Vortioxetine Reduces Marble Burying but Only Transiently Enhances Social Interaction Preference in Adult Male BTBR TItpr3/J Mice.

Vortioxetine is a multimodal antidepressant with agonist activity at serotonin (5-HT) and 5-HT receptors that blocks the 5-HT transporter (SERT). Previously in male BTBR TItpr3/J (BTBR) mice, the 5-HT partial agonist buspirone and SERT blocker fluoxetine enhanced social interaction but did not reduce marble burying. We hypothesized that vortioxetine through its actions at SERT and 5-HT could improve BTBR sociability and via 5-HT could reduce burying better than sertraline, a selective SERT blocker.

Frontal cortex dysfunction as a target for remediation in opiate use disorder: Role in cognitive dysfunction and disordered reward systems.

In this chapter, we develop a model of μ- and δ-opioid receptor (OR) effects on cellular activity in the corticostriatal circuit after reviewing clinical data on cognitive and mood impairments in opioid substance use disorder (OUD), we use this model to derive information on the relevance of opioid actions in this circuit for cognition and reward. We find that the cognitive impairments and rewarding properties of acute μ-OR activation can reasonably explained by pharmacological actions in the corticostriatal circuit. However, long-term cognitive impairments and mood dysfunction observed in OUD are probably induced by opiate abuse-related degenerative mechanisms.

Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity.

Attention impairment is a common feature of Major Depressive Disorder (MDD), and MDD-associated cognitive dysfunction may play an important role in determining functional status among this patient population. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in MDD patients, and may indirectly increase glutamate neurotransmission in brain regions classically associated with attention function. Previous non-clinical research suggests that vortioxetine has limited effects on attention.

Vortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism.

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity.

Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission.

Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation.

The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT receptor expressing interneurons: An in vitro study in rat hippocampus slices.

The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT receptor agonism, 5-HT receptor partial agonism, 5-HT, 5-HT, 5-HT receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine's functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods.

Impact of Vortioxetine on Synaptic Integration in Prefrontal-Subcortical Circuits: Comparisons with Escitalopram.

Prefrontal-subcortical circuits support executive functions which often become dysfunctional in psychiatric disorders. Vortioxetine is a multimodal antidepressant that is currently used in the clinic to treat major depressive disorder. Mechanisms of action of vortioxetine include serotonin (5-HT) transporter blockade, 5-HT receptor agonism, 5-HT receptor partial agonism, and 5-HT, 5-HT, and 5-HT receptor antagonism.

Acute effects of vortioxetine and duloxetine on resting-state functional connectivity in the awake rat.

The antidepressant vortioxetine exerts its effects via modulation of several serotonin (5-HT) receptors and inhibition of the 5-HT transporter (SERT). Additionally, vortioxetine has beneficial effects on aspects of cognitive dysfunction in depressed patients. However, a global examination of the drug effect on brain network connectivity is still missing.

A study of time- and sex-dependent effects of vortioxetine on rat sexual behavior: Possible roles of direct receptor modulation.

Treatment-related sexual dysfunction is a common side effect of antidepressants and contributes to patient non-compliance or treatment cessation. However, the multimodal antidepressant, vortioxetine, demonstrates low sexual side effects in depressed patients. To investigate the mechanisms involved, sexual behavior was assessed in male and female rats after acute, and repeated (7 and 14 days) treatment with vortioxetine, flesinoxan (a 5-HT receptor agonist), CP-94253 (a 5-HT receptor agonist), or ondansetron (a 5-HT receptor antagonist).

Serotonin Transporter-Independent Actions of the Antidepressant Vortioxetine As Revealed Using the SERT Met172 Mouse.

Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets.

Chronic vortioxetine treatment in rodents modulates gene expression of neurodevelopmental and plasticity markers.

The multimodal antidepressant vortioxetine displays an antidepressant profile distinct from those of conventional selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and possesses cognitive-enhancing properties in preclinical and clinical studies. Recent studies have begun to investigate molecular mechanisms that may differentiate vortioxetine from other antidepressants. Acute studies in adult rats and chronic studies in a middle-aged mouse model reveal upregulation of several markers that play a central role in synaptic plasticity.

In vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity.

Neuroplasticity is fundamental for brain functions, abnormal changes of which are associated with mood disorders and cognitive impairment. Neuroplasticity can be affected by neuroactive medications and by aging. Vortioxetine, a multimodal antidepressant, has shown positive effects on cognitive functions in both pre-clinical and clinical studies.

Discriminative stimulus properties of 1.25mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors.

The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects.

Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats.

Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission.

Histamine may contribute to vortioxetine's procognitive effects; possibly through an orexigenic mechanism.

Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5-HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical studies vortioxetine demonstrates positive effects on cognitive dysfunction. Vortioxetine's effect on cognitive function likely involves the modulation of several neurotransmitter systems.

Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function.

The hippocampus plays an important role in emotional and cognitive processing, and both of these domains are affected in patients with major depressive disorder (MDD). Extensive preclinical research and the notion that modulation of serotonin (5-HT) neurotransmission plays a key role in the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) support the view that 5-HT is important for hippocampal function in normal and disease-like conditions. The hippocampus is densely innervated by serotonergic fibers, and the majority of 5-HT receptor subtypes are expressed there.

A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)'s putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression.

Major depressive disorder (MDD) is primarily conceptualized as a mood disorder but cognitive dysfunction is also prevalent, and may limit the daily function of MDD patients. Current theories on MDD highlight disturbances in dendritic plasticity in its pathophysiology, which could conceivably play a role in the production of both MDD-related mood and cognitive symptoms. This paper attempts to review the accumulated knowledge on the basic biology of the activity-regulated cytoskeleton-associated protein (Arc or Arg3.

Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission.

Previous work from this laboratory hypothesized that the multimodal antidepressant vortioxetine enhances cognitive function through a complex mechanism, using serotonergic (5-hydroxytryptamine, 5-HT) receptor actions to modulate gamma-butyric acid (GABA) and glutamate neurotransmission in key brain regions like the prefrontal cortex (PFC) and hippocampus. However, serotonergic receptors have circumscribed expression patterns, and therefore vortioxetine's effects on GABA and glutamate neurotransmission will probably be regionally selective. In this article, we attempt to develop a conceptual framework in which the effects of 5-HT, selective serotonin reuptake inhibitors (SSRIs), and vortioxetine on GABA and glutamate neurotransmission can be understood in the PFC and striatum-2 regions with roles in cognition and substantially different 5-HT receptor expression patterns.

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism.

Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine.

The antidepressant drugs fluoxetine and duloxetine produce anxiolytic-like effects in a schedule-induced polydipsia paradigm in rats: enhancement of fluoxetine's effects by the α2 adrenoceptor antagonist yohimbine.

Similar to the time-course for treating depression, several weeks of administration are required for serotonin (5-HT) reuptake inhibitors to produce anxiolytic effects. Previous studies with the schedule-induced polydipsia paradigm (a putative preclinical anxiety model) have shown that repeated administration of antidepressant drugs is necessary to produce a suppression of polydipsia, which is interpreted as an anxiolytic-like effect. The present study sought to expand past findings by evaluating the selective 5-HT reuptake inhibitor (SSRI) fluoxetine and the 5-HT-norepinephrine reuptake inhibitor duloxetine in the schedule-induced polydipsia paradigm with rats.

Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice.

Cognitive decline occurs during healthy aging, even in middle-aged subjects, via mechanisms that could include reduced stem cell proliferation, changed growth factor expression and/or reduced expression of synaptic plasticity genes. Although antidepressants alter these mechanisms in young rodents, their effects in older animals are unclear. In middle-aged mice, we examined the effects of a selective serotonin reuptake inhibitor (fluoxetine) and a multimodal antidepressant (vortioxetine) on cognitive and affective behaviors, brain stem cell proliferation, growth factor and gene expression.

Serotonergic Regulation of Prefrontal Cortical Circuitries Involved in Cognitive Processing: A Review of Individual 5-HT Receptor Mechanisms and Concerted Effects of 5-HT Receptors Exemplified by the Multimodal Antidepressant Vortioxetine.

It has been known for several decades that serotonergic neurotransmission is a key regulator of cognitive function, mood, and sleep. Yet with the relatively recent discoveries of novel serotonin (5-HT) receptor subtypes, as well as an expanding knowledge of their expression level in certain brain regions and localization on certain cell types, their involvement in cognitive processes is still emerging. Of particular interest are cognitive processes impacted in neuropsychiatric and neurodegenerative disorders.

Altered γ-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants.

Evidence suggesting that central nervous system γ-aminobutyric acid (GABA) concentrations are reduced in patients with major depressive disorder (MDD) has been present since at least 1980, and this idea has recently gained support from more recent magnetic resonance spectroscopy data. These observations have led to the assumption that MDD's underlying etiology is tied to an overall reduction in GABA-mediated inhibitory neurotransmission. In this paper, we review the mechanisms that govern GABA and glutamate concentrations in the brain, and provide a comprehensive and critical evaluation of the clinical data supporting reduced GABA neurotransmission in MDD.

Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory.

Depression is frequently associated with cognitive disturbances. Vortioxetine is a multimodal acting antidepressant that functions as a 5-HT3 and 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter. Given its pharmacological profile, the present study was undertaken to determine whether vortioxetine could modulate several preclinical parameters known to be involved in cognitive processing.