Ketamine represents a significant advancement in antidepressant therapy, but the commonly used intravenous and intranasal application routes currently limit its availability beyond specialized centers. By contrast, oral ketamine treatment might constitute an alternative that is widely available, easy to administer, and has potential advantages with regard to tolerability. Forty-five patients diagnosed with a moderate to severe depressive episode received either 1 mg/kg peroral ketamine or 0.03 mg/kg midazolam solution as an active comparator, administered six times over two weeks in a double-blind trial. While statistical significance for the primary endpoint of MADRS score reduction after one week was not achieved, response rates favored ketamine with a number needed to treat (NNT) of 4.6 (95 %-CI: [2.4, 62.6]) at this timepoint. Treatment was well-tolerated, with no serious adverse events reported, potentially due to the lower exposure to ketamine compared to its metabolite norketamine measured in plasma. In a total of 592 patients, meta-analysis of randomized controlled trials on oral ketamine treatment demonstrated its antidepressant efficacy with a NNT = 4.89 (95 %-CI: [3.41, 8.66]) for response and a NNT = 9.16 (95 %-CI: [5.49, 27.59]) for remission. Despite that the current trial did not meet its primary endpoint, the cumulative evidence up-to-date suggests that oral ketamine treatment leads to relevant improvements in the outcomes of patients with depression. In light of the ease of administration and high tolerability with oral application, this evidence may contribute to removing some of the obstacles that currently restrict the availability of antidepressant treatment with ketamine to specialized centers.

Background: Ketamine represents a significant advancement in antidepressant therapy, but the commonly used intravenous and intranasal application routes currently limit its availability beyond specialized centers. By contrast, oral ketamine treatment might constitute an alternative that is easy to administer with established safety and efficacy for patients with chronic and severe pain at home. Aims: With this trial we further investigated the evidence on the efficacy and tolerability of oral ketamine as an antidepressant treatment. Method: 41 patients diagnosed with a moderate to severe depressive episode were randomized to receive either 1mg/kg peroral ketamine or 0.03mg/kg midazolam solution as an active comparator, administered six times over two weeks in a double-blind trial ([NCT02992496][1]). Results While statistical significance for the primary endpoint of MADRS score reduction after one week was not achieved, response rates favored ketamine with a number needed to treat (NNT) of 4.0 (95%-CI: [2.1, 36.2]) at this timepoint. Treatment was well-tolerated, with no serious adverse events reported, potentially due to the lower exposure to ketamine compared to its metabolite norketamine measured in plasma. In a total of 507 patients, meta-analysis of randomized controlled trials on oral ketamine treatment demonstrated its antidepressant efficacy with a NNT = 4.89 (95%-CI: [3.18, 10.54]) for response and a NNT = 6.88 (95%-CI: [4.18, 19.27]) for remission. Conclusions: Despite that the current trial did not meet its primary endpoint, possibly due to the presence of an active comparator and low immediate side effects, the cumulative evidence up-to-date suggests that oral ketamine treatment leads to relevant improvements in the outcomes of patients with depression. In light of the ease of administration and high tolerability with oral application, this evidence may contribute to removing some of the obstacles that currently restrict the availability of antidepressant treatment with ketamine to high-income areas. ### Competing Interest Statement RL received travel grants and/or conference speaker honoraria from Bruker BioSpin within the last three years and investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start- up company BM Health GmbH since 2019. SK received grants/ research support, consulting fees and/or honoraria within the last three years. He received grant/ research support from Lundbeck; he has served as a consultant or on advisory boards for Celegne, IQVIA, Janssen, Lundbeck, Mundipharma, Recordati, Takeda and Schwabe; and he has served on speaker bureaus for Angelini, Aspen Farmaceutica S.A., Janssen, Krka Pharma, Lundbeck, Medichem Pharmaceuticals Inc., Neurax- pharma, OM Pharma, Pierre Fabre, Sanofi, Servier, Schwabe, Sun Pharma. The remaining authors declare no potential conflict of interest with respect to the research, authorship, and/ or publication of this article. ### Clinical Trial NCT02992496 ### Funding Statement This research was funded in part by the Medical-Scientific Fund of the Mayor of the City of Vienna. LRS and GG were recipients of DOC fellowships of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy, Medical University of Vienna. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All study related procedures were reviewed and approved by the ethics committee of the Medical University of Vienna and carried out in accordance with ethical principles that have their origin in the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02992496&atom=%2Fmedrxiv%2Fearly%2F2025%2F04%2F06%2F2025.03.21.25324252.atom

The coronavirus disease 2019 (COVID-19) led to substantial social restriction measures. Social isolation has been demonstrated to promote psychiatric symptoms and to dysregulate gamma-aminobutyric acid (GABA) and glutamate levels. The aim of this investigation was to observe brain GABA and glutamate concentrations and depressive symptom severity in association to lockdowns in patients with recurrent major depression disorder (rMDD) and healthy individuals (HI). In this longitudinal study, 18 patients with rMDD (11 female: 37.0 ± 10.0years) and 28 HI (16 female, 28.1 ± 5.0years) underwent three magnetic resonance spectroscopy imaging (MRSI) measurements over multiple lockdowns. Ratios of GABA+ (GABA + macromolecules) and glutamate + glutamine (Glx) to total creatinine (tCr) as well as GABA+/Glx ratios were calculated for subcortical regions and the insula. Depressive symptom severity and social support were assessed at each visit. Lockdowns did not significantly change neurotransmitter ratios in individual brain regions (all pcorrected > 0.05). Further, no significant changes in Beck's Depression Inventory II (BDI-II) scores occurred along the lockdowns (all pcorrected > 0.05). Our results may be explained by ceiling effects of the beginning of the pandemic and the first lockdown, by good social support during the pandemic in HI and a small sample size. Patients with rMDD reported an insufficient social support, suggesting a special vulnerability to social isolation due to pandemics.

Abstract Background Major threatening life events can impact the functionality of brain networks as revealed by neuroimaging studies [1]. The COVID-19 pandemic was an unprecedented global event that was associated with extensive restrictions to daily life. These measures greatly challenged the whole population including specific subgroups such as patients with depression. Here, we investigated the impact of pandemic-associated lockdowns on functional connectivity (FC) of major functional brain networks. Aims and objectives We hypothesized that there would be an effect of restriction measures on the default-mode network (DMN) and associated brain regions in patients with recurrent depression (rMDD) and healthy individuals (HI). Methods For each participant up to three MRI measurements were performed between September 2020 and June 2021, during different degrees of lockdown measures (before, during, and after). All subjects received a structural brain scan and three 7-minute single-shot gradient-recalled EPI measurements on a 3T Siemens Magnetom Prisma Scanner (with TE/TR = 30/2050ms, series length: 201 frames, matrix size 100x100x35)). An adapted version of the HCP minimal processing pipeline [2], along with ICA-AROMA and global signal regression for the removal of spatially diffuse noise was applied; denoised fMRI time- series were mapped to midthickness surfaces (CIFTI format) generated with FreeSurfer, and spatially smoothed with geodesic Gaussian kernels (σ = 1.75 mm). Subgenual anterior cingulate cortex (SgACC) FC was derived using a previously validated weight-map method that uses priors of sgACC FC from 1200 HCP subjects, to impute reliable sgACC FC estimates via a weighted average of sgACC correlated time- courses [3, 4]. Network-wise sgACC FC values were derived using the Glasser parcellation (360 bilateral parcels) [5] with a prior established network assignment based on a large data set of healthy subjects and a clustering algorithm that was calibrated upon its performance in well-delineated sensory-motor networks. The same parcellation scheme was used to derive within-network FC for all 12 functional networks [6]. Group differences and changes over time were assessed with linear mixed models (LMM). Results We analysed resting-state MRI data from 19 patients with rMDD (13 females, mean age 38 years (SD± 12.5) and 26 HIs (10 females, mean age 27.9 years (SD±5.3). LMMs revealed significant changes over time in the DMN (F=4.3, p>0.017), but no interaction effect of time*group (F1.99, p>0.1). Post-hoc tests revealed a significant decrease in FC in the DMN only between time point 2 and 3 (p=0.014, corrected for 3 post-hoc tests). SgACC weight-map FC analyses revealed widespread changes of the sgACC with other DMN nodes (i.e., 10 DMN parcels). Discussion and conclusion Analyses revealed changes in functional connectivity within the DMN, a brain network heavily implicated in MDD and associated with introspection and rumination [7]. The connectivity changes were most pronounced when comparing timepoints with hard and light lockdown measures. Further, we were able to confirm that the sgACC, a key DMN brain-region causally implicated in depression and stress-regulation [8] changed connectivity over time towards other DMN nodes. However, the data at hand represent preliminary findings. Future analyses should investigate how these changes might relate to psychological outcome. References 1. Bolsinger, J., et al., Neuroimaging Correlates of Resilience to Traumatic Events-A Comprehensive Review. Front Psychiatry, 2018. 9: p. 693. 2.Glasser, M.F., et al., The minimal preprocessing pipelines for the Human Connectome Project. Neuroimage, 2013. 80: p. 105-24. 3. Elbau, I.G., et al., Functional Connectivity Mapping for rTMS Target Selection in Depression. Am J Psychiatry, 2023. 180(3): p. 230-240. 4. Cash, R.F.H., et al., Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility. Hum Brain Mapp, 2021. 42(13): p. 4155-4172. 5. Glasser, M.F., et al., A multi-modal parcellation of human cerebral cortex. Nature, 2016. 536(7615): p. 171-178. 6.Ji, J.L., et al., Mapping the human brain's cortical-subcortical functional network organization. Neuroimage, 2019. 185: p. 35-57. 7.Sheline, Y.I., et al., The default mode network and self-referential processes in depression. Proceedings of the National Academy of Sciences, 2009. 106(6): p. 1942-1947. 8.Mayberg, H.S., et al., Deep brain stimulation for treatment-resistant depression. Neuron, 2005. 45(5): p. 651-60.

Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.

Seasonal changes in neurotransmitter systems have been demonstrated in imaging studies and are especially noticeable in diseased states such as seasonal affective disorder (SAD). These modulatory neurotransmitters, such as serotonin, are influencing glutamatergic and GABAergic neurotransmission. Furthermore, central components of the circadian pacemaker are regulated by GABA (the suprachiasmatic nucleus) or glutamate (e.g., the retinohypothalamic tract). Therefore, we explored seasonal differences in the GABAergic and glutamatergic system in 159 healthy individuals using magnetic resonance spectroscopy imaging with a GABA-edited 3D-MEGA-LASER sequence at 3T. We quantified GABA+/tCr, GABA+/Glx, and Glx/tCr ratios (GABA+, GABA+ macromolecules; Glx, glutamate + glutamine; tCr, total creatine) in five different subcortical brain regions. Differences between time periods throughout the year, seasonal patterns, and stationarity were tested using ANCOVA models, curve fitting approaches, and unit root and stationarity tests, respectively. Finally, Spearman correlation analyses between neurotransmitter ratios within each brain region and cumulated daylight and global radiation were performed. No seasonal or monthly differences, seasonal patterns, nor significant correlations could be shown in any region or ratio. Unit root and stationarity tests showed stable patterns of GABA+/tCr, GABA+/Glx, and Glx/tCr levels throughout the year, except for hippocampal Glx/tCr. Our results indicate that neurotransmitter levels of glutamate and GABA in healthy individuals are stable throughout the year. Hence, despite the important correction for age and gender in the analyses of MRS derived GABA and glutamate, a correction for seasonality in future studies does not seem necessary. Future investigations in SAD and other psychiatric patients will be of high interest.

Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT 1A ) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [ carbonyl - 11 C]WAY-100635 including arterial blood sampling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation ( n = 8 and n = 3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted of excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere, time, and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group, time, and HAMD on specific distribution volume (V S ) of 5-HT 1A receptor. While post-hoc comparisons showed no significant changes of 5-HT 1A receptor V S in either group, higher 5-HT 1A receptor V S after treatment correlated with greater difference in HAMD (r = −0.62). The results of this proof-of-concept trial hint towards potential effects of TBS on the distribution of the 5-HT 1A receptor. Due to the small sample size, all results must, however, be regarded with caution.

Background: Previous studies suggest that transcranial magnetic stimulation exerts antidepressant effects by altering functional connectivity (FC). However, knowledge about this mechanism is still limited. Here, we aimed to investigate the effect of bilateral sequential theta-burst stimulation (TBS) on FC in treatment-resistant depression (TRD) in a sham-controlled longitudinal study. Methods: TRD patients (n = 20) underwent a three-week treatment of intermittent TBS of the left and continuous TBS of the right dorsolateral prefrontal cortex (DLPFC). Upon this trial's premature termination, 15 patients had received active TBS and five patients sham stimulation. Resting-state functional magnetic resonance imaging was performed at baseline and after treatment. FC (left and right DLPFC) was estimated for each participant, followed by group statistics (T-tests). Furthermore, depression scores were analyzed (linear mixed models analysis) and tested for correlation with FC. Results: Both groups exhibited reductions of depression scores, however, there was no significant main effect of group, or group and time. Anticorrelations between DLPFC and the subgenual cingulate cortex (sgACC) were observed for baseline FC, corresponding to changes in depression severity. Treatment did not significantly change DLPFC-sgACC connectivity, but significantly reduced FC between the left stimulation target and bilateral anterior insula. Conclusions: Our data is compatible with previous reports on the relevance of anticorrelation between DLPFC and sgACC for treatment success. Furthermore, FC changes between left DLPFC and bilateral anterior insula highlight the effect of TBS on the salience network. Limitations: Due to the limited sample size, results should be interpreted with caution and are of exploratory nature.

Objectives: As clinical studies demonstrated that ketamine possesses rapid-acting antidepressant and antisuicidal effects, it is increasingly used in affective disorders. The neuroplastic properties of ketamine are well described in preclinical and imaging studies, and are highly related to its antidepressive mechanism of action.Methods: Here, we report on a female patient with recurrent major depression and borderline personality disorder (BPD) who was treated with intravenous (i.v.) esketamine as rapid-acting augmentation therapy to improve severe and acute depressive symptoms and suicidal behaviour.Results: Esketamine led to an initial improvement of these symptoms. However, during the course of treatment, loosened and disinhibited behaviour and severe suicidal ideation occurred during and immediately after esketamine application. Hence, i.v. esketamine was discontinued, and she further received treatment as usual, which demonstrated to be beneficial.Conclusions: With current knowledge at hand, one cannot exclude esketamine's effects on the equilibrium of neural plasticity in brain networks, potentially initiating undesirable symptoms as impulsive behaviour and emotional dysregulation. Therefore, until investigations focus on efficacy and side effects profile of esketamine in depressed patients with (comorbid) BPD, treatment with this fast-acting medication should be considered with caution in this patient group.

Background Neuroplastic processes are influenced by selective serotonergic reuptake inhibitors, while learning in conjunction with the administration of serotonergic agents alters white matter microstructure in humans. The goal of this double-blind, placebo-controlled imaging study was to investigate the influence of escitalopram on white matter plasticity during (re)learning. Methods Seventy-one healthy individuals (age = 25.6±5.0, 43 females) underwent 3 diffusion magnetic resonance imaging sessions: at baseline, after 3-weeks of associative learning (emotional/non-emotional content) and after relearning shuffled associations for an additional 3 weeks. During the relearning phase, subjects received daily escitalopram 10 mg or placebo orally. Data were analyzed using the FMRIB Software Library (FSL) and the implemented Tract-Based Spatial Statistics (TBSS) approach. Results The TBSS analysis revealed widespread decreases in fractional anisotropy metrics in subjects that received escitalopram. In addition, axial diffusivity decreases were mainly found in the corpus callosum and in areas within the internal capsule. In subjects receiving placebo, we did not find such effects, nor did our results show diffusivity changes related to learning or relearning. Conclusion Diffusivity changes were found within several tracts in the escitalopram group, while we observed no changes in the placebo group. Although previous studies examining the effects of SSRIs on white matter tracts in humans are underrepresented, our results suggest a relationship between serotonergic agents and diffusivity parameters. The findings of this study implicate that escitalopram may directly or indirectly impact white matter microstructures in healthy subjects. Nevertheless, we did not find a relationship between serotonergic modulation, neuroplastic effects and relearning.

Background:Serotonergic agents affect brain plasticity and reverse stress-induced dendritic atrophy in key fronto-limbic brain areas associated with learning and memory. Objectives:The aim of this study was to investigate effects of the antidepressant escitalopram on gray matter during relearning in healthy individuals to inform a model for depression and the neurobiological processes of recovery. Design:Randomized double blind placebo control, monocenter study. Methods:In all, 76 (44 females) healthy individuals performed daily an associative learning task with emotional or non-emotional content over a 3-week period. This was followed by a 3-week relearning period (randomly shuffled association within the content group) with concurrent daily selective serotonin reuptake inhibitor (i.e., 10 mg escitalopram) or placebo intake. Results:Via voxel-based morphometry and only in individuals that developed sufficient escitalopram blood levels over the 21-day relearing period, an increased density of the left dorsolateral prefrontal cortex was found. When investigating whether there was an interaction between relearning and drug intervention for all participants, regardless of escitalopram levels, no changes in gray matter were detected with either surfaced-based or voxel-based morphometry analyses. Conclusion:The left dorsolateral prefrontal cortex affects executive function and emotional processing, and is a critical mediator of symptoms and treatment outcomes of depression. In line, the findings suggest that escitalopram facilitates neuroplastic processes in this region if blood levels are sufficient. Contrary to our hypothesis, an effect of escitalopram on brain structure that is dependent of relearning content was not detected. However, this may have been a consequence of the intensity and duration of the interventions. Registration:ClinicalTrials.gov Identifier: NCT02753738; Trial Name: Enhancement of learning associated neural plasticity by Selective Serotonin Reuptake Inhibitors; URL: https://clinicaltrials.gov/ct2/show/NCT02753738.

Background: Theta burst stimulation (TBS) belongs to one of the biological antidepressant treatment options. When applied bilaterally, excitatory intermittent TBS (iTBS) is commonly targeted to the left and inhibitory continuous TBS (cTBS) to the right dorsolateral prefrontal cortex. TBS was shown to influence neurotransmitter systems, while iTBS is thought to interfere with glutamatergic circuits and cTBS to mediate GABAergic neurotransmission.Objectives: We aimed to expand insights into the therapeutic effects of TBS on the GABAergic and glutamatergic system utilizing 3D-multivoxel magnetic resonance spectroscopy imaging (MRSI) in combination with a novel surface-based MRSI analysis approach to investigate changes of cortical neurotransmitter levels in patients with treatment-resistant depression (TRD).Methods: Twelve TRD patients (five females, mean age ± SD = 35 ± 11 years) completed paired MRSI measurements, using a GABA-edited 3D-multivoxel MEGA-LASER sequence, before and after 3 weeks of bilateral TBS treatment. Changes in cortical distributions of GABA+/tNAA (GABA+macromolecules relative to total N-acetylaspartate) and Glx/tNAA (Glx = mixed signal of glutamate and glutamine), were investigated in a surface-based region-of-interest (ROI) analysis approach.Results: ANCOVAs revealed a significant increase in Glx/tNAA ratios in the left caudal middle frontal area (pcorr. = 0.046, F = 13.292), an area targeted by iTBS treatment. Whereas, contralateral treatment with cTBS evoked no alterations in glutamate or GABA concentrations.Conclusion: This study demonstrates surface-based adaptions in the stimulation area to the glutamate metabolism after excitatory iTBS but not after cTBS, using a novel surface-based analysis of 3D-MRSI data. The reported impact of facilitatory iTBS on glutamatergic neurotransmission provides further insight into the neurobiological effects of TBS in TRD.

An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character-German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.

Animal studies using selective serotonin reuptake inhibitors (SSRIs) and learning paradigms have demonstrated that serotonin is important for flexibility in executive functions and learning. SSRIs might facilitate relearning through neuroplastic processes and thus exert their clinical effects in psychiatric diseases where cognitive functioning is affected. However, translation of these mechanisms to humans is missing. In this randomized placebo-controlled trial, we assessed functional brain activation during learning and memory retrieval in healthy volunteers performing associative learning tasks aiming to translate facilitated relearning by SSRIs.To this extent, seventy-six participants underwent three MRI scanning sessions: (1) at baseline, (2) after three weeks of daily associative learning and subsequent retrieval (face-matching or Chinese character–noun matching) and (3) after three weeks of relearning under escitalopram (10 mg/day) or placebo. Associative learning and retrieval tasks were performed during each functional MRI (fMRI) session. Statistical modeling was done using a repeated-measures ANOVA, to test for content-by-treatment-by-time interaction effects.During the learning task, a significant substance-by-time interaction was found in the right insula showing a greater deactivation in the SSRI cohort after 21 days of relearning compared to the learning phase. In the retrieval task, there was a significant content-by-time interaction in the left angular gyrus (AG) with an increased activation in face-matching compared to Chinese-character matching for both learning and relearning phases. A further substance-by-time interaction was found in task performance after 21 days of relearning, indicating a greater decrease of performance in the placebo group.Our findings that escitalopram modulate insula activation demonstrates successful translation of relearning as a mechanism of SSRIs in human. Furthermore, we show that the left AG is an active component of correct memory retrieval, which coincides with previous literature. We extend the function of this region by demonstrating its activation is not only stimulus dependent but also time constrained. Finally, we were able to show that escitalopram aids in relearning, irrespective of content.

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.

Background: Selective serotonin reuptake inhibitors (SSRIs) are predominantly prescribed for people suffering from major depressive disorder. These antidepressants exert their effects by blocking the serotonin transporter (SERT), leading to increased levels of serotonin in the synaptic cleft and subsequently to an attenuation of depressive symptoms and elevation in mood. Although long-term studies investigating white matter (WM) alterations after exposure to antidepressant treatment exist, results on the acute effects on the brain's WM microstructure are lacking. Methods: In this interventional longitudinal study, 81 participants were included (33 patients and 48 healthy controls). All participants underwent diffusion weighted imaging on 2 separate days, receiving either citalopram or placebo using a randomized, double-blind, cross-over design. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated within the FMRIB software library and analyzed using tract-based spatial statistics. Results: The repeated-measures ANOVA model revealed significant decreases after SSRI administration in mean diffusivity, axial diffusivity, and radial diffusivity regardless of the group (P < .05, family-wise error [FWE] corrected). Results were predominantly evident in frontal WM regions comprising the anterior corona radiata, corpus callosum, and external capsule and in distinct areas of the frontal blade. No increases in diffusivity were found, and no changes in fractional anisotropy were present. Conclusions: Our investigation provides the first evidence, to our knowledge, that fast WM microstructure adaptations within 1 hour after i.v. SSRI administration precede elevations in mood due to SSRI treatment. These results add a new facet to the complex mode of action of antidepressant therapy.

Impaired cognitive flexibility represents a widespread symptom in psychiatric disorders, including major depressive disorder (MDD), a disease, characterized by an imbalance of neurotransmitter concentrations. While memory formation is mostly associated with glutamate, also gamma-Aminobutyric acid (GABA) and serotonin show attributions in a complex interplay between neurotransmitter systems. Treatment with selective serotonin reuptake inhibitors (SSRIs) does not solely affect the serotonergic system but shows downstream effects on GABA- and glutamatergic neurotransmission, potentially helping to restore cognitive function via neuroplastic effects. Hence, this study aims to elaborate the effects of associative relearning and SSRI treatment on GABAergic and glutamatergic function within and between five brain regions using magnetic resonance spectroscopy imaging (MRSI).In this study, healthy subjects were randomized into four groups which underwent three weeks of an associative relearning paradigm, with or without emotional connotation, under SSRI (10mg escitalopram) or placebo administration. MRSI measurements, using a spiral-encoded, 3D-GABA-edited MEGA-LASER sequence at 3T, were performed on the first and last day of relearning. Mean GABA+/tCr (GABA+ = GABA + macromolecules; tCr = total creatine) and Glx/tCr (Glx = glutamate + glutamine) ratios were quantified in a ROI-based approach for the hippocampus, insula, putamen, pallidum and thalamus, using LCModel. A total of 66 subjects ((37 female, mean age ± SD = 25.4±4.7) for Glx/tCr and 58 subjects (32 female, mean age ± SD = 25.1±4.7) for GABA+/tCr were included in the final analysis.A significant measurement by region and treatment (SSRI vs placebo) interaction on Glx/tCr ratios was found (pcor=0.017), with post hoc tests confirming differential effects on hippocampus and thalamus (pcor=0.046). Moreover, treatment by time comparison, for each ROI independently, showed a reduction of hippocampal Glx/tCr ratios after SSRI treatment (puncor=0.033). No significant treatment effects on GABA+/tCr ratios or effects of relearning condition on any neurotransmitter ratio could be found.Here, we showed a significant SSRI- and relearning-driven interaction effect of hippocampal and thalamic Glx/tCr levels, suggesting differential behavior based on different serotonin transporter and receptor densities. Moreover, an indication for Glx/tCr adaptions in the hippocampus after three weeks of SSRI treatment could be revealed. Our findings are in line with animal studies reporting glutamate adaptions in the hippocampus following chronic SSRI intake. Due to the complex interplay of serotonin and hippocampal function, involving multiple serotonin receptor subtypes on glutamatergic cells and GABAergic interneurons, the interpretation of underlying neurobiological actions remains challenging.