Depression and Anxiety

• Depression and stress-related mood disorders impact 17% of the population, personal suffering, social and economic burden
• Neurobiology hasn't been fully identified but a result from molecular and cellular abnormalities that interact with genetic and environmental factors
• Its complexity and heterogeneity has made it difficult to define, diagnose and treat
• Available antidepressants are widely prescribed but have significant limitations including weeks to months for response and low response rates with 1/3 responding to first drug prescribed and 2/3 after multiple trials taking months even years
• Typical antidepressants

  Acutely block reuptake or breakdown of monoamines 5-hydroxytrptamine/ serotonin and norepinephrine
• SSRIs

  1. HT selective reuptake inhibitors which are most highly prescribed, leading to monoamine hypothesis
• Despite the initial rapid impact of antidepressants on neurotransmitters there is a delay before experiencing therapeutic effects, this is because it is more than just the immediate impact on neurotransmitters it is the slow onset adaptation in downstream signalling pathways and the regulation of specific genes – meaning it involves complex and gradual changes at cellular and genetic levels – neuroplasticity, neuroprotection and neurogenesis in adult brain
• Monoamine hypothesis proposed


  1965
• Monoamine hypothesis

  • Lack of amines = depression
  • Too much of the amines = mania
  • NADR / 5HT affecting drugs could elevate mood
• MAO inhibitors

  Break down noradrenaline by inhibiting monoamine oxidase
• Monoamine hypothesis evidence: MAO inhibitors cause increases in amine concentrations by inhibiting their catabolism. Inhibiting reuptake of amines into the presynaptic terminal increases the concentration and residence time in the synaptic cleft. Reserpine depletes the monoamines, exacerbating depression
• Monoamine hypothesis problems: Therapeutic effects are delayed 3-4 weeks, some effective atypical antidepressants don't modulate amine levels in synaptic cleft, cocaine inhibits uptake of noradrenaline but it is not an effective antidepressant, precursor amino acids increase levels of amines but not generally effective antidepressants
• NDMAr antagonists or ketamine produce rapid antidepressant action in those who are resistant to typical antidepressants, increasing glutamate transmission and induction of synaptogenesis
• SSRIs

  Block monoamine reuptake by the 5-HT transporter SERT increasing serotonin levels in synaptic cleft. Increased serotonin levels leads to regulation of postsynaptic GPCRs which transmit signals within the cell, activating second messenger systems like PKA-cAMP response element-binding (CREB) pathway. CREB is a transcription factor involved in gene expression
• Chronic SSRI treatment will activate the cAMP-PKA-CREB pathway because desensitisation of 5-HT autoreceptors are necessary so they becomes less sensitive or desensitised to the elevated serotonin levels. Serotonin therefore has a slow neuronal response
• Glutamate signalling

  Produces fast excitation of neurons through AMPAr and NMDAr receptors, rapid intracellular signalling like CAMK
• Both glutamate and serotonin signalling pathways lead to various physiological responses like synaptic plasticity and gene expression
• BDNF

  Brain-derived neurotrophic factor is a protein responsible for promoting survival, growth and differentiation of neurons. Produced in hippocampus for learning and memory and in the cortex for higher cognitive function and basal forebrain involved in motivation and emotional regulation. It is a target for antidepressant treatment and CREB signalling. BDNF is involved in neuroprotection (protects from damage or death), neuroplasticity and neurogenesis (formation of neurons) – crucial for maintaining and forming new neuronal connections
• SSRIs are though to induce expression of BDNF, increasing its levels
• Polymorphism of BDNF

  Variation in its DNA sequence, known as Val66Met (variation at position 66 in BDNF gene either a valine or methionine amino acid). There is altered functioning of BDNF, impaired trafficking of BDNF to dendrites affecting release of BDNF and may have implications for neuronal function
• BDNF and its receptor tropomyosin-related kinase B TrkB


  A transmembrane receptor with an intracellular tyrosine kinase domain. BDNF binds to TrkB activating intrinsic tyrosine kinase activity and a series of signalling cascades such as PIP3K-AKT pathway and MAPK pathway, mediating diverse effect sof BDNF on neurons survival growth and plasticity
• Stress shown to decrease expression of BDNF in hippocampus and PFC. Antidepressants increases mRNA expression but requires chronic treatment
• Antidepressants don't increase the release of BDNF (relates to delayed response and limited efficacy of these drugs) but eventually will induce changes in BDNF expression
• Studies show that BDNF is able to produce antidepressant response in behaviour models of depression. Genetic deletion or blockade of BDNF can block the effects of antidepressant treatments but deletion alone is not sufficient to induce depressive behaviour in rodent models
• Dendritic spines


  Small protrusions on the branches of neurons crucial in forming connections with other neurons (synapses) and communication. Mushroom, thin and stubby types. Newer spines are dynamic but as synaptic circuits mature spine dynamics decrease. Immature thin spines may undergo experience-dependent elimination or convert to mushroom type to form stronger synaptic connections
• Reduced spine density in rodent models of depression in PFC and hippocampus, in contrast dendritic arborisation (branching) and spine density increased in amygdala leading to hyperactive firing state, this means there is loss of inhibitory input to this region (contributing to hyperactive state)
• Hypothalamic neurons


  Receive signals from noradrenaline (NA) and serotonin (5-HT) which modulate activity of these neurons and their response to stress
• CRH

  Corticotrophin releasing hormone is a key mediator in initiating the stress response by signalling the activation of the HPA axis
• NA and 5-HT

  Regulate mood arousal and attention involved in hypothalamus fine-tuning of stress response. NA released by sympathetic nervous system during fight or flight response, suggesting it contributes to the early stages of stress response preparing the body for a rapid and intense reaction to stress. 5-HT role in mood regulation, emotional and behavioural components to stress, suggests influence in emotional processing and coping mechanisms
• Cortisol


  Released in response to ACTH, serves multiple functions including energy mobilisation and immune regulation, participates in negative feedback loop acting on hippocampus and hypothalamus to inhibit further release of CRH and ACTH
• Negative feedback loop helps prevent and exaggerated and prolonged stress response
• Depressed patients show: High levels of cortisol – overactive HPA axis due to chronic stress or impaired negative feedback regulation, Elevated levels of CRH in CSF – increased activity of HPA at the hypothalamus, Increased number of CRH-secreting neurons – elevated CRH levels, CRH binding sites are reduced in the frontal cortex – chronic exposure to stress commonly seen in depression can lead to downregulation of CRH receptors as a compensatory mechanism, Dysregulated circadian cortisol patterns – high levels in the morning and lower in the evening, Reduced hippocampal volume – chronic stress and elevated cortisol, Increased amygdala sensitivity – heightened emotional responses and generation of negative affective states
• Blockade of CRF-1 receptors reduces anxiety and depressive symptoms – supports idea that CRH dysregulation implicated in pathophysiology of depression
• Tricyclic antidepressants TCAs

  Block reuptake of serotonin and NA in synaptic cleft leading to increased levels. Desipramine and imipramine reverse synapse loss induced by stress. Imipramine increase length of apical dendrites in hippocampus and PFC. Amitriptyline enhanced spine density in hippocampal neurons
• Tianeptine


  Reverses stress-induced plasticity changes in amygdala and blocks neuronal atrophy in CA3 neurons caused by stressful events, increases NMDA and AMPA currents in hippocampus
• Monoamine oxidase inhibitors MAOIs

  Blocks MAO preventing breakdown of serotonin, NA and dopamine. Irreversible: isocarboxazid, phenelzine, tranylcypromine – non-selective and these can lead to hypersensitive response to tyramine. Reversible: moclobemide – better and newer MAOI minimizes side effects and effects aren't permanent, more selective
• Selective serotonin reuptake inhibitors SSRIs

  Targets reuptake of serotonin leading to increased levels in synaptic cleft. Fluoxetine 4 week treatment increases dendritic spine density inCA1, increasing mushroom spines and decrease in thin spines in proximal dendrites CA1. Only works chronically and side effect is anxiety
• Atypical antidepressant: mirtazapine


  Antagonises adrenergic receptors leading to increased NA and 5-HT release, also blocks histamine receptors. Blocking alpha adrenergic receptors can lead to sedative effects, blocking beta can reduce physiological responses to stress like increased heart rate and blood pressure, blocking H1 histamine receptors can cause sedation and drowsiness which can be beneficial with insomnia or anxiety associated with depression
• Electroconvulsive therapy ECT

  Induces controlled seizure which can increase BDNF levels only for severe life threatning depression who don't respond to other treatments but can cause short term memory loss
• Transcranial magnetic stimulation TMS

  Uses magnetic fields to stimulate nerve cells in the brain, major depression, more localised compared to ECT but administration can be challenging. Used in combination with other treatments