CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 13, Issue 10, 2014

Regular physical exercise/activity has been shown repeatedly to promote positive benefits in cognitive, emotional and motor domains concomitant with reductions in distress and negative affect. It exerts a preventative role in anxiety and depressive states and facilitates psychological well-being in both adolescents and adults. Not least, several meta-analyses attest to improvements brought about by exercise. In the present treatise, the beneficial effects of exercise upon cognitive, executive function and working memory, emotional, self-esteem and depressed mood, motivational, anhedonia and psychomotor retardation, and somatic/physical, sleep disturbances and chronic aches and pains, categories of depression are discussed. Concurrently, the amelioration of several biomarkers associated with depressive states: hypothalamic-pituitary-adrenal (HPA) axis homeostasis, anti-neurodegenerative effects, monoamine metabolism regulation and neuroimmune functioning. The notion that physical exercise may function as “scaffolding” that buttresses available network circuits, anti-inflammatory defences and neuroreparative processes, e.g. brain-derived neurotrophic factor (BDNF), holds a certain appeal.

Cells of the immune system and the central nervous system are capable of interacting with each other. The former cell populations respond to infection, tissue injury and trauma by releasing substances capable of provoking an inflammatory reaction. Inflammation is now recognized as a key feature in nervous system pathologies such as chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders such as anxiety/depression and schizophrenia. Neuroinflammation may also raise the brain’s sensitivity to stress, thereby effecting stress-related neuropsychiatric disorders like anxiety or depression. The cytokine network plays a large part in how immune system cells influence the central nervous system. Further, inflammation resulting from activation of innate immune system cells in the periphery can impact on central nervous system behaviors, such as depression and cognitive performance. In this review, we will present the reader with the current state of knowledge which implicates both microglia and mast cells, two of the principle innate immune cell populations, in neuroinflammation. Further, we shall make the case that dysregulation of microglia and mast cells may impact cognitive performance and, even more importantly, how their cell-cell interactions can work to not only promote but also amplify neuroinflammation. Finally, we will use this information to provide a starting point to propose therapeutic approaches based upon naturally-occurring lipid signaling molecules.

Major depressive disorder (MDD) and diabetes mellitus (DM) have reciprocal relationship and share common pathophysiological mechanisms in the central nervous system. Depression and diabetes negatively affect cognitive function and are independent risk factors for mild cognitive impairment and Alzheimers disease (AD). It has been hypothesized that alterations in the production and processing of amyloid beta (Aβ) may be the principal pathological process in AD. Furthermore, it has been increasingly demonstrated that a long preclinical course precedes AD. A derivative of this observation is the hypothesis that a convergent pathophysiological substrate subserving MDD and DM may promote beta amyloid (Aβ) deposition. The present paper will review evidence linking MDD and DM to Aβ accumulation, with a particular emphasis on original reports that report on levels of Aβ40, Aβ42 and the Aβ40/42 ratio in plasma, serum, or cerebrospinal fluid of individuals with MDD and DM. The overarching goal herein is to press the point that MDD and DM are amyloidogenic and consequently represent modifiable risk factors for AD in later life. The prognostic intervention and prevention opportunity suggested by this notion is that: 1) increased rates of mood disorders and DM in an aging population will increase the population attributable risk for AD ascribed to these conditions, 2) improved outcomes in mood disorders and DM by effective “treating to target” may exert a salutary influence on underlying dementia promoting processes, 3) novel and repurposed medications that are capable of normalizing pathophysiological processes in MDD and DM could decrease the vulnerability towards AD.

Background: Patients with mood disorder, both unipolar and bipolar, present with significant cognitive dysfunction while unwell and this persists into euthymia. This impairment is to an extent independent of mood symptoms, has significant implications for prognosis, and exerts an effect on overall functioning. Neurobiological data suggest that the cognitive dysfunction may relate to underlying dysfunction of pre-frontal cortical areas of the brain and their connections with limbic structures. Methods: In this paper we examine the theoretical and neurobiological rationale for psychological treatments which focus on the treatment of cognitive dysfunction. We systematically review preliminary studies using cognitive rehabilitation (CR) based techniques in mood disorders, focussing on clinical contexts in which CR may be particularly likely to be important. In addition we examine important methodological issues in developing such an approach. Results: There is little evidence of traditional psychotherapies having a beneficial effect on cognitive function. However, there are a small number of studies examining specific CR in major depression and in bipolar disorder. The studies are small and inconclusive. However data on neuropsychological function and neurobiology of major depression suggest that this is an approach which deserves further attention and research. Conclusion: Further research is required in carefully selected populations, using well defined CR techniques and appropriate comparator treatments. Combination of these techniques with pharmacological and broader psychological treatments is likely to be most effective.

Major depressive disorder (MDD) is frequently associated with significant cognitive dysfunction. Furthermore, MDD is often co-morbid with obesity and metabolic disorders. The aim of this review is to evaluate the pathophysiological role obesity and co-morbid metabolic disorders may play in cognitive dysfunction associated with MDD. We conducted a PubMed search from December 1st 2013 to May 31st 2014 of all English language publications including the following keywords: cognition, working memory, attention, executive functioning, inflammation, insulin, brain-derived neurotrophic factor, neurotrophins, incretins, glucagon-like peptide-1, adipokines, diabetes, oxidative stress and glucocorticoids, cross- referenced with MDD and obesity, metabolic disorders, or metabolic syndrome. Clinical and epidemiological studies indicate that metabolic disturbances may contribute to cognitive dysfunction in MDD. There are several overlapping pathophysiological mechanisms linking obesity and metabolic abnormalities to MDD including disturbances in the hypothalamic pituitary adrenal axis, abnormalities in brain-derived neurotrophic factor signaling, adipose-derived hormones, insulin signalling, inflammatory cytokines, as well as oxidative and nitrosative stress pathways. Based on current research results, this article presents several putative mechanisms underlying the effects of obesity and metabolic abnormalities on cognitive dysfunction in MDD. Metabolic MDD may represent a depression subtype with unique patho-etiological mechanisms. The diverse shared pathophysiological mechanisms elucidated in this review may provide novel targets for the prevention and/or treatment of cognitive deficits in MDD.

Major depression is one of the leading causes of disability and psychosocial impairment worldwide. Although many advances have been made in the neurobiology of this complex disorder, the pathophysiological mechanisms are still unclear. Among the proposed theories, impaired neuroplasticity and hippocampal neurogenesis have received considerable attention. The possible association between hippocampal neurogenesis, neurotrophic factors, major depression, and antidepressant responses was critically analyzed using a comprehensive search of articles/book chapters in English language between 1980 and 2014. One common emerging theme was that chronic stress and major depression are associated with structural brain changes such as a loss of dendritic spines and synapses, as well as reduced dendritic arborisation, together with diminished glial cells in the hippocampus. Both central monoamines and neurotrophic factors were associated with a modulation of hippocampal progenitor proliferation and cell survival. Accordingly, antidepressants are generally suggested to reverse stress-induced structural changes augmenting dendritic arborisation and synaptogenesis. Such antidepressant consequences are supposed to stem from their stimulatory effects on neurotrophic factors, and possibly modulation of glial cells. Of course, accumulating evidence also suggested that glutamatergic systems are implicated in not only basic neuroplastic processes, but also in the core features of depression. Hence, it is critical that antidepressant strategies focus on links between the various neurotransmitter systems, neurotrophic processes of hippocampal neurogenesis, and neurotrophic factors with regards to depressive symptomology. The identification of novel alternative antidepressant medications that target these systems is discussed in this review.

Depression is one of the most debilitating disorders of our times. Antidepressant medication, one of the most common (and often first-line) treatments to date, aim to alleviate symptoms, but finding which type of drug benefits which patient remains a daunting task. The underlying mechanism that translates neurochemical effects to symptom improvement is still far from precise. In this review we summarized the evidence on the effects of antidepressants on brain systems and cognitive functioning, and examined the possible value of these correlates as predictors of response. Studies using acute (or sub-chronic) antidepressant administrations in healthy subjects showed effects on affective cognition. In depressed patients, neuroimaging studies examining the effects of antidepressants in pre-post designs have shown changes in the activation of the anterior cingulate cortex and the limbic system after treatment. Increasing evidence shows that baseline anterior cingulate cortex activation could be a possibly critical biomarker of treatment response. The few studies performed to date also indicate potentially different pathways for antidepressants targeting the serotonergic neurotransmitter system versus those targeting the noradrenergic one, but findings are not always consistent. More studies are necessary to establish whether early cognitive effects of drugs are predictive of long-term efficacy in depressed patients. Considering the heterogeneity of depression and in order to approach a more personalized treatment, future studies should also elucidate the effects of antidepressants on different cognitive systems and subsequently on different symptom profiles.

Objectives/Introduction: Major Depressive Disorder is associated age-related medical conditions (e.g., diabetes mellitus type II, Alzheimer’s disease) that frequently manifest at an earlier age, contributing to excess and premature mortality. The foregoing observation provides the impetus to further refine potential mechanisms and molecular pathways subserving these disorders in order to more effectively treat these clinical populations by aiming to reduce and prevent cognitive impairment as well as downstream neurodegeneration. Methods: A review of computerized databases was performed to identify original studies that investigated the impact of the independent and comorbid association of major depressive disorder and type II diabetes mellitus on cognitive function and conversion to Alzheimer’s disease. English-written articles were selected for review based on the adequacy of sample size, the use of standardized diagnostic instruments, and validated assessment measures. Results: Individuals with persistent neuropsychiatric illness account for a disproportionate overall burden of disability mediated largely by decrements in cognitive performance. Mixed results from epidemiological and clinical studies suggest that insulin may mediate and/or moderate risk for cognitive dysfunction in subsets of individuals. Moreover, physiological changes, such as insulin resistance and the activation of neuroimmunoinflammatory systems result in glial and neuroendangerment. Conclusion: Disturbances in the metabolic milieu exert a neurotoxic effect on the central nervous system and poses a hazard to other organ systems.

The default mode network (DMN) describes a distributed network of brain regions that are predominantly activated and engaged during periods of spontaneous, stimulus independent thought (i.e., at rest) and remain quiescent during attention-demanding, goal-directed tasks. Replicated evidence in functional neuroimaging studies suggests that midline cortical and subcortical brain regions responsible for memory, self-relevant emotional and mental processes, as well as information integration comprise the DMN. The DMN is posited to represent self-referential mental activity via a dynamic interplay of cognitive and emotional processes by integrating information from the external environment with introspective thoughts to generate an autobiographical concept of the self. It has been amply documented that irregularities in the DMN and its functional connectivity are associated with various neuropsychiatric disorders. Moreover, accumulating evidence also suggests that individuals with select medical disorders (i.e., metabolic disorders) demonstrate alterations in DMN activity and functional connectivity. However, there is a paucity of data evaluating whether individuals with metabolically-based medical conditions, exhibiting altered DMN activity and functional connectivity, are at increased risk for developing neuropsychiatric disorders. Likewise, potential mechanisms (e.g., altered brain metabolism, insulin resistance) mediating these changes and their implications for novel treatment approaches have yet to be elucidated. Taken together, the overarching aim of this review is to provide a synthetic overview that suggests that this neural circuit may represent a common (or convergent) substrate affected in individuals with select neuropsychiatric and metabolic disorders.

Non-invasive brain stimulation (NIBS) techniques, such as repeated transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have been increasingly used in different contexts to improve cognitive performance and ameliorate depression symptoms. Considering that major depression is usually accompanied by cognitive deficits, NIBS technique could be also helpful to improve cognition in depressed patients. In this systematic review, we researched for articles published in PubMed/MEDLINE from the first date available to June 2014 that assessed cognitive performance in patients with depression before and after NIBS. Out of 191 references, 25 (16 for rTMS and 9 for tDCS) studies matched our eligibility criteria. Non-invasive brain stimulation interventions, such as rTMS and tDCS seem to be a promising tool for cognitive enhancement in MDD, although several issues and biases (e.g., blinding issues, tests without correction for multiple comparisons, placebo effects and exploratory analyses, practice effects) hinder us to conclude that NIBS technique improve cognition in patients with depression. We discussed possible shortcomings of the included studies, such as the use of different depression treatment protocols, the possibility that some findings were false-positive results of the employed cognitive tasks and whether cognition improvement could have been an epiphenomenon secondary to depression improvement. To conclude, whereas these non-pharmacological, non-invasive techniques are particularly appealing for cognitive improvement in depression, further studies are still warranted to disentangle whether NIBS technique induce positive effects on cognition beyond their antidepressant effects.

A priority clinical and research agenda in mood and anxiety disorders is to identify determinants that influence illness trajectory and outcome. Over the past decade, studies have demonstrated a bidirectional relationship between the gut microbiome and brain function (i.e., the microbiota-gut-brain axis). Probiotic treatments and developmental analysis of the microbiome may provide potential treatments and preventative measures for depressive and anxiety disorders. This systematic literature review aims to identify original studies linking the gut microbiota to major depressive disorder and anxiety disorders. Furthermore, this review searched for original reports focusing on possible therapeutic and preventative effects of probiotics for these debilitating conditions. Accumulating data indicate that the gut microbiota communicates with the CNS through neural, endocrine and immune pathways. Studies in germ-free animals indicate that the microbiota is involved in the regulation of the stress response (e.g., hypothalamic-pituitary-adrenal axis) and in CNS development at critical stages. Probiotics attenuate anxiety and depressive-like behaviors in experimental animal models. Notwithstanding some inconsistencies and methodological limitations across trials, clinical studies suggest that probiotics may mitigate anxiety symptoms. However, future studies should investigate the anxiolytic and antidepressant effects of probiotics in more phenotypically homogeneous populations. In conclusion, the emerging concept of a gut microbiota-brain axis suggests that the modulation of the gut microbiota may provide a novel therapeutic target for the treatment and/or prevention of mood and anxiety disorders.

Major depressive disorder (MDD) is associated with significant cognitive dysfunction in both ‘hot’ (i.e. emotion-laden) and ‘cold’ (non-emotional) domains. Here we review evidence pertaining to ‘hot’ cognitive changes in MDD. This systematic review searched the PubMed and PsycInfo computerized databases in May 2014 augmented by hand searches of reference lists. We included original articles in which MDD participants (or their healthy first-dregree relatives) and a healthy control group were compared on standard measures of emotional processing or reward/ punishment processing as well as systematic reviews and meta-analyses. A total of 116 articles met the inclusion criteria of which 97 were original studies. Negative biases in perception, attention and memory for emotional information, and aberrant reward/punishment processing occur in MDD. Imbalanced responses to negative stimuli in a fronto-limbic network with hyper-activity in limbic and ventral prefrontal regions paired with hypo-activity of dorsal prefrontal regions subserve these abnormalities. A cross-talk of ‘hot’ and ‘cold’ cognition disturbances in MDD occurs. Disturbances in ‘hot cognition’ may also contribute to the perpetuation of negative emotional states in MDD. Limited success in the identification of susceptibility genes in MDD has led to great research interest in identifying vulnerability biomarkers or endophenotypes. Emerging evidence points to the persistence of ‘hot’ cognition dysfunction during remission and to subtle ‘hot’ cognition deficits in healthy relatives of patients with MDD. Taken together, these findings suggest that abnormalities in ‘hot’ cognition may constitute a candidate neurocognitive endophenotype for depression.

Major depressive disorder (MDD) is a prevalent and recurring mental disorder often associated with high rates of non-recovery and substantial consequences on psychosocial outcome. Cognitive impairment is one of the most frequent residual symptoms of MDD. The persistence of cognitive impairment even in remitted phases of the disorder, notably in the domains of executive function and attention, suggests that it may serve as a mediational nexus between MDD and poor functional outcome, accounting for occupational and relational difficulties regardless of clinical improvement on depressive symptoms. The critical impact of cognitive deficits on psychosocial dysfunction invites clinicians to regularly screen and assess cognition across multiple domains, taking into account also clinical correlates of cognitive dysfunction in MDD. Despite the availability of several instruments for the screening and assessment of cognitive dysfunction, the lack of consensus guiding the choice of appropriate instruments increases the likelihood to underestimate cognitive dysfunction in MDD in clinical settings. On the other hand, the unsatisfactory effect of most antidepressant treatments on cognitive deficits for many individuals with MDD calls for the development of genuinely novel therapeutic agents with potential to target cognitive dysfunction. Notwithstanding the necessity of further investigations, this review indicates that neuropsychological deficits (e.g., impaired executive functions) are stable markers of MDD and underscores the need for the development of integrative and multi-modal strategies for the prevention and treatment of neuropsychological impairments in MDD.

Major depressive disorder (MDD) is associated with cognitive dysfunction encompassing several domains, including memory, executive function, processing speed and attention. Cognitive deficits persist in a significant proportion of patients even in remission, compromising psychosocial functioning and workforce performance. While monoaminergic antidepressants may improve cognitive performance in MDD, most antidepressants have limited clinical efficacy. The overarching aims of this review were: (1) to synthesize extant literature on putative biological pathways related to cognitive dysfunction in MDD and (2) to review novel neurotherapeutic targets for cognitive enhancement in MDD. We found that reciprocal and overlapping biological pathways may contribute to cognitive dysfunction in MDD, including an hyperactive hypothalamic-pituitary-adrenal axis, an increase in oxidative and nitrosative stress, inflammation (e.g., enhanced production of pro-inflammatory cytokines), mitochondrial dysfunction, increased apoptosis as well as a diminished neurotrophic support. Several promising neurotherapeutic targets were identified such as minocycline, statins, anti-inflammatory compounds, N-acetylcysteine, omega-3 poliunsaturated fatty acids, erythropoietin, thiazolidinediones, glucagon-like peptide-1 analogues, S-adenosyl-l-methionine (SAMe), cocoa flavonols, creatine monohydrate and lithium. Erythropoietin and SAMe had pro-cognitive effects in randomized controlled trials (RCT) involving MDD patients. Despite having preclinical and/or preliminary evidences from trials suggesting possible efficacy as novel cognitive enhancing agents for MDD, no RCT to date was performed for most of the other therapeutic targets reviewed herein. In conclusion, multiple biological pathways are involved in cognitive dysfunction in MDD. RCTs testing genuinely novel pro-cognitive compounds for MDD are warranted.

Background: Cognitive deficits differentially affect individuals with type 2 diabetes mellitus (T2DM) and mood disorders. Accumulating evidence implicates disturbances in metabolism as salient to cognitive function. Thus, the mitigation of metabolic disturbances may preserve or ameliorate cognitive function. This review aims to evaluate available evidence investigating the effects of metformin on cognitive function as well as summarize putative mechanistic properties related to these clinical effects. Methods: A PubMed search was conducted using the search words including, but not limited to: metformin, Major Depressive Disorder, type 2 diabetes mellitus, and cognitive dysfunction. All English language articles published from 1990 to July 2014 were reviewed. Results: Extant preclinical and clinical data have been mixed, wherein both cognitive disruption and pro-cognitive effects have been reported with the administration of metformin. Sound mechanistic evidence supports metformin as a treatment; however, the heterogeneity of study designs has contributed to an inability to arrive at an unequivocal conclusion regarding metformin effects upon cognition. Conclusion: Available evidence does not provide a robust signal for improvement in cognition in either mood disorder or T2DM samples. Notwithstanding, it is premature to label metformin as a “no-go” agent for further testing and development for cognitive dysfunction. A well designed, proof-of-concept trial of metformin investigating its possible cognitive effects in mood disorders is therefore warranted.

Clinical manifestations of major depressive disorder (MDD) have been linked to structural and functional alterations in fronto-limbic circuits and white matter microstructural abnormalities. However, little is known about how brain pathological changes in volume and microstructure are related to illness progression throughout aging, including course deterioration and treatment response. A comprehensive review of the literature regarding midlife- and late-onset MDD was performed through PubMed/Medline, ISI, and EMBASE electronic databases from January 2000 to May 2014. Eligible references included prospective studies in which structural neuroimaging assessments were performed in MDD samples. The course of MDD may be associated with brain aging modifications, including hippocampal, amigdalar and frontal volume reductions. White matter changes associated with MDD progression have been reported in the corpus callosum, frontal and temporal regions and may be associated with poorer response to treatment. The data suggest that both cortical and subcortical alterations may interact along the progression of MDD. Further knowledge brought by neuroimaging studies, through the integration of multimodal techniques, may help to improve the accuracy of diagnosis, disease monitoring and treatment response in MDD.

Major depression is a serious public health problem and one of the most common psychiatric disorders, and it is estimated that millions of people are affected worldwide. In addition, patients having depression present cognitive impairments, which could influence treatment adherence and long-term outcomes. Although, studies have shown that alterations in the hypothalamic–pituitary–adrenal axis, in inflammatory and antioxidant systems, and changes in intracellular pathways are involved in the cognitive impairment verified in depressive patients, it was unclear how these alterations occur. In this context, animal models of psychiatric disorders are revealed as good alternatives for the study of pathophysiology of these and associated factors. Thus, this review will highlight studies with animal models that have helped in understanding the mechanisms involved in cognitive impairment associated with depression, as well as focus on effective treatments that assist in improving both depression and cognition.