Depression (Long) Notes
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Depression (Long) Revision
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DEPRESSION The molecular neurobiology of depression Core symptoms of "clinical depression" include depressed mood, anhedonia (reduced ability to experience pleasure from natural rewards), irritability, difficulties in concentrating and abnormalities in appetite and sleep. Depressed patients are also more likely to develop coronary artery disease and type 2 diabetes. Depression also complicates the prognosis of a host of other chronic medical conditions. There are several explanations for the comparatively rudimentary knowledge of depression's pathophysiology:
1. Observing pathological changes within the brain remains markedly more difficult than for al other organs. Post-mortems are relied upon which have numerous limitations, as do neuroimaging techniques (rely upon changes in neuronal activity by using indirect markers of activation). Several animal models have also informed knowledge of the neural circuitry of depression but there are important challenges to how information gained from these models should be interpreted
2. Most depression occurs idiopathically and the limited understanding of its aetiology is reflected as a list of risk factors such as stressful life events, endocrine abnormalities, cancers and side effects of drugs, among many others. Genetic association studies have not uncovered strong and consistent genetic risk modifiers perhaps because of the sheer heterogeneity of depressive syndromes. Thus, genuine "depression genes" have not yet been identified. The official diagnosis of depression is subjective and rests on the documentation of a certain number of symptoms that significantly impair functioning for a certain duration. These diagnostic criteria overlap with other conditions such as anxiety disorders, which have a substantial comorbidity with depression. Neural circuitry of depression Several brain regions and circuits regulate emotion, reward and executive function, and dysfunctional changes within these highly interconnected "limbic" regions have been implicated in depression and antidepressant action. Studies of depressed patients show reductions in grey-matter volume and glial density in the prefrontal cortex and the hippocampus, regions thought to mediate the cognitive aspects of depression, such as feelings of worthlessness and guilt. However, the published findings are not consistent and are often complicated by co-morbid diagnoses. In contrast to structural studies, experiments assessing brain function, such as fMRI or PET show that activity within the amygdala and subgenual cingulate cortex is strongly correlated with dysphoric emotions: indices of neuronal activity within these regions are increased by transient sadness in healthy volunteers and are chronically increased in depressed individuals, reverting to normal levels with successful treatment. Inspired by these findings, it was shown that DBs applied to the white matter tracts surrounding Cg25 produced a sustained remission of depressive symptoms in a small cohort of treatmentresistant patients.
These forebrain networks are significantly modulated by monoamine projections from midbrain and brainstem nuclei (dopamine from the ventral tegmental area (VTA), serotonin from the dorsal raphe located in the PAG area and NO from the locus coeruleus). In addition to controlling alertness and awareness these NTs modulate the salience of emotional stimuli. The role of monoamines The "monoamine hypothesis" of depression, which posits that depression is caused by decreased monoamine function in the brain, originated from early clinical observations. Two structurally unrelated compounds developed for non-psychiatric conditions, namely iproniazid and imipramine, had potent antidepressant effects in humans and were later shown to enhance central serotonin or NA transmission. Reserpine, an old antihypertensive agent that depletes monoamine stores, produced depressive symptoms in a subset of patients. Today's antidepressant agesnt offer a better therapeutic index and lower rates of side effects for most patients but they are still designed to increase monoamine transmission acutely either by inhibiting neuronal reuptake (e.g. SSRIs - e.g. fluoxetine) or by inhibiting degradation 9e.g. MAO inhibitors - e.g. tranylcypromine). However, the cause of depression is far from being a simple deficiency of central monoamines. MAO inhibitors and SSRIs produce immediate increases in monoamine transmission, whereas their moodenhancing properties require weeks of treatment. Conversely, experimental depletion of monoamines can produce a mild reduction in mood in unmedicated depressed patients, but such manipulations do not alter mood in healthy controls. It is now thought that acute increases in the amount of synaptic monoamines induced by antidepressants produce secondary neuroplastic changes that are on a longer timescale and involve transcription and translational changes that mediate molecular and cellular plasticity. As one example, the serotonin 5-HT1B receptor interacts with a calcium binding protein named p11, which was upregulated in cerebral cortex on chronic treatment with SSRIs and was also found to be downregulated in post-mortem cingulate cortex samples from depressed individuals. Monoamine-based antidepressants remain the first line of therapy for depression but their long therapeutic delays and low (about 30%) remission rates have encouraged the search for more effective agents. The serotonin receptors involved in the action of SSRIs remain unknown, although selective agonists of the serotonin 5-HT4 receptor produce rapid antidepressant effects in rodents (34 days). Experiments on mice deficient in P-glycoprotein, a molecule in the BBB that transports numerous drugs back into the bloodstream, have shown that several antidepressant agents, including the SSRI citalopram, are substrates for P-glycoprotein. Human polymorphisms in the gene encoding Pglycoprotein significantly alter antidepressant efficacy in depressed individuals, suggesting the value of such a pharmacogenetic approach when selecting antidepressant agents. Neurotrophins and neurogenesis Volumetric decreases observed in the hippocampus and other forebrain regions in subsets of depressed patients have supported a popular hypothesis for depression involving decrements in neurotrophic factors - neurodevelopmentally expressed growth factors that also regulate plasticity within adult brain. These studies have focused largely on the role of BDNF, which is expressed abundantly in adult limbic structures. Support for this "BDNF hypothesis" has come from a large preclinical literature showing that several forms of stress reduce BDNF-mediated signaling in the hippocampus, whereas chronic treatment with antidepressants increases BDNF-mediated signaling.
More causal evidence for the antidepressant action of BDNF has come from experiments in rodents in which antidepressant effects were observed on direct infusion of BDNF into the hippocampus and were blocked on the conditional or inducible knockout of gene encoding BDNF from forebrain regions. However, more recent findings have necessitated a revision of this hypothesis. First, a substantial number of preclinical studies have either failed to show these patterns of changes induced by stress and by antidepressants, or have shown the opposite effects. Second, male mice with conditional forebrain deletions of BDNF or its receptor do not show depression-like behaviour. Third, in other regions (e.g. VTA, NAc) BDNF exerts a potent pro-depressant effect: chronic stress increases the amount of BDNF within the NAc and the direct infusion of BDNF into the VTA-NAc increases depression-related behaviours, whereas a selective knockout of the gene encoding BDNF from this circuit has antidepressant-like effects. Finally, a single-nucleotide polymorphism in the gene encoding BDNF, which significantly impairs the intracellular trafficking and activitydependent release of BDNF and decreases hippocampal volume, does not alter genetic vulnerability to depression. Recent studies suggest complex interactions between the BDNF G196A polymorphism (a polymorphism in the serotonin transporter gene) and stressful life events. Taken together, these results suggest that the current formulation of the BDNF hypothesis is too simplistic; BDNF-mediated signaling is involved in neuroplastic responses to stress and antidepressants but these effects are both region-specific and antidepressant-specific and function in the background of other potent genetic and environmental modifiers. A marked cellular effect of several but not ALL antidepressant treatments is the induction of adult hippocampal neurogenesis - the process by which neural progenitors of the hippocampal subgranular zone divide mitotically to form new neurons that differentiate and integrate into the dentate gyrus. Blockade of hippocampal neurogenesis inhibits the therapeutic-like effects of most antidepressant treatments in rodent models. Moreover, treatment with antidepressants, possibly through the actions of CREB or other transcriptional regulators, increases the amounts of several growth factors in the hippocampus that influence neurogenesis. These include BDNF (which promotes neuronal survival) as well as vascular endothelial growth factor and VGF which themselves have antidepressant and pro-neurogenic properties in rodents. The mechanisms by which new neurons might restore mood are largely unknown. Activity-dependent increases in neurogenesis might increase activity propagation through hippocampal subfields and allow hippocampal networks to adapt and learn new experiences. Collectively, these studies highlight the weaknesses of attempts to generate a unified theory of depression. Mechanisms that promote depressive symptoms in response to stress differ markedly between different neural circuits and can also be distinct from changes that underlie depression in the absence of external stress (endogenous depression). In addition, neuroplastic events that are required for antidepressant efficacy need not function through the reversal of stress-induced plasticity and might function through separate and parallel circuits.
Neuroendocrine and neuroimmune interactions Early clinical studies identifying reproducible by small increases in serum glucocorticoid concentrations in depression fuelled significant interest in the role of a dysfunctional hypothalamicpituitary-adrenal axis in the pathophysiology of depression. Physical or psychological stress increases serum glucocorticoid concentrations and some depression-like symptoms can be produced in rodents by chronic administration of glucocorticoids. Excess glucocorticoids, through the activation of glucocorticoid receptors, can reduce SGZ proliferation rates and produce atrophic
changes in hippocampal subregions. This could contribute to the hippocampal volume reductions seen in depression. Several metabolic abnormalities that are often associated with depression e.g. insulin resistance and abdominal obesity can be at least partly explained by an increase in glucocorticoids. Glucocorticoid and corticotrophin-releasing factor receptor antagonists are currently being tested in clinical trials. Cytokines, which are humoral mediators or innate and adaptive immunity, are also important modulators of mood. Cytokine receptors within the central nervous system are activated by both peripherally and centrally synthesized cytokines. Low doses of lipopolysaccharide or IL-1 produce "sickness behaviour" in rodents (social withdrawal and decreased exploratory, sexual behaviour) brought about by the release of pro-inflammatory cytokines such as interferon-, TNF-, Il-6 and IL1, which activate the hypothalamic-pituitary-adrenal axis and central monoamine systems. Clinical studies examining depression-associated increases in serum cytokine concentrations have been largely inconsistent; immune activation might be a signature of a small subset of depression cases, including those associated with autoimmune conditions such as rheumatoid arthritis. Administration of cytokines such as interferon- or IL-6 to rodents does not cause depression-like features. Nevertheless, recent preclinical studies indicate that blocking pro-inflammatory cytokinemediated signaling can produce antidepressant effects. Mice with target deletions of the gene encoding IL-6 or those encoding the TNF- receptors show antidepressant-like behavioural phenotypes and a centrally administered antagonist of the IL-1 receptor reversed the behavioural and antineurogenic effects of chronic stress. Future studies of the "cytokine hypothesis" must focus on elucidating the largely unknown neural circuitry involved in the behavioural effects of cytokines and must more precisely delineate the intercellular interactions involved between brain macrophages (microglia), glia and neurons within this circuitry. Epigenetic mechanisms There has been considerable recent interest in epigenetic modifications in the pathophysiology of depression and antidepressant action. These modifications encompass covalent changes to DNA (e.g. methylation) and post-translational modifications of histone N-terminal tails (acetylation, methylation) as well as non-transcriptional gene-silencing mechanisms (e.g. micro-RNAs). Given that these changes can be long-lasting, epigenetics has been invoked to explain several aspects of depression, including high discordance rates between monozygotic twins, individual differences among inbred rodents, the chronic relapsing nature of the illness and the strikingly greater prevalence of depression in women. In essence, epigenetic changes offer a mechanism by which environmental experiences can modify gene function in the absence of DNA sequence changes, and they might help to explain largely inconsistent genetic association studies of depression, for example by undermining the transcriptional impact of DNA sequence polymorphisms due to epigenetic modifications on those gene promoters. Although epigenetic changes have been implicated in numerous psychiatric conditions, the field of depression research has focused on two main chromatin-modifying processes. The first is DNA methylation which seems to be important in the influence of maternal behaviour on adult emotional processing. Adult offspring of rats born to mothers with low rates of maternal licking and grooming show increased anxiety and reduced expression of glucocorticoid reeptors within the hippocampus compared with offspring of mothers with high rates of maternal behaviours. This reduced expression of glucocorticoid receptors is mediated by increased methylation of the glucocorticoid receptor gene promoter, effectively repressing gene expression.
Histone acetylation, which is associated with transcriptional activation and decondensed chromatin, seems to be a key substrate for antidepressant action. Increased histone acetylation at the Bdnf promoter in the hippocampus was shown to be required for the ability of chronically administered imipramine to reverse certain deleterious effects of social defeat. Moreover, HDAC inhibitors show antidepressant-like effects in the social-defeat assay and other behavioural assays and efforts are underway to develop more potent agenst that are designed to target specific HDACs such as HDAC5 (a class I HDAC). The implications of these studies come with an important anatomical caveat: although inhibiting the actions of HDAC5 in the hippocampus seems to be therapeutically advantageous, mice that are globally deficient in HDAC5 are more vulnerable to social defeat. Similarly, although imipramine increases HDAC5 expression in the hippocampus, it significantly reduces HDAC5 expression within the NAc, further emphasising the regional specificity of stressrelated and antidepressant-related plasticity. Current knowledge of the diversity of chromatin-modifying enzymes, and techniques to detect and quantify chromatin modifications genome-wide, is growing fast. An important challenge in the clinical translation of these approaches will be to improve the technological ability to demonstrate causation by developing techniques to detect these modifications in vivo. Such techniques will allow researchers to examine region-specific chromatin measures associated with depression or antidepressant responses in humans. Resilience-related research Relatively little attention has been devoted to understanding how most individuals adapt well (are RESILIENT) in the face of adversity. By exploiting natural variations in the development of active escape in the learned-helplessness test, stress-induced upregulation of the transcription factor FOSB (a stable, truncated protein product of the Fosb gene) in the midbrain PAG nucleus was shown to promote a resilient phenotype. This effect was mediated through downregulating expression of substance P, a neuropeptide released during stress. A more recent report illustrated the role of mesolimbing dopamine-mediated signaling in emotional homeostatic mechanisms. By adapting the social-defeat model of depression to examine the variations in response to chronic stress, vulnerability to the development of social avoidance and other deleterious sequelae was shown to be mediated by the increased excitability of VTA dopamine neurons and their subsequent increased activity-dependent release of BDNF onto NAc neurons. Resilient mice escaped this increases in VTA neuronal excitability by upregulating voltage-gated potassium channels, which functions as a molecular compensation to restore normal excitability and maintain low levels of BDNF-mediated signaling in the NAc.
BDNF and depression Introduction
Changes in neuronal plasticity and BDNF signaling has been implicated both in the etiology of depression and in antidepressant drug action Original observations (Nibuya et al 1995) showing that antidepressant drugs increase BDNF synthesis led to the suggestion that a deficiency in NT factor synthesis and signaling could underlie depression and that antidepressant drugs would act by increasing the levels of these growth factors However, these studies were followed by findings supporting a more complex and functional role of BDNF in depression and antidepressant action It is now firmly established that BDNF signaling plays an important role in the mechanism of action of antidepressant drugs, but the role of BDNF in the pathophysiology of depression is less clear
BDNF in depression
Neurotrophins or other neurotrophic factors might be involved in the pathophysiology of depression, since: o Some types of depression involve neurodegeneration which are partially reversible by adequate treatment o There is evidence for the role of BNDF and TrkB signaling in the recovery from depression Several studies have shown that serum BDNF levels are reduced in depressed patients and can be normalized by successful treatment (Karege 2005) o No alterations found in BDNF levels in WHOLE BLOOD of depressed patients o This suggests that the difference between depressed patients and healthy controls is not in the blood levels of BDNF, but in the ability of platelets to release BDNF upon stimulation o It is unclear whether serum BDNF levels might reflect or contribute to the BDNF levels in the brain o BDNF does not pass through the BBB but plasma BDNF could influence those brain regions where the BBB is leaky, such as some parts of the hypothalamus The role of BDNF in depression has also been investigated in animal models of depression o Essentially all of these models are unsatisfactory in one way or another - bulk of literature has failed to produce evidence of depression-like behaviour in animals with reduced BDNF levels or TrkB signaling o A recent study reported that a region-specific knock-down of BDNF in the dentate gyrus induces depression-like behaviour (Taliaz 2009) - possible that the behavioural effects of antidepressants are relatively weak in normal animals and the tests should perhaps be conducted in animals previously exposed to stress or glucocorticoids BDNF INCREASES depression-like behaviour when injected into the VTA and inhibition of BDNF signaling n the NAc (target area of dopaminergic pathway from VTA) produces an antidepressant-like response Therefore, behavioural outcome of drug treatment does not appear to directly reflect the roles of BDNF, but perhaps the functional role of BDNF within a particular network
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