Week 12

• Anxiety


  Differs from fear
• Anxiety disorders affect 14.4% of Australians from ages 16-85 each year and more women than men
• Some patients experience a combination of anxiety with depression or anxiety with a substance abuse disorder
• Symptoms of depression and anxiety


  • Resemble each other as both conditions can impact the mental and physical health differently in individuals
• Diagnosis of clinical anxiety or depression may take time and the use of various survey tools
• Some individuals may suffer both anxiety and depression
• Stress


  Usually short term and linked to a specific cause
• Anxiety


  May not have an identifiable reason
• Anxiety


  An umbrella term, meaning that there are many subtypes that fit under the anxiety label
• Disorders under the anxiety umbrella

  • Phobias
  • Generalised anxiety disorders
  • Social anxiety disorders
  • Panic disorders
  • Obsessive compulsive disorders
• Generalised anxiety disorder

  Persistent and excessive worry that tends to interfere with daily activities
• Phobias

  Persistent and excessive fear around a particular object, activity or situation
• Social anxiety disorders

  Intense anxiety about being embarrassed or rejected in social situations
• Symptoms of major depressive disorder

  • Chronic emptiness/change in mood states
  • Depressed mood
  • Anhedonia (lacking ability to feel pressure)
  • Weight loss or gain
  • Poor self esteem
  • Negative thought content
  • Hopelessness
  • Fatigue
  • Unyielding sadness
  • Restlessness
  • No interest of hobbies
  • Disrupted sleep
  • Lack of motivation, energy and concentration
  • Social withdrawal
  • Decline in self care
  • Thoughts of death and suicide attempts or suicide
  • Hallucinations and psychosis
• Irreversible Monoamine Oxidase Inhibitors (MAOIs)

  The oldest drug class of antidepressants
• MAOIs were originally developed for treatment of tuberculosis
• Iproniazid


  The first MAOI
• How Iproniazid works


  1. Inhibits the enzyme monoamine oxidase

  2. Monoamine oxidase breaks down neurotransmitters such as serotonin, norepinephrine and dopamine in the brain

  3. Inhibiting monoamine oxidase increases the levels of serotonin, norepinephrine and dopamine in the brain, which alleviates the symptoms of depression
• MAOI mechanism of action

  1. MAOI is capable of blocking the intracellular MAO enzyme

  2. The MAO enzyme is responsible for the degradation of monoamines in their respective pre-synaptic neurons

  3. Protection of 5-HT or noradrenaline from degradation means that they are packaged more quickly into synaptic vesicles for re-release, enhancing the speed with which the pre-synaptic neuron can respond to an action potential and therefore alleviates the presumed deficiency of monoamines in depression

  4. There are two different type of MAO enzymes: MOA-A works on noradrenaline and serotonin, MOA-B metabolises dopamine within the CNS

  5. MOA-A is present in the digestive tract where it serves an important role in metabolising dietary tyramine

  6. If MAO-A is inhibited by MAOIs taken orally, tyramine is absorbed into the blood supply, making its way to the BBB which it readily crosses

  7. Tyramine can pass through the reuptake transporters for noradrenaline and subsequently displaces noradrenaline from it synapses, leading to its unregulated release into synapses, which may cause hypertensive crisis, which may be fatal due to increase in blood pressure, heart rate, heart palpitations and sweating
• Common side effects of MAOIs

  • Dry mouth
  • Nausea
  • Diarrhoea or constipation
  • Headache
  • Insomnia
  • Drowsiness
  • Dizziness or light-headedness
• Less common side effects of MAOIs

  • Hypotension
  • Reduced sexual desire
  • Weight gain
  • Muscle cramps
• Tricyclic antidepressants (TCAs)


  • The first TCA was imipramine, initially created to treat schizophrenia
  • TCAs work on many different receptors and receptor subtypes
  • TCAs are known for their lack of receptor selectivity, especially at muscarinic, alpha-adrenergic and histaminergic receptors
• TCA mechanism of action


  Tricyclic antidepressants block SERT, NET and histamine H3 receptor and MAChr, which increases serotonin and norephedrine in the synaptic cleft
• Tricyclic antidepressants


  • Due to their lack of receptor selectivity, TCAs have a narrow therapeutic window
  • Many patients struggle with tolerating side effects
• Side effects of TCAs

  • Dry mouth
  • Blurred vision
  • Constipation
  • Difficulty urinating
  • Sedation
  • Sexual problems
  • Weight gain
• Alcohol interacts with TCAs

  Increasing sedation
• Selective serotoninergic reuptake inhibitors (SSRIs)


  • A class of medications widely used in the treatment of depression, anxiety disorders and other psychiatric conditions
  • SSRIs represent one of the most commonly prescribed types of antidepressants due to their efficacy, safety profile, and relative tolerability compare to older antidepressants like tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs)
  • Fluoxetine is the first SSRI
  • They were designed to target the serotonin system without affecting neurotransmitters, which help minimise side effects associated with older antidepressants
• Clinical use of SSRIs

  • Depression: SSRIs are the first-line treatment for major depressive disorders due to their effectiveness and safety profile
  • Anxiety disorders: SSRIs are used in the treatment of various anxiety disorders, including generalised anxiety disorder, panic disorder and social anxiety disorder, as well as obsessive-compulsive disorder
  • Other conditions: SSRIs are prescribed for a range of other conditions such as post-traumatic stress disorder, premenstrual dysphoric disorder and certain eating disorders
• SSRI mechanisms of actions

  Selective serotoninergic reuptake inhibitors inhibit the serotonin reuptake transporter, which slows the clearance if serotonin and increases the likelihood of it binding to post-synaptic receptors, which is though to improve mood
• Common side effects of SSRIs

  • Nausea
  • Difficulty going to sleep
  • Nervousness
  • Headaches
  • Sexual problems
• Rarely SSRIs cause diarrhoea
• Very rarely SSRIs can cause extreme agitation, jerky movements, a high temperature and confusion - these are symptoms of serotonin toxicity and require urgent medical attention
• Neurophysiology: auto receptors


  1. Activation of the post-synaptic 5-HT1A receptors are key for anti-depressant effects as well as other important physiological functions depending in the brain region affected. In addition there are pre-synaptic 5-HT1A auto receptors on serotonergic neurons

  2. In normal functioning, auto receptors detect the presence of serotonin that is released into the synaptic gap following an action potential by the serotonergic neuron itself

  3. Activation of the auto receptor leads to gradual reduction in serotonin release - a negative feedback process

  4. Activation of postsynaptic 5-HT 1A receptors mediates therapeutic properties, whereas activation of raphe autoreceptors is implicated in delay of therapeutic inset of antidepressants

  5. Hypothalamic 5-HT 1A receptors are involved in thermoregulation and neuroendocrine control whereas septum/hippocampal receptors control Ach release and aspects of memory function

  6. A biased agonist preferentially targeting cortical 5-HT 1A receptors could exhibit a wider margin between therapeutic effects and side effects

  7. SSRI treatment results in higher concentrations of serotonin and over time it is thought the auto-receptors are downregulated and desensitized

  8. As a response to serotonin stimulation, the serotonergic neuron reduces the number of 5HT1A receptors, this phenomenon is known as downregulation

  9. Following this 2-3 week period there are less 5HT1A receptors expressed and the neuron is now disinhibited and as a consequence the firing rate is increased, which increases serotonin release to the synaptic space, stimulating postsynaptic serotonin receptors
• Serotonin and noradrenaline reuptake inhibitors (SNRIs)

  • The first SNRI was venlafaxine
  • Venlafaxine was developed on the hypothesis that increasing the levels of more than one neurotransmitter could provide a more comprehensive treatment for depression
  • Duloxetine further expanded the utility of SNRIs by not only being effective for major depressive disorder but also being approved for generalised anxiety disorder, fibromyalgia and chronic musculoskeletal pain
• SNRI mechanisms of action

  1. SNRIs antagonise reuptake transporters of both noradrenaline and serotonin

  2. At lower doses SNRIs primarily inhibit the reuptake of serotonin, with relatively little effect in norepinephrine reuptake, this selective action is similar to SSRIs, making them functionally similar at these doses

  3. As the dose increases the effect of SNRIs on norepinephrine reuptake becomes more pronounced

  4. The dual inhibition is important for a SNRIs effectiveness in treating a broader range of symptoms or more complex cases of depression and other disorders

  5. The increased influence on norepinephrine is believed to contribute to improved energy, alertness and overall cognitive function, as well as pain modulation

  6. SNRIs selectively inhibit the reuptake of serotonin and norepinephrine

  7. SNRIs are designed to be selective for serotonin and norepinephrine receptors without affecting other systems significantly, which helps to minimise side effects

  8. Tricyclic antidepressants also increase serotonin and norepinephrine levels by inhibiting their reuptake, but they are nit selective

  9. TCAs also affect other neurotransmitter systems, including muscarinic and histamine receptors, which leads to a broader range of pharmacological effect and associated side effects
• Noradrenergic and specific serotonergic antidepressants (NASSAs)

  Mirtazapine is a noradrenergic and specific serotonergic antidepressants, which is a unique antidepressant that targets both noradrenergic and serotonergic neurotransmitter systems but with a mechani
• Norepinephrine


  Increased influence contributes to improved energy, alertness, cognitive function, and pain modulation
• SNRIs


  Selectively inhibit the reuptake of serotonin and norepinephrine
• SNRIs


  Designed to be selective for serotonin and norepinephrine receptors without affecting other systems significantly, which helps to minimise side effects
• Tricyclic antidepressants (TCAs)


  Also increase serotonin and norepinephrine levels by inhibiting their reuptake, but they are not selective