Background: Major depressive disorder (MDD) is among the most common psychiatric conditions in the U.S., affecting 8.3% of adults in 2021.1 Globally, depression is the leading cause of disability.2 Among veterans who died by suicide in 2021, 38.4% had a documented depression diagnosis.3 Despite its prevalence, there is no reliable biological marker for diagnosing depression or predicting treatment response. Traditional antidepressants take weeks to show effects, and about one-third of patients fail to reach remission even after multiple treatment attempts.4 The heterogeneity of depression complicates diagnosis and treatment, while current approaches—relying on clinic visits and subjective surveys—lack accuracy and can delay care. There is a critical need for objective, cost-effective diagnostic and monitoring tools. Research has linked depression and antidepressant response to changes in cyclic AMP (cAMP) signaling.5,6 In 2023, our team published findings from a 19-subject study showing a promising link between depression severity and Gsα activity.7 PGE1 stimulation of adenylyl cyclase activity increased by at least 30% from the screen assessment in 8 of the 11 responders (72.7%) on contrast to 2 of the 8 non-responders (25.0%) in this small group of subjects (Fisher exact=0.07), and the positive predictive value of PGE1 activation for treatment response was 80.0%.

Objective: The purpose of this study is to replicate the study described above in a larger sample and identify the palmitoylation status of Veterans who responded clinically to antidepressant treatment compared to non-responders. By understanding the utility of using the Gsa biomarker, we can validate a robust blood biomarker to diagnose patients with depression and visualize the efficacy of ongoing antidepressant treatment on veterans undergoing treatment at VA clinic.

Methods: Veterans diagnosed with depression were recruited through the mood disorder and interventional psychiatric clinic at VA-GLA to our research study. Once participants had given verbal consent and enrolled in the study, they completed the PHQ-9, HAM-D, and blood draw at the initiation of treatment, one to two weeks after initiation, and eight to ten weeks after initiation. The collected blood was centrifuged, processed to collect platelets, and stored at -80°C, which will be shipped with dry ice to Jesse Brown VAMC. The samples will be analyzed using mass spectrometry. 

Results: Thus far, 9 participants (8 men and 1 woman, mean age = 54.5 ± 19.3 years) have been enrolled, and 4 have completed the study. Of the 9 participants, 6 were treated with TMS and 3 were treated ketamine (2 with Spravato, 1 ketamine infusion). Preliminary analysis was performed on data from the 4 participants (all received TMS) who had completed the study. For the PHQ-9, participants showed a mean reduction of 6.75 ​​± 5.04 (SD) points for their total score (p=0.27), corresponding to a -39% change from visit 1 to visit 3. For the HAM-D, participants showed a mean reduction of 13.5 ​​± 9.1 (SD) points for their total score (p=0.059), corresponding to a -57% change from visit 1 to visit 3. Measures of Gsα activity via processing of the blood samples are pending.

Conclusions: Preliminary findings from the first four participants who completed the study suggest that TMS treatment may be associated with meaningful reductions in depressive symptoms. Although not statistically significant, participants demonstrated a 39% average reduction in PHQ-9 scores and a 57% average reduction in HAM-D scores from baseline to visit 3. The observed trends, particularly the near-significant improvement in HAM-D (p = 0.059), are promising and warrant further investigation as additional participants complete the study. Further analysis will also compare responses to TMS versus ketamine. Analysis of Gsα activity in the future may provide further insight into underlying biological changes and allow for comparison to see if depressive symptoms based on participants’ reports through the surveys correspond with changes in Gsα activity.

References:

1. National Institute of Mental Health. (2023, July). Major depression. U.S. Department of Health and Human Services. https://www.nimh.nih.gov/health/statistics/major-depression

2. World Health Organization. (2017, March 30). “Depression: let’s talk” says WHO, as depression tops list of causes of ill health. https://www.who.int/news-room/detail/30-03-2017--depression-let-s-talk-says-who-as-depression-tops-list-of-causes-of-ill-health

3. U.S. Department of Veterans Affairs, Office of Mental Health and Suicide Prevention. 2023 National Veteran Suicide Prevention Annual Report. 2023. Retrieved Apr 21, 2025. 

4. Mendlewicz J. Towards achieving remission in the treatment of depression. Dialogues Clin Neurosci. 2008;10(4):371-5. doi: 10.31887/DCNS.2008.10.4/jmendlewicz. PMID: 19170394; PMCID: PMC3181889.

5. Barylko B, Wilkerson JR, Cavalier SH, Binns DD, James NG, Jameson DM, Huber KM, Albanesi JP. Palmitoylation and Membrane Binding of Arc/Arg3.1: A Potential Role in Synaptic Depression. Biochemistry. 2018 Feb 6;57(5):520-524. doi: 10.1021/acs.biochem.7b00959. Epub 2017 Dec 26. PMID: 29264923; PMCID: PMC10370338.

6. Mitroshina EV, Marasanova EA, Vedunova MV. Functional Dimerization of Serotonin Receptors: Role in Health and Depressive Disorders. Int J Mol Sci. 2023 Nov 16;24(22):16416. doi: 10.3390/ijms242216416. PMID: 38003611; PMCID: PMC10671093.

7. Targum SD, Schappi J, Koutsouris A, Bhaumik R, Rapaport MH, Rasgon N, Rasenick MM. A novel peripheral biomarker for depression and antidepressant response. Mol Psychiatry. 2022 Mar;27(3):1640-1646. doi: 10.1038/s41380-021-01399-1. Epub 2022 Jan 5. PMID: 34969978; PMCID: PMC9106819.