Anxiety/Depression- AHN

Question 1

Why is depression so important to study?

Answer 1

Major depressive disorder (MDD) is one of the most common psychiatric disorders, affecting up to 20% of the world population across their lifetime. The World Health Organization has predicted that MDD will be the second leading cause of disability worldwide by the year 2020

1) Depression is the fourth leading cause of disability and disease worldwide.
2) Each year, 6% of adults experience an episode of depression, and over the course of their lifetime more than 15% of the population will experience an episode
3) About two-thirds of adults will at some time experience depressed mood of sufficient severity to interfere with their normal activities
4) Prevalence rates have consistently been found to be 1.5–2.5 times higher in women than in men in the age group 18–64 years.
5) 1/4 of adults with depression don’t really respond to antidepressants- little to no benefits

Question 2

How is depression diagnosed?

Answer 2

The DSM-IV outlines the following criterion to make a diagnosis of depression. The individual must be experiencing five or more symptoms during the same 2-week period and at least one of the symptoms should be either (1) depressed mood or (2) loss of interest in “pleasure”- sex, food, socialising

Low self esteem, thoughts of worthlessness

Recurrent thoughts of death and suicide

Decreased ability to concentrate and think Weight change

Aggression in males
Sleep disturbance
Agitation or fatigue (locomotion)
Cognitive impairment (deficits in working memory, verbal fluency, processing speed, attention, and executive function)

Question 3

Epidemiology of anxiety

Answer 3

Anxiety disorders, including panic disorder with or without agoraphobia, generalized anxiety disorder, social anxiety disorder, and PTSD are the most prevalent mental disorders. As a result they are associated with immense health care costs and a high burden of disease. According to large population-based surveys, up to 33.7% of the population are affected by an anxiety disorder during their lifetime.

Anxiety disorders are also highly comorbid with other mental disorders, such as depression

Question 4

Define anxiety

Answer 4

Anxiety disorders are marked by excessive fear (and avoidance), often in response to specific objects or situations and in the absence of true danger, and they are extremely common in the general population.

Anxiety disorders have been viewed as maladaptive fear responses in that the frightening object becomes generalized to many other similar but non-threatening stimuli.

Question 5

What did Kupfer et al.,2012 say?

Answer 5

It was a review stating that the neural systems that are involved in emotion and reward processing (amygdala and nucleus accumbens), regulating emotion (hippocampus, medial prefrontal cortex and anterior cingulate cortex) and cognitive control of emotion (ventrolateral prefrontal cortex and dorsolateral prefrontal cortex) are dysfunctional in depression.

Neuroimaging studies suggestuggest abnormally increased amygdala, ventral striatal, and medial prefrontal cortex activity, mostly to negative emotional stimuli, such as fearful faces. Additionally, abnormally reduced ventral striatal activity to positive emotional stimuli (Epstein et al., 2006) and in anticipation of reward (Pizzagali et al.,2009) with depression have also been reported. These findings support a bias of attention towards negative emotional stimuli, and away from positive emotional and reward-related stimuli in individuals with major depression.

Question 6

What causes depression and anxiety disorders?

Answer 6

The pathogenesis of depression and anxiety remains largely unknown, however genetic factors have been shown to play an important role in conferring vulnerability and to the heritability of these mental disorders. The heritability of depression, for instance, estimated by family, twin and adoption studies, is 35–40% (Sullivan et al.,2000). It is important to note that depression is a multifactorial disease. A genetic predisposition or environmental risk factor per se is not sufficient to cause depression. It is generally accepted that in most people, depression is caused by interactions between a genetic predisposition and some environmental factors.

Furthemore, many groups have demonstrated the function of epigenetic mechanisms in mediating the risk and development of anxiety and depression. For instance it has been shown that adverse early experiences (e.g., low maternal care, abuse) can affect glucocorticoid receptor (GR) gene (NR3C1) expression, which stably predisposes one to anxiety and depression (Smart et al., 2015; Conti and Alvares da Silva-Conforti, 2016).

The HPA axis is known to be a major control module of the stress response in mammals, besides the autonomic nervous system. Interestingly, the hyperactivity/dysfunction of the hypothalamic-pituitary-axis (HPA) axis, which is one of the most consistent biological findings in patients with depression (Pariante and Lightman, 2008), is mediated by the GR. Furthermore FKBP51 has been shown to decrease ligand binding sensitivity of the GR, thereby directly affecting stress system (re)activity. As a result, it is no surprise that single nucleotide polymorphisms of FKBP51 have been linked to psychiatric disorders (Binder et al.,2004)

The combined evidence of early life stress and trauma and dysfunction of a major control module of the stress response propose a strong link between persistent stress and depression and anxiety. However it is difficult to verify absolutely.

Question 7

Define stress… what is generally belived about its link to depression

Answer 7

Stress is a term often used to describe situations that are emotionally and physiologically challenging. In biological terms, stress is characterized as a state of disturbed body homeostasis. Hans Selye, a pioneer of stress research, defined stress as the ‘non-specificresponse of the body to any demand for change’.

Usually, the mediation of a stress response is beneficial, as long as the adaptive systems are activated for a short period of time and efficiently shot off again, without being chronically overstimulated. It is generally agreed that averse experiences and excessive challenges such as chronic stress clearly impose a major risk factor for the development of depression and other stress-mediated disorders (Holsboer, 2000

Question 8

Outline the stress pathway

Answer 8

Upon stress, the HPA axis is activated and thereby cortiocotropin-releasing hormone (CRH) and vasopressin (AVP) are secreted from neurons of the paraventricluar nucleus. (Sapolsky et al., 2000). At the pituitary, CRH and AVP bind to their respective receptors and synergistically trigger the synthesis and release of pro-opiomelanocortin (POMC), the precursor for andreno- corticotropic hormone (ACTH).

Circulating ACTH reaches the secretory cells of the zona fasciculate and the zona reticluaris of the adrenal cortex via the blood stream and stimulates them to synthesize and secrete glucocorticoids (GCs) into the systemic circulation.

Glucocorticoids (cortisol in humans and corticosterone in rodents), the main hormonal end products of the HPA axis, then act on numerous organ systems, including the brain, to modulate physiology and behavior. This includes peripheral function such as metabolism and immunity, but also effects on the brain such as the regulation of neurogenesis.

The nature of a stressor can differ largely and therefore so can the stress response, as it is mediated via the HPA axis, which arises from interactions of several distinct stress-sensitive brain circuits and neuronal populations of the PVN.

Question 9

What test can be predictive of depression?

Answer 9

Among asymptomatic first-degree relatives of depressed patients, higher stress-hormone release was detected following dexamethasone supression-test administration (Holsboer et al. 1995). In addition, individuals with childhood trauma have an increased plasma cortisol response to the dexamethasone suppression test under both conditions, with or without current major depression (Heim et al. 2008a).

The increased cortisol release may be due to impaired GR signalling.

So dexamethasone suppression test (DST) reveal increased activity/ impaired activity of HPA not only in people with MDD but with men exposed to childhood trauma. Provides an explanation as to why a risk factor for depression is childhood trauma. Heim suggests a sensitisation of the neuroendocrine stress response after childhood trauma so you are more vulnerable to getting depression after later exposure to stress.

Question 10

What evidence other than impaired HPA axis show that a modified GR gene causes depression?

Answer 10

Weaver, 2004
Through undefined epigenetic processes, maternal effects influence the development of defensive responses to threat in organisms ranging from plants to mammals. In the rat, such effects are mediated by variations in maternal behavior, which serve as the basis for the transmission of individual differences in stress responses from mother to offspring.

Offspring of mothers that showed high levels of licking and arched-back nursing were found to have higher levels of demethylation of the GR DNA and higher serotonin levels, as compared to offspring of ‘low-LG-ABN’ mothers. As demethylation of GR DNA and serotonin levels drive transcription factor levels and cause increased GR expression, these offspring have a more modest HPA response to stress.

Eliminating the difference in hippocampal GR levels abolishes the effects of early experience on HPA responses to stress in adulthood, suggesting that the difference in hippocampal GR expression serves as a mechanism for the effect of early experience on the development of individual differences in HPA responses to stress5.

Question 11

What role does serotonin have in the stress response?

Answer 11

Serotonin seems to play a key role in regulating GR transcription:

The observed effects of high versus low licking and grooming on the pups are thought to be mediated by serotonin (5-HT) projections to hippocampal neurons that stimulate 5-HT7 receptors, which are in turn coupled to cyclic AMP.
In primary hippocampal neurons in culture, activation of the cyclic AMP pathway increases the expression of the transcription factor NGFI-A ( aka zif- 268), which binds and activates the Nr3c1 (Glucocorticoid Receptor gene) promoter 5.

Furthermore, t has been suggested that serotonin can also affect local neuronal circuits projecting to the PVN, given the fact that serotonergic neurons project to regions adjacent to the PVN (Leonard, 2005).

Question 12

What do patients with Cushings syndrome further give evidnece for?

Answer 12

Further evidence that continuous elevation of cortisol underlies depression is the fact that the majority of Cushing’s syndrome patients who suffer from hypercortisolemia also suffer from depression.

Question 13

Holsboer and Ising, 2010

Answer 13

Major depression frequently shows signs of a disinhibited HPA axis due to an increased parvocellular CRH expression which drives production and secretion of pituitary ACTH and subsequently cortisol. CRH overexpression reflects an impaired negative GR feedback regulation as evidenced by a reduced inhibition of cortisol secretion after application of the synthetic glucocorticoid dexamethasone

Question 14

Why does early life trauma have lasting effects?

Answer 14

The brain is highly plastic during early life and encodes acquired information into lasting memories that normally subserve adaptation.

Question 15

What is the monoamine theory of depression? What are some of the criticisms of it?

Answer 15

This hypothesis states that MDD results from the deficiency of monamines such as serotonin and dopamine in the brain. As most of the currently available antidepressants work on monoamine transporters or receptors inhibiting reuptake (imipramine) or metabolism (iproniazid) of monoamine neurotransmitters (5-HT and NE) this does give evidence to support this hypothesis.

A criticism of this hypothesis is that it accounts for the complicated and heterogeneous clinical manifestations of MDD to deficiency of a molecule and that is far too simplistic and seen to misguide our understanding of the complexity of this disorder.

Furthermore, numerous findings, inconsistent with this hypothesis, have arisen from daily clinical observations, clinical researches and preclinical studies since the proposal of this hypothesis.

For instance there is a delayed onset of efficacy (3-4 weeks) of antidepressants, which may imply a second stage. Similarly there is an inadequate response/remission rate of typical antidepressants- 1 in 3 respond to first line treatment.

Question 16

Evidence from studies that Increased Synaptic Serotonin (or NE, DA) Concentration Does Not Account for The Antidepressant Efficacy of Antidepressants

Answer 16

Several published reviews have casted doubt on the low 5-HT hypothesis of MDD and summarized the evidence inconsistent with this hypothesis (Lacasse and Leo, 2005; Fischer et al., 2014. One article even hypothesized that depression is a result of elevated 5-HT concentration rather than deficiency of 5-HT (Andrews et al., 2015).

Question 17

How should stress and depression be linked?

Answer 17

Numerous theories has been proposed for interpretation of this phenomenon, among which the vicious circle between the dysregulation of hypothalamic-pituitary-adrenocortical (HPA) axis and morphological and functional deficits of hippocampal formation is considered as the key route between stress and depression. Specifically, the elevation of circulating cortisol during chronic stress response would exert neurotoxic effect on hippocampal neurons through glucocorticoid receptor and its downstream effects, which would result in decreased neurogenesis, synaptogenesis and dendritic spines and increased apoptosis of neurons (Holsboer and Barden, 1996; Holsboer, 2000; de Kloet et al., 2005). The morphological loss of neurons further leads to functional deficits loss of long-term potentiation (LTP) or long-term depression (LTD) of hippocampus, which gives rise to decreased GABAergic control of the HPA axis from the bed nucleus of stria terminalis (BNST) normally driven by the action of hippocampus (Holsboer, 2000; Egeland et al., 2015), and the the disinhibition of HPA axis would inversely exacerbate the morphological and functional loss of hippocampus. Thus, a vicious circle is formed and the hippocampal formation gradually goes to structural atrophy and functional deficit, which are commonly seen in depression.

Question 18

What is the neurogensis theory of depression?

Answer 18

In a landmark study, Eriksson et al., 1998 showed that the human hippocampus, particularly the sub ventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus retains its ability to generate neurons (neurogenesis) throughout life.

Since this studyadult hippocampal neurogenesis has been hypothesized to play a potentially important role on the pathology and successful treatment of depression.

It has been suggested that reduced adult hippocampal neurogenesis may underlie the pathoetiology of depression, while antidepressant efficacy depends on the upregulation of hippocampal neurogenesis

Question 19

What evidence supports the neurogensis theory of depression? (1)

Answer 19

Magnetic resonance imaging studies have consistently shown a reduction in hippocampal volume in people with recurrent depression relative to age- and sex-matched controls (Campbell et al 2004). As well as the decreased volume Gould et al 2007 demonstrated that there is impaired hippocampal function/ hippocampal dysfunction in depressed patients compared to their controls by measuring performance in a virtual-reality spatial memory navigation task. He found that depressed subjects performed significantly worse than controls.

The above evidence resulted in the proposition that decreased neurogenesis may underlie the decreased hippocampal volume and dysfunction in depressed patients.

Question 20

What evidence supports the neurogensis theory of depression? (2)

Answer 20

One of the primary catalysts for focusing on adult hippocampal neurogenesis in depression is the observation that most antidepressants and environmental interventions that result in antidepressant- like behavioral effects require neurogenesis. This is shown in many studies, one of which done by Santarelli et al 2003, where X-irradiation which results in depletion of AHN in mice prevented prevented the neurogenic and behavioral effects of two classes of antidepressants, which suggests that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus. This is also further supported by evidence which shows that the time course of maturation of newly generated neurons in the dentate gyrus, is generally consistent with the delayed onset of therapeutic action of antidepressants (Ming et al.,2011)

Question 21

Outline the evidence that does not support the neurogensis theory of depression.

Answer 21

For instance it was shown by Jayatissa et al., 2010 that ablation of neurogenesis does not always cause depressive-like symptoms. Likewise it was shown that stress does not always decrease neurogenesis (Lagace et al.,2010) and some effects of antidepressants are neurogenesis-independent (David et al., 2009).

Furthermore, whilst depressed people have been shown to have hippocampal dysfunction (Gould et al., 2007) and altered stress responses it is unclear as to whether these might be factors that are predisposing to depression or causative factors in depression.

These conflicting results do not necessarily disprove the neurogenic hypothesis of depression. The differences in results observed may be accounted for when considering the diverse and dynamic factors which regulate neurogenesis; in other words the neurogenic interactome. (Eisch and Petrik, 2012)

Question 22

Why does evidence that seems to negate the neurogensis of depression hypothesis actually don’t?

Answer 22

This ability of newly generated neurons to decelerate the stress response appears important in times of moderate to extreme or unpredictable stress as demonstrated by Lyons et al.,2010 but not as important under conditions of mild or predictable stress as demonstrated by Jayatissa et al., 2010. As a result the nature of stress appears to result in different affects on AHN and may account for the conflicting results previously described. Supporting this idea is work by Kirby et al., 2011 who shows that inactivation of the amygdala (a structure involved in emotional memory) suppresses AHN. Stimulation of the amygdala results in upregulated AHN and it has been demonstrated that under chronic, predictable mild stress the amygdala is stimulated and results in increased hippocampal neurogenesis (Parihar et al.,2011), providing an explanation as to why results from Jayatissa’s and colleagues were observed. However more experimental tests are required for the conformation of this hypothesis.

Different behavioral tests for depression and anxiety induce different levels of stress and/or fear and thus activate different subsystems of the neurogenic interactome. This secondarily can modulate the behavioral output of these subsystems and also influence adult neurogenesis and neurogenesis- dependent behavior

Question 23

Why is it thought that the control of AHN over mood and memory may be more interrelated than previously appreciated?

Answer 23

Adult-generated hippocampal neurons provide a type of neuronal plasticity, pattern separation, that allows acquisition and separation of closely spaced memories (Clelland et al.,2009). However, it is unclear how adult neurogenesis controls pattern separation and concurrently influences mood, and vice versa. Pattern separation may not only be important for learning and memory but also for recognizing dangerous and stressful signals, such as cue recognition during conflict or stress, thus triggering or aggravating anhedonic or depressive behavior (Anacker and Pariante, 2011)

Question 24

What did Deng et al.,2010 show?

Answer 24

Deng et al.,2010 showed that neuronal precursor cells exhibit strong plasticity and can undergo LTP. As a result it is thought that they may contribute to pattern separation and so memories may be of a higher resolution with increased AHN. Therefore reduced AHN may result in contextual confusion leading to /triggering anxiety and PTSD.

Question 25

What did Snyder et al., 2011 show?

Answer 25

As all novel theories, the neurogenesis model of depression has triggered reactions ranging from messianic conviction to total scepticism. The recent paper by Snyder et al., 2011 helps us refine this model, by introducing a crucial link with a major biological system consistently disrupted in depression, the hypothalamic–pituitary–adrenal (HPA) axis (Pariante and Lightman 2008) The main finding is that inhibition of neurogenesis induces the classical neuroendocrine phenotype described in major depression: increased HPA axis activity and glucocorticoid resistance, that is, impaired suppression of HPA axis activity by dexamethasone. As stress and high levels of glucocorticoid hormones are well known to inhibit neurogenesis, the authors suggest that stress, by inhibiting neurogenesis, may lead to enhanced HPA axis responsiveness to future stressors, and thus establish a potentially vicious circle leading to the development of depressive behaviour.

Question 26

Why do people say that AHN buffers the stress response?

Answer 26

Of course, it is possible that neurogenesis buffers the behavioural effects of stress not only by supporting a normal HPA axis activity but also through other behaviourally relevant paths, such as the recently described ability to enhance encoding of new memories and respond to contextual changes, (Sahay et al.,2011) which may be protective against behavioural despair in the face of repeated stressors.

Question 27

What is PTSD?

Answer 27

The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization.

Question 28

How is this generalisation of fear which underlies PTSD thought to occur?

Answer 28

Studies over the past two decades on the time-dependent reorganization and consolidation of episodic memories have generated tremendous insights into how loss of precision of remote aversive memories contribute to overgeneralization of fear in PTSD ( Kim and Fanselow, 1992)

Building on different theories of systems consolidation, the hippocampal index theory, and the general property of episodic memories to become more semantic with time. Hardt et al (2013) proposed that levels of interference in the hippocampus dictates the episodic-to-semantic shift in consolidated memories to influence time-dependent generalization. Specifically, a time-dependent decay of the hippocampal index would increase interference between overlapping cortical traces and render the memory less conjunctive and more semantic-like. This loss of episodic details in remote memories could induce overgeneralization of fear as fear is no longer constrained by conjunctive representation of the trauma and it is evoked by individual or elemental features of the traumatic context (Acheson et al, 2012).

One mechanism by which interference between new information (ambiguous and uncertain threats) and previously stored similar memories is minimized in the hippocampus is pattern separation in the DG–CA3 circuit. Pattern separation is the process by which similar cortical inputs are made more distinct, thereby minimizing interference during storage, and is thought to require the DG (McClelland and Goddard, 1996).

A crucial unanswered question is whether pattern separation in the DG is impaired in individuals with PTSD. Although a high-resolution structural MRI study found a selective reduction in volumes of DG and CA3 subfields in individuals with PTSD (Wang et al., 2010), how these structural changes affect pattern separation–completion balance in the DG–CA3 circuit is yet to be determined.

Question 29

Prefrontal cortex and Depression

Answer 29

The prefrontal cortex (PFC), as a significant nerve center of thinking and behavior regulation in the brain, is also associated with depression. In view of anatomical connectivity and functional specialisation, the prefrontal cortex is divided into two subregions: ventromedial prefrontal cortex (vmPFC) and dorsolateral sectors (dlPFC). VmPFC involves the regulation of affection, including the generation of negative emotion, and dlPFC mediates cognitive functions, such as intention formation, goal-directed action, and attentional control. The two sectors have both been shown to have significant roles in depression. However, their effects present discrepancies, according to reports in the literature. Functional imaging studies have shown opposite changes of activity in the two sectors: during the progression of depression, hyperactivity appeared in the vmPFC, while hypoactivity appeared in dlPFC; in the recovery phase in response to psychotherapy or medication for depression, hypoactivity was found in the vmPFC, while hyperactivity was found in dlPFC (Koenigs and Grafman 2009)

Question 30

Evidence of PFC underlying depression

Answer 30

The prefrontal cortex (PFC) is thought to participate in high-level control over generation of behaviors (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by hopeless and depressive symptoms. Warden et al.,2010 showed that electrical stimulation of the rodent mPFC projection to the dorsal raphe (DR) induces an antidepressant-like reduction in immobility in the forced swim test (FST) (

Question 31

Warden et al 2012

Answer 31

Direct optogenetic activation of mPFC neurons has no effects on behaviour. But selective activation of outputs to dorsal raphe (a major source of 5HT to the forebrain) induced increased swim behaviour in the forced swim test (FST). In the FST, rodents are placed in a tank of water from which it is not possible
to escape.

Question 32

How does ketamine treat depression?

Answer 32

Ketamine studies all that the blockade of NMDA receptor and potentiation of AMPA receptor is of key significance in ketamine’s antidepressant efficacy.

Blocking NMDA receptor and activating AMPA receptor may promote the expression of BDNF gene and promote neuroplasticity synergistically.

Ketamine produces rapid antidepressant results in some patients with severe depression (Li et al 2010) shows that chronic stress decreases synaptic connections and produces depressive like bahvioural. It was demonstrated by Li et al 2010 that ketamine reverses the deficits in synapse number as it modulates protein synthesis through mTOR signalling pathway.