Stress, depression, and neuroplasticity: a convergence of mechanisms.

Increasing evidence demonstrates that neuroplasticity, a fundamental mechanism of neuronal adaptation, is disrupted in mood disorders and in animal models of stress. Here we provide an overview of the evidence that chronic stress, which can precipitate or exacerbate depression, disrupts neuroplasticity, while antidepressant treatment produces opposing effects and can enhance neuroplasticity. We discuss neuroplasticity at different levels: structural plasticity (such as plastic changes in spine and dendrite morphology as well as adult neurogenesis), functional synaptic plasticity, and the molecular and cellular mechanisms accompanying such changes. Together, these studies elucidate mechanisms that may contribute to the pathophysiology of depression. Greater appreciation of the convergence of mechanisms between stress, depression, and neuroplasticity is likely to lead to the identification of novel targets for more efficacious treatments.     

Preclinical discovery of duloxetine for the treatment of depression

INTRODUCTION: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases are associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several new antidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD. AREAS COVERED: The article reviews and discusses the biochemical and functional profile of duloxetine splitting the review into acute and long-term treatment with this dual monoamine reuptake inhibitor. In addition, the authors summarize available preclinical behavioral research data, which have demonstrated among other effects, the antidepressant-like activity of duloxetine in several animal models. The authors focus on the most recent literature on synaptic neuroplasticity modulation of this antidepressant drug. Finally, the authors briefly mention other approved indications of duloxetine. EXPERT OPINION: Duloxetine inhibits 5-HT and NA reuptake, effectively desensitizes various autoreceptors and promotes neuroplasticity. Clinically, duloxetine is an effective antidepressant that is well tolerated and has significant efficacy in the treatment of MDD.     

Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders

Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way 'involved' in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Preclinical discovery of duloxetine for the treatment of depression

Introduction: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases are associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several new antidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD.

Areas covered: The article reviews and discusses the biochemical and functional profile of duloxetine splitting the review into acute and long-term treatment with this dual monoamine reuptake inhibitor. In addition, the authors summarize available preclinical behavioral research data, which have demonstrated among other effects, the antidepressant-like activity of duloxetine in several animal models. The authors focus on the most recent literature on synaptic neuroplasticity modulation of this antidepressant drug. Finally, the authors briefly mention other approved indications of duloxetine.

Expert opinion: Duloxetine inhibits 5-HT and NA reuptake, effectively desensitizes various autoreceptors and promotes neuroplasticity. Clinically, duloxetine is an effective antidepressant that is well tolerated and has significant efficacy in the treatment of MDD.     

Neurotrophins Role in Depression Neurobiology: A Review of Basic and Clinical Evidence

Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially in developed countries. Research has devoted much of its attention to this problematic and many drugs have been developed and are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs, which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even in the cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment and remission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapy present a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets, besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated with several structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophic factor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronal atrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed in depressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatment enhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here we review some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiological mechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis.     

新型抗抑郁药物的研究进展

近年来对抑郁症发病机制和药物治疗靶标的研究取得了很大进展,围绕神经可塑性、神经发生、下丘脑-垂体-肾上腺(HPA)轴等后续神经系统适应性改变以及免疫系统变化,确定了谷氨酸受体、神经肽受体、糖皮质激素受体、褪黑激素受体和细胞因子受体等抗抑郁药物作用的新靶标。目前,已发现大量具有抗抑郁作用的新化合物,褪黑激素受体激动剂阿戈美拉丁、促肾上腺皮质激素释放激素受体拮抗剂喹硫平已经上市,神经激肽2受体拮抗剂沙瑞度坦、糖皮质激素受体拮抗剂米非司酮正在进行Ⅲ期临床研究,10余个药物进入临床研究阶段。本文对近5年新型抗抑郁药物的研究进展进行简要综述。     

Dual effects of bryostatin-1 on spatial memory and depression

Dementia and depression are clinical symptoms commonly associated in patients. Emerging evidence suggests that the two diseases share many profiles in their development and underlying neural/molecular mechanisms. Thus, interest is raised in developing new classes of antidepressant agents with activity of cognitive enhancement. Here, we show that bryostatin-1, a protein kinase C substrate activator, at bilateral intracerebroventricular doses of 0.64 or 2 pmol/site, significantly enhanced learning and memory of rats in a spatial water maze task. When applied at the doses at which it exhibits memory-enhancing activity, bryostatin-1 showed a significant antidepressant activity, as determined in an open space swim test. Both effects were not observed when a smaller dose was administered and were largely eliminated by co-administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), a protein kinase C inhibitor. These results support the hypothesis that memory processing and mood regulation share common neural mechanisms. Restoring impaired mood regulation with antidepressant agents that also exhibit memory-enhancing activity may represent one of the new strategies in the fight against depression associated with memory impairments.     

Neurobiological and clinical effects of the antidepressant tianeptine

The precise neurobiological processes involved in depression are not clear, but it is recognized that numerous factors are involved, including changes in neurotransmitter systems and brain plasticity. Neuroplasticity refers to the ability of the brain to adapt functionally and structurally to stimuli. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, learning, memory and emotions are altered in depression. The mechanisms underlying alterations in neuroplasticity are believed to relate to changes in neurotransmitters, hormones and growth factors. Structural changes in the hippocampus that have been proposed to be associated with depression include dendritic atrophy, reduced levels of cerebral metabolites, decreased adult neurogenesis (generation of new nerve cells) and reduced volume. Increased dendritic branching occurs in the basolateral nucleus of the amygdala. Reduced neuronal size and glial cell density occur in the prefrontal cortex. Clinically, tianeptine is an antidepressant effective in reducing symptoms of depression in mild to moderate-to-severe major depression, including over the long term. Tianeptine is also effective in alleviating the symptoms of depression-associated anxiety. It is generally well tolerated, with little sedation or cognitive impairment. The efficacy profile of tianeptine could be explained by its neurobiological properties observed in animal models. Tianeptine prevents or reverses stress-associated structural and cellular changes in the brain and normalizes disrupted glutamatergic neurotransmission. In particular, in the hippocampus, it prevents stress-induced dendritic atrophy, improves neurogenesis, reduces apoptosis and normalizes metabolite levels and hippocampal volume. Tianeptine also has beneficial effects in the amygdala and cortex and can reverse the effects of stress on neuronal and synaptic functioning. The neurobiological properties of tianeptine may provide an explanation not only for its antidepressant activity, but also for its anxiolytic effects in depressed patients and its lack of adverse effects on cognitive function and memory.     

Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited

INTRODUCTION: Major depression is one of the most prevalent forms of mental illnesses and is among the leading causes of disability, affecting about 121 million people worldwide. Approximately 30% of patients fail to respond to present therapies. Therefore, the search for novel antidepressant drugs continues. AREAS COVERED: The most prescribed antidepressants are serotonin reuptake inhibitors and/or noradrenaline reuptake inhibitors, which only indirectly affect dopaminergic neurotransmission. As a consequence, residual symptoms remain, including impaired motivation and impaired pleasure. This article reviews the development of new broad-spectrum antidepressants, the triple reuptake inhibitors, which also increase brain dopamine levels. EXPERT OPINION: In this review, a distinction is made between the subtypes of melancholic and atypical depressions and their associated brain abnormalities and dysfunctions in neurotransmitter systems. Subsequently, we propose a hypothetical model: 'the monoamine hypothesis revisited' to predict what kind of pharmacological treatment will be effective in the different subtypes of depression. It is expected that the triple reuptake inhibitors, inhibiting the reuptake of all three monoamines, can produce a greater efficacy than traditional antidepressants especially in atypical depression. Since triple reuptake inhibitors may also dampen states of hyperglutamatergic activity and subsequent excitotoxicity, it is suggested that these new drugs have a considerable neuroprotective potential in major depression, especially in melancholic depression.     

Recent progress in pharmacological and non-pharmacological treatment options of major depression

In spite of recent progress in the pharmacotherapy of depression major issues are still unresolved. These include the non-response rate of approximately 30% to conventional antidepressant pharmacotherapy, side effects of available antidepressants and the latency of several weeks until clinical improvement. The only non-pharmacological biological treatment options available so far which exert more rapid antidepressant efficacy are electroconvulsive therapy and, as an augmentation strategy, sleep deprivation. Current pharmacological treatments aim to enhance serotonergic and/or noradrenergic neurotransmission. In spite of emerging knowledge, the crucial mechanisms underlying both non-pharmacological treatments, which are responsible for antidepressant efficacy, are not yet clear so far. In the meantime several new pharmacological principles are under investigation with regard to their putative antidepressant potency. These include 5-HT1A receptor agonists, tachykinin receptor antagonists and various interventions within the hypothalamic-pituitary-adrenal system. While there is evidence for antidepressant properties of these new treatments in animal studies, in case series, in open studies and to some degree also in placebo controlled studies, no definite proof for the antidepressant efficacy of these new pharmacological strategies according to the requirements for evaluation of antidepressant drugs has been furnished so far. In contrast, for the established non-pharmacological treatment strategies including bright light therapy the clinical efficacy has been proven at least in subgroups of depression, but more knowledge of the main mechanisms underlying their antidepressant efficacy is still necessary. In addition new non-pharmacological treatments like repetitive transcranial magnetic stimulation, magnetic seizure therapy and Vagus nerve stimulation are currently under development. Nevertheless, a follow-up of both the new pharmacological strategies and non-pharmacological treatment options is of major importance to provide even better strategies for the clinical management of depression, which also is of great socio-economic impact.     

Rapid-acting antidepressants and the circadian clock

A growing number of epidemiological and experimental studies has established that circadian disruption is strongly associated with psychiatric disorders, including major depressive disorder (MDD). This association is becoming increasingly relevant considering that modern lifestyles, social zeitgebers (time cues) and genetic variants contribute to disrupting circadian rhythms that may lead to psychiatric disorders. Circadian abnormalities associated with MDD include dysregulated rhythms of sleep, temperature, hormonal secretions, and mood which are modulated by the molecular clock. Rapid-acting antidepressants such as subanesthetic ketamine and sleep deprivation therapy can improve symptoms within 24 h in a subset of depressed patients, in striking contrast to conventional treatments, which generally require weeks for a full clinical response. Importantly, animal data show that sleep deprivation and ketamine have overlapping effects on clock gene expression. Furthermore, emerging data implicate the circadian system as a critical component involved in rapid antidepressant responses via several intracellular signaling pathways such as GSK3β, mTOR, MAPK, and NOTCH to initiate synaptic plasticity. Future research on the relationship between depression and the circadian clock may contribute to the development of novel therapeutic strategies for depression-like symptoms. In this review we summarize recent evidence describing: (1) how the circadian clock is implicated in depression, (2) how clock genes may contribute to fast-acting antidepressants, and (3) the mechanistic links between the clock genes driving circadian rhythms and neuroplasticity.Subject terms: Neuroscience, Circadian rhythms and sleep     

New approaches to developing antidepressants by enhancing monoaminergic neurotransmission

Major depressive disorder (MDD) is a serious illness with far reaching societal and economic ramifications. The monoamine-deficiency hypothesis that depressive symptoms are associated with reductions in monoamine neurotransmission, particularly serotonin and noradrenaline, is supported by both neurochemical findings and the successful treatment of MDD with compounds that enhance monoaminergic neurotransmission. This review focuses on novel compounds in different stages of development for the treatment of MDD that enhance monoaminergic neurotransmission via a number of different mechanisms, including re-uptake inhibition of one or more monoamines, monoamine oxidase inhibitors, the combination of monoamine antagonists with re-uptake inhibitors and monoamine receptor subtype agonists. Compounds that enhance individual monoamines have antidepressant properties and compounds that enhance multiple monoamines appear to have a synergistic antidepressant effect and potentially faster onset of action. The differing mechanisms of action possessed by these novel monoamine-enhancing compounds will offer greater treatment flexibility in the therapeutic management of MDD.     

Microdialysis and the neurochemistry of addiction

Drug addiction is a process beginning with the initial exposure to a drug of abuse, and leading, in some individuals, to chronic habitual use, and high rates of relapse. Microdialysis allows researchers to monitor the neurochemical changes that occur in the brain after the initial exposure to a drug, and the neurochemical changes that occur with repeated exposure. These changes in the brain are often referred to as drug-induced neuroplasticity, and the aim of this article is to review studies that have utilized microdialysis to increase our understanding of the neuroplasticity that occurs in the process of addiction. We will review how several neurotransmitter systems, including glutamate, GABA, the monoamines, and others, are altered after chronic drug exposure, and how microdialysis can be used to determine if putative treatments for addiction can reverse the drug-induced neuroplasticity in these systems. We will also briefly discuss our recent research using a known change in GABA neurotransmission that occurs during reinstatement of drug-seeking to screen for possible novel treatments to prevent relapse. Overall, microdialysis in combination with other behavioral and pharmacological techniques has greatly increased our understanding of addiction-related neuroplasticity, and provides a means for discovering new ways to prevent these changes and treat addiction.     

Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited

Introduction: Major depression is one of the most prevalent forms of mental illnesses and is among the leading causes of disability, affecting about 121 million people worldwide. Approximately 30% of patients fail to respond to present therapies. Therefore, the search for novel antidepressant drugs continues.

Areas covered: The most prescribed antidepressants are serotonin reuptake inhibitors and/or noradrenaline reuptake inhibitors, which only indirectly affect dopaminergic neurotransmission. As a consequence, residual symptoms remain, including impaired motivation and impaired pleasure. This article reviews the development of new broad-spectrum antidepressants, the triple reuptake inhibitors, which also increase brain dopamine levels.

Expert opinion: In this review, a distinction is made between the subtypes of melancholic and atypical depressions and their associated brain abnormalities and dysfunctions in neurotransmitter systems. Subsequently, we propose a hypothetical model: ‘the monoamine hypothesis revisited’ to predict what kind of pharmacological treatment will be effective in the different subtypes of depression. It is expected that the triple reuptake inhibitors, inhibiting the reuptake of all three monoamines, can produce a greater efficacy than traditional antidepressants especially in atypical depression. Since triple reuptake inhibitors may also dampen states of hyperglutamatergic activity and subsequent excitotoxicity, it is suggested that these new drugs have a considerable neuroprotective potential in major depression, especially in melancholic depression.     

A role for AMPA receptors in mood disorders

Major antidepressant agents increase synaptic levels of monoamines. Although the monoamine hypothesis of depression remains a cornerstone of our understanding of the pathophysiology of depression, emerging data has suggested that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subtype of glutamate receptor may also play a pivotal role in depression. Positive allosteric modulators of AMPA receptors increase brain levels of brain-derived neurotrophic factor (BDNF) that impacts the viability and generation of neurons in key brain structures. AMPA receptor potentiators are active in rodent models predictive of antidepressant efficacy. The mechanisms by which AMPA receptor potentiators produce these biological effects, however, are uncertain. Current evidence points to an antidepressant mechanism that is independent of monoaminergic facilitation that is driven by neurogenesis, a process facilitated by increased BDNF expression. However, alternative hypotheses need to be considered given uncertainties in the relationship between BDNF increases and the effects of conventional antidepressant medications. Electrophysiological and protein conformational data indicate that structural variants of AMPA receptor potentiators can differentially modulate AMPA receptor-mediated currents, although the manner in which this impacts antidepressant efficacy is yet to be understood. Conventional antidepressants such as fluoxetine positively modulate AMPA receptors. This potentiation is engendered by specific phosphorylation pathways activated through the dopamine- and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32). Other novel compounds with antidepressant-like effects in rodents may also produce their in vivo effects through potentiation of AMPA receptors. Thus, AMPA receptor potentiation might be a general mechanism through which the clinical outcome of antidepressant efficacy is achieved.     

EXAMINATION OF DEVELOPMENTAL NEUROTOXICITY BY THE USE OF TISSUE CULTURE MODEL SYSTEMS

1. The rotation-mediated three-dimensional reaggregate culture system is uniquely suited for studies on developmental neurotoxicity. In this system, it is possible to reconstruct central neuronal pathways and follow their development. 2. Exposure to drugs of abuse including methamphetamine and methylenedioxyamphetamine or the appetite suppressant, fenfluramine, reduces monoamines in the cultures in a dose-dependent manner and interrupts normal monoaminergic development. 3. While the monoaminergic neurones may attain normal rates of development following drug removal, the affected neurones are not capable of overcoming the drug-induced insults and a deficiency in monoamines persists throughout development. 4. In addition, the production of immortalized monoclonal hybrid cells obtained by fusion of fetal mesencephalic neurones with a neuroblastoma has yielded cell lines expressing a dopaminergic phenotype. 5. Such cells have been useful in establishing the relationship of neurotoxicity to cell lineage and can serve as models for the study of the cellular and molecular mechanisms of neurotoxicity.     

Recent advances in the neurobiology of depression

Elucidation of the neurobiological basis of depression and other mood disorders is rapidly increasing. Considerable experimental and clinical evidence supports the fundamental roles of serotonin and norepinephrine, as well as the interactions between these systems in the etiology of depression. Substantial evidence has accrued, including changes in neurotransmitter and neurotransmitter metabolite concentrations, reuptake sites, and receptors, to support the hypothesis that alteration in neuronal serotonergic and noradrenergic function occurs in the central nervous system of patients with major depression. Serotonin and norepinephrine represent the major targets of current therapeutic interventions, which may induce longer-term adaptive changes via modulation of the activity of these neurotransmitters. In addition, two neuropeptide neurotransmitters--substance P and corticotropin-releasing factor--have been implicated in the pathophysiology of mood disorders. Preliminary studies have reported the clinical efficacy of a tachykinin NK1 receptor antagonist and a CRF1 receptor antagonist in depressive disorders. Further clarification of the precise neurobiological changes occurring in depression has implications for the use and development of novel effective treatments for this disorder.     

Brain neurotoxic amyloid-beta peptides: their potential role in the pathophysiology of depression and as molecular therapeutic targets

The monoamine hypothesis ascribes an important role to the underactivity of brain monoamines such as 5-HT, noradrenaline and dopamine to the pathophysiology of depression. This view emerged more than 50 years ago and has guided development of most medications currently used for the treatment of this disorder. However, large numbers of depressed individuals treated with currently available antidepressant agents, or even with various combinations, do not respond. Residual symptoms, relapses and recurrences are common while receiving adequate doses of these medications. In a recent issue of the BJP, Colaianna et al. describe results suggesting that a new neurobiological mechanism with treatment implications should be considered for the development of depression in humans, namely, elevations in potentially neurotoxic brain amyloid-β peptides.

LINKED ARTICLE

To view the paper by Colaianna et al. visit http://dx.doi.org/10.1111/j.1476-5381.2010.00669.x