Research, 2Proteomics and Mass Spectrometry Facility and. Department of Biochemistry and Molecular Pharmacology,. University of Massachusetts Medical ...
Biological Psychiatry
Thursday Abstracts
1
Zucker Hillside Hospital; Feinstein Institute for Medical Research, 2Proteomics and Mass Spectrometry Facility and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 3Department of Quantitative Health Sciences, University of Massachusetts Medical School, 4Center for Comparative Neuroimaging, University of Massachusetts Medical School, 5Center for Psychopharmacologic Research & Treatment, University of 6 Massachusetts Medical School, Center for Psychopharmacologic Research & Treatment, University of Massachusetts Medical School; National Institute of Environmental Health Sciences, Research Triangle, NC, 7 Proteomics and Mass Spectrometry Facility and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 8National Institute of Environmental Health Sciences, Research Triangle, NC, 9Department of Psychiatry, Harvard Medical School; Brain Imaging Center, McLean Hospital, 10Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine; F.M. Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute Background: Peripartum fluctuations in neuroactive steroids (NAS), potent allosteric modulators of GABAergic function, may contribute to postpartum depression (PPD). We measured peripartum plasma NAS, plasma GABA and postpartum brain GABA1/Creatine (GABA1/Cr) in bilateral ACC and OCC. Methods: Fifty-six medication-free women were evaluated with serial mood and blood assessments at four peripartum time points. Plasma NAS and GABA were quantified by liquid chromatography/mass spectrometry. Women who developed PPD (PPD: N 5 24) and healthy comparison women (HCW: N 5 25) were examined using proton magnetic resonance spectroscopy (1H-MRS). MRS data was acquired with 3.0T Philips Achevia MR system using phased-array receiver SENSE head coil. Edited MRS spectra were acquired using MEscherGArwood Point-REsolved Spectroscopy Sequence (TE568 msec and TR52000 msec). Results: Plasma GABA concentration was 1.9 6 0.7 ng/mL (p50.005) lower and plasma progesterone and pregnanolone were 16.0 6 7.6 and 1.4 6 0.7 ng/mL higher in women at-risk for PPD as compared to HCW, respectively (p50.04 for both). HAM-D was inversely associated with plasma GABA concentration (β520.16 6 0.06, p50.005) and positively associated with pregnanolone (β50.18 6 0.07, p50.01) concentration. GABA1/Cr was significantly lower in the OCC in PPD than HCW (t 5 2.209, df 5 44, p 5 0.032). There was no between-group difference in GABA1/Cr in the ACC (t 5 -0.107, df 5 44, p 5 0.915). Higher EPDS scores were associated with lower OCC GABA1/Cr (Pearson correlation: r 5 -0.326, p 5 0.027, N 5 46). Conclusions: NAS and GABA may play an important role in the pathophysiology of peripartum depression. Supported By: K23MH097794 (KMD), Ul1TR000161 (KMD) and Worcester Foundation for Biomedical Research (KMD), 1S10RR027107 (SAS), MH07399 (CMM) and UMMS Start-up funds (CMM) Keywords: neuroactive steroids, GABA, peripartum, Depression, Magnetic Resonance Spectroscopy
70. Cortical Inhibition as a High Potential Biomarker of Response across Brain Stimulation Modalities in Treatment Resistant Depression Daphne Voineskos1, Daniel M. Blumberger2, Yinming Sun3, Nigel Rogasch4, Reza Zomorrodi5, Faranak Farzan2, Tarek Rajji6, and Zafiris J. Daskalakis2 University of Toronto and CAMH, 2Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto; University of Toronto, 3Centre for Addiction and Mental Health, 4Monash University, Melbourne, 5Center for Addiction and Mental Health, 6 Centre for Addiction and Mental Health, University of Toronto 1
Background: The gold standard of therapy in Treatment Resistant Depression (TRD) is brain stimulation. However, there has previously been no defined biological marker to predict or understand therapeutic response to brain stimulation. Dysfunctional cortical inhibition (CI) has been postulated as a mechanism through which MDD symptoms are mediated. Our lab has conducted several investigations in cortical inhibition (CI), utilizing investigational TMS to understand response across brain stimulation therapies (ECT, rTMS and MST). Methods: 25 patients underwent TMS-EMG CI paradigms before and after ECT. 30 patients underwent TMS-EEG CI paradigms before and after rTMS. 27 patients underwent TMS-EEG CI paradigms before and after MST. All patients were diagnosed with TRD. TMS-EMG CI paradigms included the cortical silent period (CSP). TMS-EEG CI paradigms included N100 response and LICI. Baseline TMS measures were assessed within 1 week prior to the initiation of acute brain stimulation and post-TMS measures within 48h of the final treatment. Results: In ECT subjects, baseline CSP predicted therapeutic response to ECT with sensitivity of 80% and specificity of 60%. In rTMS subjects, a strong correlation appeared between Δ N100 Amplitude and Δ HDRS (r 5 0.63, p5 0.002) in the active rTMS group. In MST subjects, N100 and LICI predicted remission of suicidal ideation with 90% sensitivity and 89% specificity. Conclusions: Our results suggest cortical inhibition has high potential in TRD as a biomarker of response across brain stimulation therapies. These findings suggest that stronger inhibitory neurotransmission at baseline reflects the integrity of interneuronal networks, optimal targets for brain stimulation therapy in TRD. Keywords: Treatment Resistant Depression, Brain Stimulation, Cortical Inhibition, Biomarkers
71. Improving the Regional Specificity of CNS Drugs by Targeting Accessory Proteins: Proof-of-Concept Using Glutamate Receptors Michael Maher, Nyantsz Wu, Suchitra Ravula, Michael Ameriks, Brad Savall, Brian Lord, Jose Matta, Nicholas Carruthers, and Timothy Lovenberg Janssen Research and Development
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
S29
Biological Psychiatry
Thursday Abstracts
Background: Mood disorders can be considered as imbalances in the activity of specific neuronal circuits. The alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediates the majority of fast synaptic transmission within the mammalian brain. The ubiquitous expression of the primary subunits of AMPA receptors (AMPARs), and the lack of pharmacological selectivity amongst them, preclude regional or neuronal subtype specificity. In vivo, AMPARs comprise a variety of accessory proteins. Of particular interest, TARP-gamma8 is highly expressed in the hippocampus, part of the limbic circuitry that putatively is overactive in recurrent mood disorders. Methods: We used high-throughput screening to discover compounds that selectively modulate AMPARs containing TARP-gamma8. Subsequent medicinal chemistry efforts were used to improve potency and pharmacokinetics of the hits. Assays were developed to measure target occupancy and functional effects of the compounds in vivo. Results: These compounds possess a novel mechanism-ofaction consistent with a partial attenuation of the interaction between the TARP and the pore-forming subunits of the channel. Lead molecules with oral bioavailability and high brain penetration allowed demonstration of a strong relationship between pharmacokinetics and pharmacodynamics. The compounds show anticonvulsant and anxiolytic profiles in rodent. Molecules in this class provide large safety margins relative to non-specific AMPAR inhibitors due to the improved regional specificity of TARP-gamma8 modulators. Conclusions: AMPAR modulators selective for TARP-gamma8 have the potential to be novel treatments for anxiety/depression, bipolar disorder, temporal lobe epilepsy, and/or prodromal schizophrenia. This project also represents proof-of-concept for pharmacological targeting of accessory proteins and smallmolecule modulation of protein-protein interactions. Keywords: ionotropic glutamate receptors, Pharmacology, Mood disorders, anticonvulsants, Hippocampus
72. Light Therapy for Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial of Bright White versus Dim Red Light for Bipolar Depression Dorothy Sit1, James McGowan2, Christopher Wiltrout2, Rasim Somer Diler2, John (Jesse) Dills3, James Luther3, Howard Seltman4, Stephen Wisniewski3, Michael Terman5, and Katherine L Wisner1 1
Northwestern University, Feinberg School of Medicine, University of Pittsburgh Medical Center, 3University of Pittsburgh, Graduate School of Public Health, 4Carnegie Mellon University, Department of Statistics, 5Columbia University, New York State Psychiatric Institute 2
Background: Patients with Bipolar Disorders (BD) have recurrent major depression, residual mood symptoms, and limited treatment options. We conducted a 6-week, double-blind, parallel, placebo-controlled trial to investigate the efficacy of midday bright light therapy for bipolar depression. The aims were to determine remission rates, depression severity, and the rate of mood polarity switch in patients randomized to 7000-lux bright white or 50-lux dim red light.
S30
Methods: We enrolled depressed adults with BD Type-I or II and receiving stable-dosed antimanic medication. We excluded patients with hypomania, mania, mixed symptoms or rapid cycling. We assessed mood symptoms weekly with the Structured Interview Guide for the Hamilton Depression Scale with Atypical Depression Supplement, the Mania Rating Scale. Remission was defined by a SIGH-ADS # 8. Patients used the assigned study light box at home or work, starting with 15minutes daily at midday (12:00-2:30 PM). The light-dose was increased by 15-minutes every week to reach a target dose of 60 minutes at Week 4 unless remission was attained. Results: We randomized 23 to bright white and 23 to dim red light. At baseline, both groups had moderate depression severity and no hypomanic symptoms. At Week 6, the group randomized to bright white compared to dim red light had a significantly higher remission rate (56.5%, 13/26 versus 14.3%, 3/26; adjusted odds ratio56.0, p50.03) and significantly fewer depressive symptoms (10.368.2 versus 17.969.6 adjusted β526.066, p50.02). No mood polarity switch was observed. Conclusions: Findings provide robust evidence which confirms the efficacy of midday bright light therapy for bipolar depression. Supported By: National Institute of Mental Health, K23 MH 082114, Career Development Award, PI – D. Sit; The Brain and Behavioral Research Foundation, NARSAD 2013 Young Investigator Grant, PI – D. Sit; Uplift Technologies, Inc. for their donation of study light boxes for use in the K23 research study; and Department Funds from the University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Chair, Dr. David Lewis, M.D. Keywords: bipolar depression, Light Therapy, Clinical Trials, Novel Intervention, Bipolar Disorder
73. Efficacy of Transcranial Direct Current Stimulation in Unipolar and Bipolar Depression: Results from an International Randomized Controlled Trial Colleen Loo1, Sarah Lisanby2, Mustafa Husain3, William McDonald4, Scott Aaronson5, John O’Reardon6, Donel Martin1, Angelo Alonzo7, Shawn McClintock8, and Cynthia Shannon Weickert9 University of New South Wales, 2Now at the National Institute of Mental Health. Dr. Sarah H. Lisanby contributed to this article while at Duke University, prior to joining NIMH. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health or the United States Government, 3UT Southwestern Medical Centre, 4Emory University, 5 Sheppard Pratt Health System, 6Now at Psychiatry at the Pavilions. Dr O’Reardon contributed to this study while at the University of Medicine & Dentistry of New Jersey, 7 School of Psychiatry UNSW, 8The University of Texas Southwestern Medical Center, Department of Psychiatry, 9 Neuroscience Research Australia 1
Background: Evidence suggests transcranial Direct Current Stimulation (tDCS) has antidepressant efficacy. Large, well designed trials are required to confirm efficacy, and further assess safety, including in bipolar depression. Prior research
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
