antidepressant

SSFN Webinar - Depression and antidepressants

Decoding ketamine: Neurobiological mechanisms underlying its rapid antidepressant efficacy

Unlike traditional monoamine-based antidepressants that require weeks to exert effects, ketamine alleviates depression within hours, though its clinical use is limited by side effects. While ketamine was initially thought to work primarily through NMDA receptor (NMDAR) inhibition, our research reveals a more complex mechanism. We demonstrate that NMDAR inhibition alone cannot explain ketamine's sustained antidepressant effects, as other NMDAR antagonists like MK-801 lack similar efficacy. Instead, the (2R,6R)-hydroxynorketamine (HNK) metabolite appears critical, exhibiting antidepressant effects without ketamine's side effects. Paradoxically, our findings suggest an inverted U-shaped dose-response relationship where excessive NMDAR inhibition may actually impede antidepressant efficacy, while some level of NMDAR activation is necessary. The antidepressant actions of ketamine and (2R,6R)-HNK require AMPA receptor activation, leading to synaptic potentiation and upregulation of AMPA receptor subunits GluA1 and GluA2. Furthermore, NMDAR subunit GluN2A appears necessary and possibly sufficient for these effects. This research establishes NMDAR-GluN2A activation as a common downstream effector for rapid-acting antidepressants, regardless of their initial targets, offering promising directions for developing next-generation antidepressants with improved efficacy and reduced side effects.

Influence of the context of administration in the antidepressant-like effects of the psychedelic 5-MeO-DMT

Psychedelics like psilocybin have shown rapid and long-lasting efficacy on depressive and anxiety symptoms. Other psychedelics with shorter half-lives, such as DMT and 5-MeO-DMT, have also shown promising preliminary outcomes in major depression, making them interesting candidates for clinical practice. Despite several promising clinical studies, the influence of the context on therapeutic responses or adverse effects remains poorly documented. To address this, we conducted preclinical studies evaluating the psychopharmacological profile of 5-MeO-DMT in contexts previously validated in mice as either pleasant (positive setting) or aversive (negative setting). Healthy C57BL/6J male mice received a single intraperitoneal (i.p.) injection of 5-MeO-DMT at doses of 0.5, 5, and 10 mg/kg, with assessments at 2 hours, 24 hours, and one week post-administration. In a corticosterone (CORT) mouse model of depression, 5-MeO-DMT was administered in different settings, and behavioral tests mimicking core symptoms of depression and anxiety were conducted. In CORT-exposed mice, an acute dose of 0.5 mg/kg administered in a neutral setting produced antidepressant-like effects at 24 hours, as observed by reduced immobility time in the Tail Suspension Test (TST). In a positive setting, the drug also reduced latency to first immobility and total immobility time in the TST. However, these beneficial effects were negated in a negative setting, where 5-MeO-DMT failed to produce antidepressant-like effects and instead elicited an anxiogenic response in the Elevated Plus Maze (EPM).Our results indicate a strong influence of setting on the psychopharmacological profile of 5-MeO-DMT. Future experiments will examine cortical markers of pre- and post-synaptic density to correlate neuroplasticity changes with the behavioral effects of 5-MeO-DMT in different settings.

Neuromodulation of subjective experience

Many psychoactive substances are used with the aim of altering experience, e.g. as analgesics, antidepressants or antipsychotics. These drugs act on specific receptor systems in the brain, including the opioid, serotonergic and dopaminergic systems. In this talk, I will summarise human drug studies targeting opioid receptors and their role for human experience, with focus on the experience of pain, stress, mood, and social connection. Opioids are only indicated for analgesia, due to their potential to cause addiction. When these regulations occurred, other known effects were relegated to side effects. This may be the cause of the prevalent myth that opioids are the most potent painkillers, despite evidence from head-to-head trials, Cochrane reviews and network meta-analyses that opioids are not superior to non-opioid analgesics in the treatment of acute or chronic non-cancer pain. However, due to the variability and diversity of opioid effects across contexts and experiences, some people under some circumstances may indeed benefit from prolonged treatment. I will present data on individual differences in opioid effects due to participant sex and stress induction. Understanding the effects of these commonly used medications on other aspects of the human experience is important to ensure correct use and to prevent unnecessary pain and addiction risk.

Use of brain imaging data to improve prescriptions of psychotropic drugs - Examples of ketamine in depression and antipsychotics in schizophrenia

The use of molecular imaging, particularly PET and SPECT, has significantly transformed the treatment of schizophrenia with antipsychotic drugs since the late 1980s. It has offered insights into the links between drug target engagement, clinical effects, and side effects. A therapeutic window for receptor occupancy is established for antipsychotics, yet there is a divergence of opinions regarding the importance of blood levels, with many downplaying their significance. As a result, the role of therapeutic drug monitoring (TDM) as a personalized therapy tool is often underrated. Since molecular imaging of antipsychotics has focused almost entirely on D2-like dopamine receptors and their potential to control positive symptoms, negative symptoms and cognitive deficits are hardly or not at all investigated. Alternative methods have been introduced, i.e. to investigate the correlation between approximated receptor occupancies from blood levels and cognitive measures. Within the domain of antidepressants, and specifically regarding ketamine's efficacy in depression treatment, there is limited comprehension of the association between plasma concentrations and target engagement. The measurement of AMPA receptors in the human brain has added a new level of comprehension regarding ketamine's antidepressant effects. To ensure precise prescription of psychotropic drugs, it is vital to have a nuanced understanding of how molecular and clinical effects interact. Clinician scientists are assigned with the task of integrating these indispensable pharmacological insights into practice, thereby ensuring a rational and effective approach to the treatment of mental health disorders, signaling a new era of personalized drug therapy mechanisms that promote neuronal plasticity not only under pathological conditions, but also in the healthy aging brain.

From pecking order to ketamine - neural mechanism of social and emotional behavior

Emotions and social interactions color our lives and shape our behaviors. Using animal models and engineered manipulations, we aim to understand how social and emotional behaviors are encoded in the brain, focusing on the neural circuits underlying dominance hierarchy and depression. This lecture will highlight our recent discoveries on how downward social mobility leads to depression; how ketamine tames depression by blocking burst firing in the brain’s antireward center; and, how glia-neuron interaction plays a surprising role in this process. I will also present our recent work on the mechanism underlying the sustained antidepressant activity of ketamine and its brain region specificity. With these results, we hope to illuminate on a more unified theory on ketamine’s mode of action and inspire new treatment strategies for depression.

From pecking order to ketamine - neural mechanism of social and emotional behavior

Emotions and social interactions color our lives and shape our behaviors. Using animal models and engineered manipulations, we aim to understand how social and emotional behaviors are encoded in the brain, focusing on the neural circuits underlying dominance hierarchy and depression. This lecture will highlight our recent discoveries on how downward social mobility leads to depression; how ketamine tames depression by blocking burst firing in the brain’s antireward center; and, how glia-neuron interaction plays a surprising role in this process. I will also present our recent work on the mechanism underlying the sustained antidepressant activity of ketamine and its brain region specificity. With these results, we hope to illuminate on a more unified theory on ketamine’s mode of action and inspire new treatment strategies for depression.

Ebselen: a lithium-mimetic without lithium side-effects?

Development of new medications for mental health conditions is a pressing need given the high proportion of people not responding to available treatments. We hope that presenting ebselen to a wider audience will inspire further studies on this promising agent with a benign side-effects profile. Laboratory research, animal research and human studies suggest that ebselen shares many features with the mood stabilising drug lithium, creating a promise of a drug that would have a similar clinical effect but without lithium’s troublesome side-effect profile and toxicity. Both drugs have a common biological target, inositol monophosphatase, whose inhibition is thought key to lithium’s therapeutic effect. Both drugs have neuroprotective action and reduce oxidative stress. In animal studies, ebselen affected neurotransmitters involved in the development of mental health symptoms, and in particular, produced effects of serotonin function very similar to lithium. Both ebselen and lithium share behavioural effects: antidepressant-like effects in rodent models of depression and decrease in behavioural impulsivity, a property associated with lithium's anti-suicidal action. Human neuropsychological studies support an antidepressant profile for ebselen based on its positive impact on emotional processing and reward seeking. Our group currently is exploring ebselen’s effects in patients with mood disorders. A completed ‘add-on’ clinical trial in mania showed ebselen’s superiority over placebo after three weeks of treatment. Our ongoing experimental research explores ebselen’s antidepressant profile in patients with treatment resistant depression. If successful, this will lead to a clinical trial of ebselen as an antidepressant augmentation agent, similar to lithium.

Astroglial modulation of the antidepressant action of deep brain and bright light stimulation

Even if major depression is now the most common of psychiatric disorders, successful antidepressant treatments are still difficult to achieve. Therefore, a better understanding of the mechanisms of action of current antidepressant treatments is needed to ultimately identify new targets and enhance beneficial effects. Given the intimate relationships between astrocytes and neurons at synapses and the ability of astrocytes to "sense" neuronal communication and release gliotransmitters, an attractive hypothesis is emerging stating that the effects of antidepressants on brain function could be, at least in part, modulated by direct influences of astrocytes on neuronal networks. We will present two preclinical studies revealing a permissive role of glia in the antidepressant response: i) Control of the antidepressant-like effects of rat prefrontal cortex Deep Brain Stimulation (DBS) by astroglia, ii) Modulation of antidepressant efficacy of Bright Light Stimulation (BLS) by lateral habenula astroglia. Therefore, it is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant efficacy of DBS or BLS. Collectively, these results pave also the way to the development of safer and more effective antidepressant strategies.

Neuronal plasticity and neurotrophin signaling as the common mechanism for antidepressant effect

Neuronal plasticity has for a long time been considered important for the recovery from depression and for the antidepressant drug action, but how the drug action is translated to plasticity has remained unclear. Brain-derived neurotrophic factor (BDNF) and its receptor TRKB are critical regulators of neuronal plasticity and have been implicated in the antidepressant action. We have recently found that many, if not all, different antidepressants, including serotonin selective SSRIs, tricyclic as well as fast-acting ketamine, directly bind to TRKB, thereby promoting TRKB translocation to synaptic membranes, which increases BDNF signaling. We have previously shown that antidepressant treatment induces a juvenile-like state of activity in the cortex that facilitates beneficial rewiring of abnormal networks. We recently showed that activation of TRKB receptors in parvalbumin-containing interneurons orchestrates cortical activation states and is both necessary and sufficient for the antidepressantinduced cortical plasticity. Our findings open a new framework how the action of antidepressants act: rather than regulating brain monoamine concentrations, antidepressants directly bind to TRKB and allosterically promote BDNF signaling, thereby inducing a state of plasticity that allows re-wiring of abnormal networks for better functionality.

Modelling affective biases in rodents: behavioural and computational approaches

My research focuses, broadly speaking, on how emotions impact decision making. Specifically, I am interested in affective biases, a phenomenon known to be important in depression. Using a rodent decision-making task, combined with computational modelling I have investigated how different antidepressant and pro-depressant manipulations that are known to alter mood in humans alter judgement bias, and provided insight into the decision processes that underlie these behaviours. I will also highlight how the combination of behaviour and modelling can provide a truly translation approach, enabling comparison and interpretation of the same cognitive processes between animal and human research.

Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by amyloid-β (1-42) oligomers in mice: implication of transforming growth factor-β1 and oxidative stress

A long-term treatment with antidepressants reduces the risk to develop AD and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently studied for their neuroprotective properties in AD. An impairment of neurotrophic factors signaling seems to be a common pathophysiological event in depression and AD. In particular a deficit of transforming growth factor-β1 (TGF-β1) and increased oxidative stress have been found both in depression and AD. In the present work the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype in a non-transgenic mouse model of AD (i.c.v. Aβ1-42 injection) by rescue of TGF-β1 signaling. The same drugs were also tested for their ability to modulate the expression of pro-oxidant genes as well as of genes related to the antioxidant machinery.

The anxiolytic and antidepressant effects of urocortin 2 and urocortin 3 fragments in mice

Differentially methylated regions in antidepressant response- a methylome-wide association study from the EMC trial

Intranasal Delivery of Galanin 2 and Neuropeptide Y1 Agonists Enhanced Spatial Memory Performance and antidepressant effects through Neuronal Precursor Cells Proliferation in the hippocampus

Novel insights into antidepressant-induced TrkB signaling

Exploring the effects of psilocybin and ketamine (novel antidepressants) on the electroencephalogram (EEG) of C57BL/6 mice: A comparative analysis

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M1 acetylcholine receptor in somatostatin interneurons mediates cortical excitation/inhibition balance and antidepressant responses

Altered circadian clock gene expression in the mPFC of mouse model of depression and its modulation by rapid antidepressant treatments

Antidepressant actions of ketamine engage cellular mechanisms of endoplasmic reticulum stress by the eIF2α pathway

Antidepressant-like effect of long-term systemic administration of irisin in young mice

Antidepressant-like effects of the iron chelator deferiprone in a mouse model of depression

Cannabidiol as an add-on therapy to overcome the slow-onset and – possibly – resistance to antidepressant treatment: involvement of NAPE-PLD in the medial prefrontal cortex

Comparing the antidepressant-like effects and neurochemical correlates of desipramine in male and female adult rats

Comparing the antidepressant-like efficacy of ketamine, cannabidiol and fluoxetine in male and female adolescent rats

The effect of sex and age on the antidepressant- and anxiolytic-like activity of HBK-15 in mice

Effect of antidepressant mirtazapine intake during gestation on the excitability of hippocampal neurons observed in the offspring

Sex as a factor in mice paradigms modeling aspects of depressive behavior: differential responses to antidepressant drugs with SERT and DAT blocker profiles

Galanin(1-15) enhanced the antidepressant-like effects of Escitalopram in the olfactory bulbectomy rats in the forced swimming test through 5-HT1A receptors

Glutamatergic and cytoskeletal protein phosphorylation associated with the antidepressant-like properties of the iron chelator deferiprone in a mouse model of depression

Hippocampus proteomics profiling of major depression and antidepressant treatment reveals pathways involved in cell proliferation, differentiation and connectivity

The interaction between antidepressants and environment determines treatment outcome in a preclinical model of adolescence-onset depression

miR-135 as a New Target for Antidepressant Therapy: Preclinical Study

Multidimensional predictors of antidepressant response: using computational approaches to integrate biological networks, environmental factors and clinical outcomes

A novel endocannabinoid hydrolase FAAH inhibitor as a potential antidepressant induces gene expression changes in nucleus accumbens in a BALB/c mice acute stress model

Pre-gestational stress and perinatal treatment with antidepressants in rats affect levels of synapse-related proteins in hippocampus of adult offspring in a sex-dependent manner

A primate subcallosal cingulate area 25 network fractionates anhedonia, anxiety and rapid antidepressant response

The procognitive but not antidepressant-like effect of HBK-15 requires BDNF in the unpredictable chronic mild stress in mice

Response eQTL of GPR56 expression are associated with antidepressant response

Role of adult hippocampal neurogenesis in the antidepressant effects of lactate

A secondary metabolite of Umbilicaria hirsuta, gyrophoric acid, increases hippocampal neurogenesis and shows antidepressant effects in related forms of behavior

A specific GPR56/ADGRG1 splicing isoform to monitor response to antidepressant treatment in patient with major depressive disorder: a digital PCR assay

Sphingomyelin synthases in depression and antidepressant treatment

The Unpredictable chronic mild stress paradigm as a model of individual variability of antidepressant response

Antidepressant-like effect of curcumin in olfactory bulbectomized model of depression in male Wistar albino rats: Antidepressant behavior screening tests

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The antidepressant effect of Bifidobacterium adolescentis NGB329 postbiotic in rat model of depression

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Antidepressant-like effects of psychedelics in a chronic despair mouse model: Is the 5-HT2A receptor the unique player?

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Assessing the therapeutic potential of antidepressant and anti-inflammatory drugs in an inflamed depression mouse model: A comparative study of efficacy

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Behavioural control training promotes antidepressant/anxiolytic-like reversal of chronic stress-induced behavioural deficits: Endocannabinoidergic and prolactinergic mechanisms

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Chemogenetic stimulation of the prefrontal cortex exerts antidepressant effect in a mouse model of depression

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Cortical miR-16 involvement in the antidepressant effects of pharmacological elevation of anandamide in a rat model for depression

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Differences between first- and second-generation antidepressants and modulation of affective biases in Lister Hooded rats

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