Research Institute, Westmead 12 Department of Psychiatry, University of Melbourne, Professorial Unit 13 University of Bremen, University of Bremen, Bremen, Germany 14 Centre for Adolescent Health, Murdoch Children’s Research Institute, VIC, Australia 15 Black Dog Institute, NSW, Australia 16 University of South Carolina, Department of Epidemiology & Biostatistics- Arnold School of Public Health, Columbia, USA 17 University of South Carolina, Cancer Prevention and Control Program- Arnold School of Public Health, Columbia, USA 18 Connecting Health Innovations, LLC, Columbia, SC Introduction: Bipolar depression is often the hardest phase to treat in bipolar disorder. While current pharmacotherapies are useful, they often target mania symptoms, leaving a potential shortfall in recovery for people experiencing depressive episodes [1]. Underlying these symptoms are disturbances in neuroinflammation, oxidative stress, mitochondrial activity and neurotransmitters [2]. These processes could be modulated by diet quality (that is often poor in people with bipolar disorder) and this may have an impact on treatment outcomes [3]. Abstracts Therefore, the current study aimed to assess if participants diet quality, dietary inflammatory index and body mass index (BMI) predict response to treatment in a clinical trial [4]. Methods: Participants with bipolar depression (n=181) took part in a three-arm, 16-week trial. Participants were randomised to receive one of three treatments, the first being a combination treatment of mitochondrial enhancing agents consisting of N-acetylcysteine (NAC), Acetyl L-carnitine (ALC), ubiquinone (Co Q10), Alpha Lipoic acid, magnesium, a-tocopherol, cholecalciferol, retinyl palmitate, calcium ascorbate dehydrate, vitamin B co-factors: thiamine hydrochloride, nicotinamide, riboflavin, calcium pantothenate, pyridoxine hydrochloride, Biotin, folic acid and cyanocobalamin. The second arm of the study was NAC alone treatment and the third arm was placebo. Participants were assessed every four weeks of the study including a post discontinuation of study medication visit at week 20. Diet quality was measured by a Food Frequency Questionnaire converted into an Australian Recommended Food Score and Dietary Inflammatory Index. BMI was measured at baseline. Participants with post-baseline and dietary intake data (n=133) were included in the analysis. Linear Mixed Models were used to assess if diet quality, dietary inflammatory index or BMI predicted response to the significant outcomes of the study, week 20 scores for: depression symptoms (measured by the Montgomery Åsberg Depression Rating Scale), clinician rated improvement (measured by Clinical Global Impression-Improvement), Social and Occupational Functioning Scale and Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool. Summary of Results: BMI significantly predicted Clinical Global Impression-Improvement in relation to treatment received. Participants with lower BMI and in the combination treatment arm showed greater Clinical Global Impression-Improvement over time in the study (p=0.020). Participants with lower BMI also predicted a greater Clinical Global Impression-Improvement for those randomised to the NAC only arm (p=0.020). BMI, dietary inflammatory index and Australian recommended Food Scores were further explored as predictors for social and occupational functioning, impairment of functioning, and depression symptoms. Conclusions: Diet quality, in particular the inflammatory capacity of a diet, and BMI of participants with bipolar disorder may predict response to treatment. Participants who have lower BMI may show greater clinician rated improvement when receiving the combination mitochondrial enhancing treatments. Further research is required for a more comprehensive assessment of diet quality and other common bipolar disorder treatments. References [1] Berk, M., Post, R., Ratheesh, A., Gliddon, E., Singh, A., Vieta, E., Carvalho, A.F., Ashton, M.M., Berk, L., Cotton, S.M., McGorry, P.D., 2017. Staging in bipolar disorder: From theoretical framework to clinical utility. World Psychiatry 16 (3), 236–244. [2] Data-Franco, J., Singh, A., Popovic, D., Ashton, M., Berk, M., Vieta, E., Figueira, M.L., Dean, O.M., 2017. Beyond the therapeutic shackles of the monoamines: new mechanisms in bipolar disorder biology. Progress in Neuro-Psychopharmacology and Biological Psychiatry 72, 73–86. S65 [3] Marx, W., Moseley, G., Berk, M., Jacka, F., 2017. Nutritional psychiatry: the present state of the evidence. Proceedings of the Nutrition Society 76 (4), 427–436. [4] Dean, O.M., Turner, A., Malhi, G.S., Ng, C., Cotton, S.M., Dodd, S., Sarris, J., Samuni, Y., Tanious, M., Dowling, N., Waterdrinker, A., 2015. Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression. Revista Brasileira de Psiquiatria 37 (1), 03–12. doi: 10.1016/j.euroneuro.2018.11.1042 P.040 Repetitive transcranial magnetic stimulation combined with antidepressants for major depressive disorder: A meta-analysis and systematic review B. Maneeton 1,∗, N. Maneeton 1, P. Woottiluk 2, A. Oonarom 1 1 Chiang Mai University, Department of Psychiatry- Faculty of Medicine, Chiang Mai, Thailand 2 Chiang Mai University, Psychiatric Nursing Division- Faculty of Nursing, Chiang Mai, Thailand Background Some evidences have indicated the repetitive transcranial magnetic stimulation (rTMS) combined with antidepressants is able to accelerate and augment the efficacy in the treatment of major depressive disorder (MDD) in the first episode,1-3 a meta-analysis, a more powerful means for calculating the true effect size, is possibly applicable method to determine the efficacy, acceptability and tolerability in the treatment of such patients. Objectives The aims of study were to systematically review the efficacy, acceptability and tolerability of rTMS combined with selective serotonin reuptake inhibitors (SSRIs) in treatment of the first episode MDD. Study eligibility criteria, participants, and interventions Eligible RCTs had to report (i) severity of MDD, (ii) response and remission rates, (iii) overall discontinuation rate, or (iv) discontinuation rate due to adverse events. Results A total of 108 randomized patients, aged 18-45 years, of two RCTs were included in this study [1,2]. Duration of the first included trial was 4 weeks, including either rTMS plus citalopram or sham plus citalopram treatments for the first 2 weeks and citalopram treatment alone for 2 weeks afterwards [1]. While duration of the last included study was 8 weeks, including either rTMS plus paroxetine or sham plus paroxetine treatments for the first 4 weeks and paroxetine treatment alone for 4 weeks afterwards [2]. Either the 17-item Hamilton Depression Rating scale (HAMD17) or 24-item Hamilton Depression Rating scale (HAMD-24) was used in evaluation severity of depressive symptoms in each RCT. The pooled mean-changed scores of the HAMD in 1, 2 and 4 weeks for rTMS plus SSRIs were greater than that of sham plus SSRIs with SMD (95% CI) of -0.54(-0.93, -0.14), I2=0%, -0.84(-1.24, -0.43) I2=0% and -1.23(-2.36, -0.11), I2=85%, respectively. However, mean-end scores of HAMD in 8 weeks between two groups were not significantly different [2]. Considered in dichotomous outcomes, early improvement rate (a 20% reduction of HAMD-17 scores) in the rTMS plus citalopram-treated group was significantly greater than that of sham plus citalopram-treated group [1]. The