Lecture 5

• Anxiolytics


  Drugs used to treat anxiety
• Examples of current anxiolytics

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin noradrenaline reuptake inhibitors
  • Tricyclic antidepressants
  • Monoamine oxidase inhibitors
  • Buspirone
• Selective serotonin reuptake inhibitors (SSRIs)


  • First line of treatment
  • Used for most anxiety disorders
  • Generally well tolerated
  • Usually only used if comorbid with depression
• Serotonin noradrenaline reuptake inhibitors


  • Used for generalised anxiety disorder
• Tricyclic antidepressants


  • Used for panic disorder, generalised anxiety disorder
• Monoamine oxidase inhibitors


  • E.g. imipramine
  • Used for panic disorder, generalised anxiety disorder
• Buspirone


  • 5-HT1A receptor agonist
  • Only used for generalised anxiety disorder
• Use of anxiolytics depends on efficacy vs side effects - e.g. MAOIs have serious side effects so only used if other treatments ineffective
• Anxiolytics have a delayed onset of action
• Mechanism of action of current anxiolytics

  1. SSRIs, TCAs and SNRIs: Block 5-HT reuptake into the presynaptic neurone, prolonging 5-HT presence in the synaptic cleft

  2. MAOIs: Inhibit monoamine oxidase enzyme for metabolising 5-HT into 5-HIAA, increasing 5-HT supply

  3. Buspirone: Agonist at 5-HT1A autoreceptor (inhibitory), decreasing amount of serotonin in the synaptic cleft
• Initial increase then decrease in anxiety after 6 weeks with main anxiolytic drugs


  Except for buspirone, which doesn't cause initial increase but has a delayed therapeutic action
• 1. 5-HT receptors involved in anxiogenesis

  • 5-HT1A: Inhibitory receptors, decreased function = anxiety
  • 5-HT2C: Agonists increase anxiety-like behaviour, antagonists reduce anxiety-like behaviour
• How chronic SSRIs affect anxiogenesis

  1. Decrease CRF mRNA increase caused by stress, reducing activation of the amygdala

  2. Decrease HPA axis response

  3. Reverse insensitivity of noradrenergic system
• Chronic SSRIs


  Promote new positive emotional associations through neurogenesis/dendritic regrowth, facilitated by increased brain-derived neurotrophic factor
• Problems with SSRIs


  • Common adverse events: insomnia, other sleeping problems, sedation, headache
  • Non-responders - biological and environmental factors contribute to SSRI response
  • Delay in onset leading to dropout
  • Increase in initial anxiety
• Noradrenergic anxiolytics


  • Beta blockers: Non-selective β1 and β2 adrenergic receptor antagonists, block action of adrenaline and NA, used to control persistent hypertension, tachycardia triggered anxiety, migraine and headaches
• Examples of CRF receptor antagonists


  • CRF-R1 and CRF-R2 receptors
  • Development stopped due to elevation in liver enzymes
  • Currently no treatments recommended
• Non-sedating anxiolytic is the holy grail of pharmacology
• Ideal GABAA receptor anxiolytic


  • Higher affinity for a2/3 subunit containing receptors than a1 subunit
  • Higher efficacy at a2/3/5 subtypes than a1
  • Reduced anxiety without sedation
• Examples of GABAA receptor anxiolytics in development


  • CVL-865 (Pfizer): Higher affinity for a1 than 2/3/5, higher efficacy at 2/3/5 subtypes, reduced anxiety in preclinical studies
  • MRK-409 (Merck): Equal affinity for a1/2/3/5 subtypes but higher efficacy at a3, no sedation in preclinical studies
  • TPA-023 (Merck): Equal affinity for a1/2/3/5 subtypes but efficacy only at a2/3, reduced anxiety and no sedation in preclinical studies
• Challenges with current clinical trials of GABAA receptor anxiolytics: Preclinical models failed to predict sedation, humans particularly sensitive to a1 efficacy
• How research can assess acute 5-HT anxiolysis

  1. Microinjection of 5-HT into the amygdala increases anxiety

  2. Acute SSRIs and TCAs increase anxiety
• Chronic stress/glucocorticoids


  Decrease 5-HT1A receptor expression
• Animal tests for 5-HT2C receptor expression


  1. Social interaction test: Quantify time interacting with others

  2. Elevated T maze: Quantify latency to enter open arm

  3. Chronic antidepressant treatment reduces 5-HT2C receptor facilitated neurotransmission in basolateral amygdala
• Research on chronic SSRIs and anxiogenesis

  1. Chronic SSRIs decrease CRF mRNA increase caused by stress

  2. Chronic SSRIs decrease HPA axis response

  3. Chronic SSRIs reverse insensitivity of noradrenergic system
• Research on CRF receptor antagonists

  SC admin of R121919 has anxiolytic effect on high anxiety rats on elevated-plus maze, no significant changes in low anxiety rats