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Neuron, Brain, and Behavior (III) > Basic Science of Depression and Anxiety (Suss) - 10/13/16 > Flashcards

Basic Science of Depression and Anxiety (Suss) - 10/13/16 Flashcards

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1
Q

Areas involved in mood disorders

A

Hippocampus and prefrontal cortex:

  • Cognitive abnormalities: memory impairments, hopelessness, worthlessness, guilt

Amygdala

  • Anxiety and fear
  • Dysphoric emotions

Nucleus acumbens:

  • Anhedonia
  • Decreased motivation

Hypothalamus

  • Neurovegetative symptoms (sleep, appetite, etc…)
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2
Q

Anatomical Observations in Depression

A
  • Enlarged ventricles
  • Increased CSF
  • Periventricular hyperintensity
  • Reduced volume in limbic structures:
    • Caudate and basal ganglia
    • Hippocampus
    • Frontal cortex
    • Gyrus rectus
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3
Q

Anatomical risk factor for MDD

A

Thinner right lateral cortex

(Thinning of right cortex is not associated with MDD but puts you at risk)

  • Right: attention, visuospatial memory

Current MDD/anxiety DOES correlate with thinner left medial cortex

Thicker in ORBITOFRONTAL and SUBGENUAL cortex

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4
Q

Neuronal activity correlates for depression

What structures are activated and what structures are deactivated?

A

Activated:

  • areas mediating emotional and stress response (thalamus, amygdala, and orbital and medial prefrontal cortex including subgenual cingulate cortex Cg25)

Deactivated:

  • areas implicated in attention and sensory processing (anterior cingulate cortex)
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5
Q

Anatomical observations in PTSD: Cause or Effect?

Smaller hippocampal volume

Smaller pregenual anterior cingulate cortex volume

A

Smaller hippocampal volume may predispose TO PTSD (regardless of exposure to combat)

Smaller pregenual anterior cingulate cortex volume may result FROM PTSD

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6
Q

Neuronal activity in patients with Obsessive Compulsive Disorder

A

Hyperactivity observed in:

  • Head of caudate
  • Anterior cingulate gyrus
  • Orbitofrontal cortex

Hyperactivity can be reduced in one of two ways:

  1. SSRIs
  2. CBT
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7
Q

OCD relates to Tourette’s and Huntingdon’s Disease

A

Same pathways affected resulting in hyperactivity of motor function (frontal cortex)

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8
Q

PANDAS

A

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Strep

Strep: body launches autoimmune attack against stretococcal bacteria and instead of attacking the bacteria, it attacks basal ganglia

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9
Q

Neuronal activity correlates for Panic Disorder

GABA receptors

A

Panic disorder patient has fewer GABA receptors (red) –> increased activity

GABA - normally inhibitory

Less GABA receptors means more hyperactivity

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10
Q

Hypotheses for Depression:

1. Monoamine Hypothesis

  1. Hypothalamic Pituitary Adrenal (HPA) Axis Hypothesis
A

Depression results from decreased availability of either 5-HT (raphe nuclei) or NE (locus coeruleus) or both

Metabolic levels are detected in CSF, plasma and urine:

  • Depression: decreased 5-HT, dopamine, and NE
  • Mania: increased dopamine
  • Anxiety: decreased GABA, increased NE, altered 5-HT
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11
Q

Current Anti-Depressant Drugs

Role of MAO inhibitors

Role of TCAs, SSRIs, SNRIs

A

MAOIs: prevent degradation of serotonin and NE so that more is around to act on receptor

TCAs, SSRIs, SNRIs: prevent re-uptake of serotonin or NE into presynaptic terminals

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12
Q

3 major caveats to monoamine hypothesis

A
  1. 30-46% of patients = treatment resistant
  2. Increased monoamine transmission can strengthen memory of aversive life event
  3. Long delay of efficacy
    1. Desensitization of presynaptic 5-HT inhibitor autoreceptors
    2. Neuronal adaptation:
      1. Gene expression
      2. Neurogenesis
      3. Synaptogenesis
      4. Survival
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13
Q

Hypotheses for Depression:

  1. Monoamine Hypothesis

2. Hypothalamic Pituitary Adrenal (HPA) Axis Hypothesis

A

Problems in glucocorticoid release feedback mechanism cause mood disorders

Normally, glucocorticoids feedback at multiple levels of pathway (negative feedback)

In depressed patients, either don’t have glucocorticoid receptors OR receptors are not functioning properly so there is continuous release of more glucocorticoid

Hippocampus: negatively inhibits pathway

  • If you have small hippocampus, will get less (-) feedback

Amygdala: activates pathway

  • Hyperactivity

Result: hitting this pathway on many different levels

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14
Q

Hypotheses for Depression:

  1. Monoamine Hypothesis
  2. Hypothalamic Pituitary Adrenal (HPA) Axis Hypothesis

3. Neurotrophin Hypothesis

A

Neurotrophins = growth factors in brain

Brain-Derived Neurotrophic Factor (BDNF) mediate neuroanatomical changes during stress and antidepressant treatment

  • Enhance dendritic branching
  • Enhance synapse number

Depressed patients w/o treatment:

Unchecked glucocorticoid regulation → low levels BDNF

  • High levels of cortisol
  • Patients fail dexamethasone feedback test

Depressed patients w/ treatment:

Monoamines inc levels of BDNF

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15
Q

Neurogenesis - required for antidepressant action

Lack of neurogenesis → depression-like behavior

Factors that enhance and inhibit neurogenesis

A

Enhance:

  • Neurotrophins and neuropeptides
  • Antidepressants (inc. expression of glucocorticoid receptors so that feedback mech can be reactivated)
  • Deep Brain Stimulation
  • Running
  • Seizures
  • Learning

Inhibit:

  • Stress
  • Drugs of abuse
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16
Q

Interaction between HPA Axis and Neurotrophin Hypotheses

A
17
Q

Hypotheses for Depression:

  1. Monoamine Hypothesis
  2. Hypothalamic Pituitary Adrenal (HPA) Axis Hypothesis
  3. Neurotrophin Hypothesis

4. Altered Neurotransmission Hypothesis

A

Reduced GABAergic neurotransmission → Depression

Evidence for:

  • GABA levels are reduced in CSF and plasma and fewer GABAergic neurons in depression
  • GABA agonists have antidepressant effects
  • Antidepressants affect GABAergic function

Reduced Glutamate neurotransmission → Depression

  • Glutamate levels + synthetic enzymes/transporters reduced in prefrontal cortex in depression
  • Ketamine (club drug) which inhibits NMDA receptors but increases AMPA (GluR1) receptor levels has strong antidepressant effects
    • 63% of SSRI treatment resistant patients respond to ketamine treatment
    • Works within 2 hrs of IV infusion
    • Therapeutic response lasts 2 weeks
18
Q

Hypotheses for Depression:

  1. Monoamine Hypothesis
  2. Hypothalamic Pituitary Adrenal (HPA) Axis Hypothesis
  3. Neurotrophin Hypothesis
  4. Altered Neurotransmission Hypothesis

5. Immune/Cytokine Hypothesis

A

Humoral mediators of immunity affect mood

Cytokines have effects on monoamines and HPA axis pathway

Evidence for this hypothesis:

  1. Blocking cytokine pathways in mice -> antidepressant-like phenotype
  2. Patients w/ autoimmune diseases often suffer from depression
  3. Antidepressants have anti-inflammatory effects
19
Q

Genetics of Mood Disorders

Candidate Genes

  • Monoamine hypothesis
  • HPA Axis hypothesis
  • Neurotrophin hypothesis
A

Candidate Genes

  • Monoamine hypothesis
    • 5-HT transporter (SERT or 5TT) promoter
      • If you have either form of transporter and no mistreatment as a child, you have an equal chance of getting MDD as an adult (doesn’t matter which form of transporter you have)
      • If you have short form of transporter of transporter and were mistreated as child, you have 2x odds of developing MDD compared to individual homozygous for long form of transporter
  • HPA Axis hypothesis
    • CRH receptor 1
    • GC cochaperone FKBP5
  • Neurotrophin hypothesis
    • BDNF (C281A is protective, Val66Met is risk)
20
Q

Environmental Influences (4)

A
  • Stress
  • Estrogen
    • Mood disorders more comen in women than men
    • Reduced in women w/ depression
    • Linked to HPA axis
    • Estrogen reeptors in hippocampus and amygdala
    • Enhances synaptogenesis in hippocampus (BDNF)
  • Exercise and enriched environment
    • Can cause antidepressant effects
    • Increase neurogenesis
  • Maternal care
    • Increases GR expression
    • Results in better response to stress as adult
      • Tactile stimulation of infants inc. level of glucocorticoid receptors (better feedback mech in HPA axis)
      • If child is neglected or abused, will have lower levels of glucocorticoid receptors
      • When become an adult, will have a worse response to stress
21
Q

Epigenetic Mechanisms

A

Stress inc. histone and DNA methylation

Result: reduced transciption of genes involved in antidepressant effects (inc. likelihood of depression)

Stress may affect level of genes (BDNF, Glucocorticoid receptor gene) and therefore the proteins resulting from those genes and your ability to handle stress responses as an adult

Histone acetylation PROMOTES transcription so histone deacetylase (HDAC) inhibitors act as antidepressants [GOOD THING]

22
Q

Epigenetic Effects of Stress

A

Suggests that this must be a self perpetuating effect… so if you have a child that grows up to be an adult who has a poor stress response…. as a mother, they are going to be less attentive to their children… that may feedforward

23
Q

New Treatment Approaches - Pharmacologic

  • Monoamine hypothesis
  • HPA axis hypothesis
  • Neurotrophin hypothesis
  • Neurotransmission hypothesis
  • Immune hypothesis
  • Epigenetic mechanisms
A
  • Monoamine hypothesis
    • Want to activate serotonin receptors
    • ​5-HT receptor agonists (vilazodone)
  • HPA axis hypothesis
    • ​Want to prevent activation of HPA axis
    • CRH receptor antagonists
  • Neurotrophin hypothesis
    • ​BDNF receptor agonist and antagonists (b/c there are risk factors as well as protective factors)
  • Neurotransmission hypothesis
    • ​Sub-anesthetic doses of ketamine
  • Immune hypothesis
    • To prevent cytokine activation
    • ​IL-1 beta antagonist
  • Epigenetic mechanisms
    • ​Will allow transcription of good genes that are needed for stress response
    • HDAC inhibitors
24
Q

Non-pharmacologic Treatment:

Electroconvulsive Therapy (ECT)

Deep Brain Stimulation (DBS)

A

ECT

  • Electrodes induce grand mal seizure (tonic clonic)
    • Inc. sensitivity and number of 5 HT receptors
    • Inc. neurogenesis
  • Used for antidepressant non-responders, suicidal or elderly patients (fast onset effectiveness)
  • Major side effect: retrograde amnesia

DBS

  • Subgenual cingulate cortex (Cg25), VTA/NAc or anterior limb of internal capsule for OCD and MDD
  • Possible mechanisms to inhibit activity:
    • Activate GABA neurons
    • Synaptic failure induced by high frequency stimulation
    • Interrupt cortical inputs
  • Caveats: control of timing, need to find best target

Neuron, Brain, and Behavior (III) (23 decks)

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