CNS III: Antidepressant drugs

Question 1

What is the most prevalent form of mental illness in the US and Canada?

Answer 1

Major Depression

It can be triggered by stressful incidents or idiopathic onset (no clear cause)

The role of genetic factors is unclear, there is a higher incidence of depression in offspring of parents with depression.

Usually diagnosed once debilitating.

Question 2

What are the four goals of pharmacotherapy for depression?

Answer 2

• Relieve depressive symptoms
• Prevent suicide
• Restore optimal functioning
• Prevent recurrence

Question 3

What is Iproniazid?

Answer 3

MAO inhibitor

An early antimycobacterial agent that was used for tuberculosis. Found to have anti-depressive properties

Question 4

What do tricyclic antidepressants do?

Answer 4

Block removal of NE and 5-HT from synapses

Question 5

What are the three classes of antidepressant drugs?

Answer 5

• MAO inhibitors
• Amine reuptake blocking drugs (SSRIs and nonselective: tricyclics, heterocyclics)
• α2 blockers

All three classes take 2-3 weeks before relief of symptoms.

Question 6

MAO degrades which three NTs?

Answer 6

• Norepinephrine
• 5-HT (to 5-HIAA)
• Dopamine to homovanillic acid

It is a mitochondrial enzyme and in CNS neurons, degradation happens in presynaptic neurons.

Question 7

What are three possible adverse effects due to MAO inhibitors?

Answer 7

• Hypertensive crisis from NE accumulation
• Tyramine levels can increase (MAO catalyses the cheese reaction), tyramine is a component of fermented foods and facilitates NE release (causing arrhythmia/hypertension)
• Risk of serotonin syndrome (MAOI and TCA or SSRI leading to elevated 5-HT, causing mild headache, confusion or abnormal temp regulation, coma and seizures)

Question 8

What is the mechanism of action of tricyclic and heterocyclic antidepressants?

Answer 8

Block reuptake of NT (NE, dopamine or 5-HT)

Older tricyclics affected all three of these, but hetercyclics are a little more specific to NE or 5-HT or both.

SSRIs only affect 5-HT reuptake and are used for orexia, anxiety and OCD (in addition to depression)

Question 9

What are four possible issues with long term use of tricyclic and heterocyclic antidepressants?

Answer 9

• Excessive sedation
• Antimuscarinic effects (GI effects)
• Sympathomimetic effects
• Orthostatic hypotension, EEG abnormalities (from blocking peripheral α1, dropping blood pressure)

SSRIs have fewer anticholinergic side effects than TCAs (less GI problems)

Question 10

List 5 adverse effects with SSRIs

Answer 10

• Nausea
• Headache
• Anxiety, agitation (esp in adolescents)
• Insomnia
• Sexual dysfunction

Question 11

What is mirtazapine?

Answer 11

An antidepressant/anxiolytic.

Blocks presynaptic α2 autoreceptors and increases NE and 5-HT release.

Question 12

What is bupropion?

Answer 12

An antidepressant.

Weak inhibitor of DA, 5-HT and NE uptake.

Few side effects (eg. no sedation, decreased CV effects and no sexual dysfunction. Frequently used by patients who want to quite smoking.

Question 13

Describe monoamine theory where monoaminergic treatments to depression take time to have therapeutic benefit, even when the cellular effect is immediate.

Answer 13

• Changes in post or pre synaptic receptors
• More receptors (supersensitivity), fits with increased monoamine transmission.
• Drugs that hinder monoamine transmission can cause depression symptoms

The long term effect of reuptake inhibitors is receptor population normalization and autoreceptor down regulation.

Question 14

What is the second theory for treatments to depression taking time to have therapeutic benefit, even when the cellular effect is immediate?

Answer 14

Activation of second messenger pathways can affect gene transcription: the neurotrophic hypothesis of depression.

• Structural changes (particularly in cortex and hippocampus) when depressed.
• Decrease in growth factors (eg. BDNF), synaptic plasticity and neurogenesis.
• Reduction of dendritic sprouts

Drugs that increase monoaminergic transmission may lead to the transcription of genes that lead to increase in growth factors.

Question 15

Give the three most likely hypotheses for depression

Answer 15

• Monoamine, neurotrophic and neuroendocrine systems are interelated in important ways
• Stress and steroid abnormalities (HPA axis) lead to decreased neurotrophic factors (BDNF) which in turn results in synaptic alterations in monoaminergic nerves in key brain areas affecting neurotransmission
• Chronic activation of monoamine receptors by antidepressants increases BDNF and may normalize neuroendocrine functions.