Poster No:
500
Submission Type:
Abstract Submission
Authors:
Che Liu1, Sherwood Brown2, Jayme Palka2, Francesca Filbey1
Institutions:
1Center for BrainHealth, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, 2Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX
First Author:
Che Liu, PhD
Center for BrainHealth, School of Behavioral and Brain Sciences, University of Texas at Dallas
Dallas, TX
Co-Author(s):
Jayme Palka, PhD
Department of Psychiatry, UT Southwestern Medical Center
Dallas, TX
Francesca Filbey
Center for BrainHealth, School of Behavioral and Brain Sciences, University of Texas at Dallas
Dallas, TX
Introduction:
Pregnenolone is an endogenous neurosteroid and the precursor to all other neurosteroids in the brain. In patients with depression, lower levels of cerebrospinal fluid (CSF) pregnenolone were linked to depressed states (George, Guidotti et al. 1994). Previous clinical trials showed that adjunctive pregnenolone treatment improved depressive symptoms in patients with bipolar disorder (Osuji, Vera-Bolanos et al. 2010, Brown, Park et al. 2014), and reduced negative symptoms such as blunted affect, alogia and anhedonia (Marx, Keefe et al. 2009, Ritsner, Bawakny and Kreinin 2014) in patients with schizophrenia. However, to date, little research has examined its effect on resting state functional connectivity (rsFC), especially in patients with major depressive disorder (MDD). The dorsolateral prefrontal cortex (DLPFC), a key node of executive control network, is thought to be responsible for regulation of negative emotion (Phillips, Drevets et al. 2003, Koenigs and Grafman 2009), plays a critical role in the pathophysiology of depression (Koenigs and Grafman 2009), and is a target to treat depression (Koenigs and Grafman 2009, Kupfer, Frank and Phillips 2012). A post-mortem study showed that the endogenous production of steroids (i.e., dehydroepiandrosterone and its sulfate metabolite) is altered in the DLPFC of patients with MDD (Qi, Luchetti et al. 2018). Thus, FC of DLPFC may serve as markers for dose-dependent pregnenolone treatment.
Methods:
In a cross-over clinical trial, twelve adult women (mean ± SD= 46.08 ± 6.96, range: 36-57 years) with mild or moderate MDD underwent three treatment conditions in a randomized order: 500mg/day, 800 mg/day pregnenolone and placebo. Each treatment lasted for 7 days with a 14-day washout period between treatments. Structural MRI and 6-min rsfMRI data were collected after completion of each treatment condition using a 3-T Philips Achieva scanner. Depressive symptoms were assessed using Hamilton Rating Scale for Depression (HRSD) at baseline (mean ± SD= 12.67 ± 4.03, range: 6-21). The DLPFC mainly corresponds to Brodmann area (BA)9 and BA46 (Jung, Lambon Ralph and Jackson 2022). The left and right BA9 and BA46 were selected as the seed regions and used to conduct seed-based voxel-wise connectivity analyses. Data were preprocessed and analyzed using CONN toolbox (v.22a). The rsfMRI data of one participant was excluded due to excessive head motion. Repeated measures analyses of covariances (ANCOVA) controlling for the sequence orders were conducted for the comparisons between treatment conditions. A whole-brain voxel-level uncorrected P<.001, cluster-level P-FDR<.05 and a minimum cluster size of 10 voxels were used to identify significant clusters.
Results:
Compared to placebo, pregnenolone dose 500mg/day increased FC of right BA46 with posterior and anterior cingulate gyri (P-FDR=.005) and left anterior supramarginal gyrus (P-FDR=.031), of right BA9 with precuneus (P-FDR=.040), but reduced FC between right BA46 and bilateral occipital poles (P-FDR=.005). However, FC of BA46 or 9 did not significantly differ between pregnenolone dose 800mg/day and placebo. Compared to pregnenolone dose 500mg/day, lower FC were found following higher dose 800 mg/day between right BA9 and precuneus (P-FDR≤.005), between left BA46 and left frontal pole (P-FDR=.0497), and between right BA46 and left frontal pole (P-FDR=.0003) and temporooccipital part of left inferior temporal gyrus (P-FDR=.024).
Conclusions:
Administration of pregnenolone 500mg/day could represent a new potential treatment for women with MDD. Quantifying FC of DLPFC holds the promise for the prediction of pregnenolone response in depression. In addition, higher FC of DLPFC also predicted better symptom scores after treatment.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 1
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
fMRI Connectivity and Network Modeling 2
Keywords:
DISORDERS
FUNCTIONAL MRI
Pharmacotherapy
Treatment
Other - Pregnenolone; Major Depressive Disorder; Dorsolateral Prefrontal Cortex; Functional Connectivity; Posterior Cingulate; Anterior Cingulate; Precuneus
1|2Indicates the priority used for review
Provide references using author date format
Brown, E. S., J. Park, C. E. Marx, L. S. Hynan, C. Gardner, D. Davila, A. Nakamura, P. Sunderajan, A. Lo and T. Holmes (2014), 'A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression', Neuropsychopharmacology, vol. 39, no. 12, pp. 2867-2873.
George, M. S., A. Guidotti, D. Rubinow, B. Pan, K. Mikalauskas and R. M. Post (1994), 'CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI', Biol Psychiatry, vol. 35, no. 10, pp. 775-780.
Jung, J., M. A. Lambon Ralph and R. L. Jackson (2022), 'Subregions of DLPFC Display Graded yet Distinct Structural and Functional Connectivity', J Neurosci, vol. 42, no. 15, pp. 3241-3252.
Koenigs, M. and J. Grafman (2009), 'The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex', Behav Brain Res, vol. 201, no. 2, pp. 239-243.
Kupfer, D. J., E. Frank and M. L. Phillips (2012), 'Major depressive disorder: new clinical, neurobiological, and treatment perspectives', Lancet, vol. 379, no. 9820, pp. 1045-1055.
Marx, C. E., R. S. Keefe, R. W. Buchanan, R. M. Hamer, J. D. Kilts, D. W. Bradford, J. L. Strauss, J. C. Naylor, V. M. Payne, J. A. Lieberman, A. J. Savitz, L. A. Leimone, L. Dunn, P. Porcu, A. L. Morrow and L. J. Shampine (2009), 'Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia', Neuropsychopharmacology, vol. 34, no. 8, pp. 1885-1903.
Osuji, I. J., E. Vera-Bolanos, T. J. Carmody and E. S. Brown (2010), 'Pregnenolone for cognition and mood in dual diagnosis patients', Psychiatry Res, vol. 178, no. 2, pp. 309-312.
Phillips, M. L., W. C. Drevets, S. L. Rauch and R. Lane (2003), 'Neurobiology of emotion perception II: Implications for major psychiatric disorders', Biol Psychiatry, vol. 54, no. 5, pp. 515-528.
Qi, X. R., S. Luchetti, R. W. H. Verwer, A. A. Sluiter, M. R. J. Mason, J. N. Zhou and D. F. Swaab (2018), 'Alterations in the steroid biosynthetic pathways in the human prefrontal cortex in mood disorders: A post-mortem study', Brain Pathol, vol. 28, no. 4, pp. 536-547.
Ritsner, M. S., H. Bawakny and A. Kreinin (2014), 'Pregnenolone treatment reduces severity of negative symptoms in recent-onset schizophrenia: an 8-week, double-blind, randomized add-on two-center trial', Psychiatry Clin Neurosci, vol. 68, no. 6, pp. 432-440.