Treatment Outcome in Major Depressive Disorder

Summary

Major Depressive Disorder (MDD) is one of the most severe and frequently occurring brain disorders worldwide. It has been linked to serotonergic dysfunction, sexual dysfunction, vulnerability to stress and neuro-inflammation. However, at the same time the etiological understanding is limited. Most antidepressants act on the serotonin (5- HT) system, yet between 30-50 % of patients with MDD does not respond successfully to 5-HT acting drugs. Recent experimental models from our group suggest that cerebral 5-HT levels in vivo can be indexed through molecular brain imaging of the 5-HT 4 receptor (5-HT4R) with a novel Positron Emission Tomography (PET) ligand (11C-SB207145). Also, our human studies have confirmed that cerebral synaptic 5-HT is inversely related to 5-HT4R binding and this technique thus can be used to investigate the role of 5-HT tone in the brain in MDD with differential responses to standard antidepressant treatment. By using multimodal neuroimaging technology, we aim to determine the status of the 5-HT system prior to and after either successful or failed neuropharmacological intervention in a non-randomized longitudinal open clinical trial. 100 untreated patients with moderate to severe MDD will be included. Data collection from various neurobiological domains (i.e, 5-HT4R PET imaging, Magnetic Resonance Imaging (MRI), functional MRI (fMRI), electroencephalogram (EEG), psychometrics, neuropsychological tests, and peripheral biomarkers) will be conducted before, during and after 12 weeks of antidepressant treatment. The objective is to identify predictors of pharmacological antidepressant treatment response in depressed individuals before and after 8 weeks of antidepressant treatment.

Timeline

Start

2016-08

Primary completion

2019-07

Completion

2019-07

Publications

• Background Ostergaard SD, Bech P, Miskowiak KW. Fewer study participants needed to demonstrate superior antidepressant efficacy when using the Hamilton melancholia subscale (HAM-D(6)) as outcome measure. J Affect Disord. 2016 Jan 15;190:842-845. doi: 10.1016/j.jad.2014.10.047. Epub 2014 Nov 7.
• Jensen KHR, Aarestrup MR, Larsen SV, Kohler-Forsberg K, Knudsen GM, Jorgensen MB, Frokjaer VG. Psychoneuroendocrine profiles of unmedicated men with major depressive disorder and associations to treatment effects and sexual side-effects. Neurosci Appl. 2024 Feb 23;3:104050. doi: 10.1016/j.nsa.2024.104050. eCollection 2024.
• Sankar A, Ozenne B, Dam VH, Svarer C, Jorgensen MB, Miskowiak KW, Frokjaer VG, Knudsen GM, Fisher PM. Association between brain serotonin 4 receptor binding and reactivity to emotional faces in depressed and healthy individuals. Transl Psychiatry. 2023 May 11;13(1):165. doi: 10.1038/s41398-023-02440-3.
• Ip CT, Ganz M, Ozenne B, Olbrich S, Beliveau V, Dam VH, Kohler-Forsberg K, Jorgensen MB, Frokjaer VG, Knudsen GM. Association between the loudness dependence of auditory evoked potential, serotonergic neurotransmission and treatment outcome in patients with depression. Eur Neuropsychopharmacol. 2023 May;70:32-44. doi: 10.1016/j.euroneuro.2023.02.008. Epub 2023 Feb 28.
• Weber S, Frokjaer VG, Armand S, Nielsen JH, Knudsen GM, Joergensen MB, Stenbaek DS, Giraldi A. Sexual function improves as depressive symptoms decrease during treatment with escitalopram: results of a naturalistic study of patients with major depressive disorder. J Sex Med. 2023 Feb 14;20(2):161-169. doi: 10.1093/jsxmed/qdac016.
• Dam VH, Stenbaek DS, Kohler-Forsberg K, Cheng Ip, Ozenne B, Sahakian BJ, Knudsen GM, Jorgensen MB, Frokjaer VG. Evaluating cognitive disturbances as treatment target and predictor of antidepressant action in major depressive disorder: A NeuroPharm study. Transl Psychiatry. 2022 Nov 8;12(1):468. doi: 10.1038/s41398-022-02240-1.
• Fisher PM, Ozenne B, Ganz M, Frokjaer VG, Dam VN, Penninx BW, Sankar A, Miskowiak K, Jensen PS, Knudsen GM, Jorgensen MB. Emotional faces processing in major depressive disorder and prediction of antidepressant treatment response: A NeuroPharm study. J Psychopharmacol. 2022 May;36(5):626-636. doi: 10.1177/02698811221089035. Epub 2022 May 13.
• Ip CT, Olbrich S, Ganz M, Ozenne B, Kohler-Forsberg K, Dam VH, Beniczky S, Jorgensen MB, Frokjaer VG, Sogaard B, Christensen SR, Knudsen GM. Pretreatment qEEG biomarkers for predicting pharmacological treatment outcome in major depressive disorder: Independent validation from the NeuroPharm study. Eur Neuropsychopharmacol. 2021 Aug;49:101-112. doi: 10.1016/j.euroneuro.2021.03.024. Epub 2021 Apr 25.
• Kohler-Forsberg K, Jorgensen A, Dam VH, Stenbaek DS, Fisher PM, Ip CT, Ganz M, Poulsen HE, Giraldi A, Ozenne B, Jorgensen MB, Knudsen GM, Frokjaer VG. Predicting Treatment Outcome in Major Depressive Disorder Using Serotonin 4 Receptor PET Brain Imaging, Functional MRI, Cognitive-, EEG-Based, and Peripheral Biomarkers: A NeuroPharm Open Label Clinical Trial Protocol. Front Psychiatry. 2020 Jul 23;11:641. doi: 10.3389/fpsyt.2020.00641. eCollection 2020.

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