Lecture 5.2

Question 1

How do selective serotonin reuptake inhibitors (SSRIs) work?

Answer 1

They block the serotonin transport pump, preventing serotonin reabsorption.

Question 2

What is downregulation?

Answer 2

Reduced cell sensitivity to the signaling molecule.

Question 3

What is meant when a neuron is disinhibited?

Answer 3

Normal inhibitory signals are temporarily suppressed, leading to a greater chance of neuronal firing.

Question 4

How do serotonin norepinephrine reuptake inhibitors (SNRIs) work?

Answer 4

They selectively target norepinephrine and serotonin transporters.

Question 5

What is the number needed to treat (NNT) metric?

Answer 5

It estimates the number of patients who need to be treated to have an impact on one person.

Question 6

What is the number needed to harm (NNH) metric?

Answer 6

It describes how many people need to be treated or exposed to a risk factor for one person to have a particular adverse effect.

Question 7

What is habituation in terms of drugs?

Answer 7

Benefits reduce with duration of use.

Question 8

What do the 2-Hit Models of MDD suggest?

Answer 8

Vulnerability to depression develops through a combination of two factors.

Question 9

What are auto receptors?

Answer 9

Receptors that respond to neurotransmitters released from the same neuron they are located on, then affecting the neuron that they communicate to.

Question 10

What are opioids?

Answer 10

Any drug that affects an opioid receptor.

Question 11

What are opiates?

Answer 11

Drugs derived from the opium poppy.

Question 12

What are the second-generation antidepressants?

Answer 12

SSRIs and SNRIs.

Question 13

What drug laid the foundation for other SSRIs?

Answer 13

Fluoxetine.

Question 14

What is the affinity of SSRIs for norepinephrine?

Answer 14

Relatively weak affinity.

Question 15

SSRIs have no ability to block what?

Answer 15

Adrenergic receptors. Muscarinic receptors. Histamine receptors. Sodium channels.

Question 16

What type of agonist are SSRIs and thus, how do they work with the transport pump?

Answer 16

Indirect agonist, blocking the serotonin transport pump.

Question 17

In what way do SSRIs have a flow-on effect?

Answer 17

Over time, as serotonin levels rise, presynaptic 5HT-1a auto receptors become desensitized and downregulate.

Question 18

How are SSRIs administered?

Answer 18

Orally as tablets or capsules.

Question 19

What are Australian examples of SSRIs?

Answer 19

Citalopram. Escitalopram. Fluoxetine. Sertraline.

Question 20

What are the more common and predictable side effects of SSRIs? What are the less common but possible side effects of SSRIs?

Answer 20

○ More common and predictable, including:
§ Nausea.
§ Insomnia.
§ Sexual dysfunction.
§ Vomiting.
§ Drowsiness.
§ Weight gain.
§ Headache.
§ Initial increased anxiety.
○ Less common, but possible, including:
§ Bleeding (platelet serotonin).
§ Blurred vision.
§ Serotonin syndrome.
§ Arrhythmia.
§ Tachycardia.

Question 21

What are the 3 contraindications for SSRIs?

Answer 21

○ Risk factors for:
§ Seizures; due to downstream effects of GABA that lower seizure threshold (although not as significantly as TCAs).
§ Cardiovascular changes; due to prolonged QT interval (EEG) that increases risk of dangerous rhythms.
○ Other antidepressants / history of heart, lung or kidney problems / pregnancy.
○ Withdrawal, causing:
§ Flu-like symptoms.
§ Insomnia.
§ Nausea.
§ Poor balance.
§ Sensory changes.
§ Irritability.
§ Dizziness.
§ Tingling sensations.
§ Vomiting.

Question 22

Compared to placebo, SSRIs are what?

Answer 22

More effective at reducing depressive symptoms overall and more effective at reducing specific symptoms, resulting in fewer dropout rates (only for fluoxetine).

Question 23

What is the current first-line treatment for MDD?

Answer 23

SNRIs.

Question 24

Compared to SSRIs, SNRIs are what?

Answer 24

More effective at reducing depressive symptoms and associated with a more severe side-effect profile (higher treatment withdrawal/greater dropout rates).

Question 25

Compared to TCAs, MAOIs are what?

Answer 25

More effective at reducing depressive symptoms (especially in medication-naïve patients).

Question 26

Compared to MAOIs, TCAs are what?

Answer 26

Associated with a more severe side effect profile (worse or more severe symptoms ending treatment / more adverse events).

Question 27

When comparing SSRIs, SNRIs, and TCAs, ...?

Answer 27

TCAs have non-significant dropout rates and response rates. SNRIs have the second-highest response rate and lower dropout rates than TCAs. SSRIs have a significant response rate and the second-highest dropout rate.

Question 28

What are the general response patterns to MAOIs, TCAs, SSRIs, and SNRIs?

Answer 28

1/3 full remission, 1/3 some benefit, and 1/3 don't get any benefit, and habituation.

Question 29

How many people need to take SSRIs for one person to benefit?

Answer 29

6.5

Question 30

How many people need to take SNRIs for one person to benefit?

Answer 30

6

Question 31

How many people need to take TCAs for one person to benefit?

Answer 31

8.5

Question 32

What is the NNHs for SSRIs and TCAs? What does this mean?

Answer 32

NNH is 20-90 for SSRIs and 4-30 for TCAs, meaning TCAs are less tolerated than SSRIs where the majority of withdrawals are related to side effects.

Question 33

What are the 2 proposed refinements to the Monoamine Hypothesis?

Answer 33

The 2-Hit Models of MDD and Serotonergic Receptor Subtypes.

Question 34

What are the 'hits' in the 2-Hit Model of MDD?

Answer 34

Early life experiences and later life stressor.

Question 35

What does the 2-Hit Model of MDD assume?

Answer 35

An overall relationship between monoamine levels and positive mood, but this may only be the case for some people (predisposition).

Question 36

What studies support the 2-Hit Model of MDD and what evidence does it conclude?

Answer 36

Depletion studies in depressed populations, particularly those with a history of depression, where relapse or worsening of symptoms are associated with tryptophan depletion.

Question 37

If 5HT-1a receptors are located on the cell body of a presynaptic neuron, ...?

Answer 37

This would reduce serotonin neuron firing.

Question 38

The outcome of SSRIs ultimately depends on what?

Answer 38

The relative effects on the pre- and post-synaptic receptors, particularly whether the pre- or post-synaptic receptors normally have an effect. If the person has a problem with pre- or post-synaptic 5HT1a receptors (individual differences). Whether there's a relative sensitization or habituation of the pre- and post-synaptic 5HT-1a receptors..

Question 39

Pre-synaptic 5HT-1a auto receptors are normally designed to do what? How do SSRIs affect this?

Answer 39

Reduce serotonin release (hyperpolarize); as serotonin levels rise following SSRI administration, pre-synaptic 5HT-1a auto receptors habituate to excess serotonin, leading to their downregulation.

Question 40

In comparison to the Monoamine Hypothesis, what are 2 useful neurotransmitter systems where serotonin mediates that might be more beneficial to look at?

Answer 40

The Glutamatergic and Opioid systems.

Question 41

What are 4 features of glutamate?

Answer 41

Primary excitatory neurotransmitter. Contributes to over half of the brain's synapses. Main receptor is NMDA which activates sodium and calcium ion channels, causing depolarisation. In the CNS, it's involved in excitation, learning, memory, neuroplasticity, and metabolism.

Question 42

What is the theory behind the increased glutamate in depressed patients?

Answer 42

Depression may be associated with NMDA hyperfunction (subcortical) and hypofunction (cortical).

Question 43

What is the evidence for the involvement of glutamate in depression?

Answer 43

Ketamine, an NMDA antagonist, has antidepressant effects.

Question 44

In what way are opioid receptors 'action dependent'?

Answer 44

Opioid receptors, including G-protein coupled receptors that act on GABAergic neurotransmission, are action-dependent on which receptor it binds to, becoming agonism or antagonism at that receptor.

Question 45

What evidence is there for opioid involvement in depression?

Answer 45

From the 1850s-1950s, opioids were found to produce rapid reduction of depressive symptoms and suicidal ideation in depressed patients; however, it was extremely addictive.