【Pharmacology】Antidepressants

Antidepressants

Depression: experience unusually long periods of sadness guilt and decreased interest in activities

• can occur alone or a part of a larger disorder such as bipolar disorder 
• people with bipolar disorder experience periods of depression alternating with periods of mania in which person feels abnormally optimistic euphoric and energetic 
• Treatment: Antidepressant drugs which work by elevating levels of certain neurotransmitters in the brain
• led to development of monoamine hypothesis

Content:

1. Monoamine hypothesis
2. Five different classes
3. Serotonergic neuron & Noradrenergic neuron
4. Drug
    a. Selective serotonin reuptake inhibitors (SSRIs)
    b. Serotonin norepinephrine reuptake inhibitors (SNRIs)
    c. Tricyclic antidepressants (TCAs)
    d. Monoamine oxidase inhibitors (MAOIs)
    e. Atypical antidepressants
5. Lithium
6. Reference

1. Monoamine hypothesis

• states that depression results from deficiency in one or more of the three key monoamines namely serotonin, norepinephrine and dopamine
• states that this monoamine depletion could also cause the postsynaptic receptors to upregulate, thus leading to depression
• monoamine hypothesis of gene expression suggests that there might be an abnormal functioning gene that is responsible for causing depression

**hypotheses are overly simplistic and they don't accurately explain everything that we observed in research studies. However they do give us partial explanation as to why antidepressants work.

2. Five different classes

1. Selective serotonin reuptake inhibitors (SSRIs)
2. Serotonin norepinephrine reuptake inhibitors (SNRIs)
3. Tricyclic antidepressants (TCAs)
4. Monoamine oxidase inhibitors (MAOIs)
5. Atypical antidepressants

3. Serotonergic neuron & Noradrenergic neuron

Presynaptic serotonergic neuron (serotonin producing neuron)

Postsynaptic receptors: serotonin (5-HT receptors)

• Serotonin is synthesized from an amino acid tryptophan by serotonergic neurons
• Stored in vesicles awaiting regulated release
• When these neurotransmitters are released, stimulate the receptors and transported from the synapse back to their neurons (reuptake)
• serotonin is reabsorbed by serotonin transporter (SERT)
• Back to the neuron, 
• partially repackaged into synaptic vesicles 
• partially broken down into inactive metabolites by an enzyme monoamine oxidase (MAO) 

Presynaptic noradrenergic neuron (norepinephrine producing neuron)
Postsynaptic receptors: beta and alpha-1

• Norepinephrine is synthesized from an amino acid tyrosine by noradrenergic neurons
• Stored in vesicles awaiting regulated release
• When these neurotransmitters are released, stimulate the receptors and transported from the synapse back to their neurons (reuptake)
• norepinephrine is reabsorbed by norepinephrine transporter (NET)
• Back to the neuron, 
• partially repackaged into synaptic vesicles 
• partially broken down into inactive metabolites by an enzyme monoamine oxidase (MAO) 

4. Drug

a. Selective serotonin reuptake inhibitors (SSRIs)

• inhibit reuptake of serotonin by blocking serotonin transporter
• results in increased levels of serotonin, available to bind to postsynaptic receptors
• Drug:
• Citalopram 
• Escitalopram 
• Fluoxetine 
• Fluvoxamine 
• Paroxetine
• Sertraline
• Treat: 
• Depression
• Generalized anxiety post-traumatic stress disorder
• Obsessive-compulsive disorder

Why these antidepressants take weeks to produce maximum benefit?

Recently scientists discovered that in people with depression, G-proteins tend to cluster in the patches of brain cell membranes rich in cholesterol, called lipid rafts. 

When stuck on these rafts, G-proteins lack access to molecule, called cyclic AMP which is necessary to work and transmit signals of serotonin.

However, later on it was discovered that SSRIs also tend to build up in these lipid rafts which resulted in the gradual movement of G-proteins out of the rafts toward regions of membrane where they are able to function better.

Side effects

• Insomnia → increase anxiety and irritability
• excessive stimulation of serotonin receptors in the brain
• Erectile dysfunction
• excessive stimulation of spinal serotonin receptors
• Nausea, Vomiting, and Diarrhea
• stimulation of serotonin receptors in the gastrointestinal tract & CNS
• Headache, Nausea, Vomiting, Agitation and Sleep disturbances
• abrupt withdrawal of an SSRI → temporary deficiency of synaptic serotonin

b. Serotonin norepinephrine reuptake inhibitors (SNRIs)

• work by inhibiting reuptake of serotonin via inhibition of serotonin transporter
• additionally inhibit norepinephrine transporter
• results in increased levels of both serotonin and norepinephrine, which can then bind to the postsynaptic receptors
• Drug:
• Venlafaxine
• Desvenlafaxine
• Duloxetine
• Levomilnacipran
• Treat:
• Depression 
• Anxiety and panic disorders
• Fibromyalgia as well as other pain caused by neuropathy
• effective in reducing pain (related to enhanced noradrenergic activity)

Side effects

• Similar to SSRIs
• Increase blood pressure & heart rate
• additional noradrenergic activity

c. Tricyclic antidepressants (TCAs)

• was named after their core chemical structure which contains three rings connected together
• primarily inhibit reuptake of both serotonin and norepinephrine by blocking both of their transporters
• however different tricyclic agents do this with different level of selectivity
• eg, Desipramine more selective inhibitors of norepinephrine transporter then serotonin transporter
• TCAs also block many other receptors
• alpha receptors 
• histamine receptors
• muscarinic receptors
• responsible for their side effects more than their antidepressant activity
• Drug:
• Amitriptyline 
• Amoxapine 
• Clomipramine 
• Desipramine 
• Doxepin 
• Imipramine
• Maprotiline 
• Nortriptyline 
• Protriptyline
• Treat:
• Depression
• Amitriptyline and Nortriptyline: migraine prevention & treatment of neuropathic pain
• Doxepin: Insomnia

Side effects

• Orthostatic hypotension & Dizziness
• inhibition of alpha receptors
• Sedation
• inhibition of histamine receptors
• Anticholinergic effects such as blurred vision, dry mouth, constipation and urinary retention
• inhibition of muscarinic receptors
• Cardiac conduction abnormalities
• block cardiac sodium channels and produce effects similar to antiarrhythmic agents such as Quinidine

d. Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase is a mitochondrial enzyme that degrades monoamines such as serotonin and norepinephrine.

MAO exists in two subtypes: A and B

differently distributed in tissues such as brain, gut, and liver

i. MAO subtype A 

preferentially metabolizes serotonin, but will also metabolize norepinephrine and dopamine

inhibition of MAO subtype A is thought to be responsible for antidepressant effects

ii. MAO subtype B preferentially metabolizes dopamine

MAOIs inhibit the activity of MAO enzymes, preventing breakdown of monoamine neurotransmitters, ultimately increasing their availability

Drug:

• Isocarboxazid 
• Phenelzine
• Tranylcypromine
• irreversible inhibitors of both MAO subtype A and MAO subtype B
• effective for treatment of depression
• Selegiline
• selective inhibitor of MAO subtype B
• reducing symptoms of Parkinson's disease (depletion of dopamine) 

In practice, MAOIs usually a very last choice....

MAOIs show not only high incidence of drug-drug interactions, but also drug-food interactions. 

This is because MAO enzymes are present in the gut and play important role in breakdown of monoamines ingested in food.

When inhibited, MAO enzymes can't metabolize tyramine which is contained in foods that have been aged or fermented.

Built-up tyramine is taken up into the synaptic nerve terminals where it acts as a catecholamine releasing agent.

The release of large amount of catecholamines caused by tyramine leads to hypertensive crisis and potentially a stroke.

Hence, patients that are prescribed MAOIs should avoid tyramine-rich foods

e. Atypical antidepressants

includes agents that have actions at several different sites and thus don't exactly fit into the other classes

Drug:

Bupropion 

• a weak norepinephrine and dopamine reuptake inhibitor
• Treat:
• depression
• reducing nicotine cravings and withdrawal symptoms

Mirtazapine 

• alpha-2 receptor antagonist
• By blocking presynaptic alpha-2 receptors, Mirtazapine increases noradrenergic and serotonergic neurotransmission
• have some postsynaptic serotonin receptor blocking activity & antihistaminic activity 
• sedating effects

Trazodone & Nefazodone 

• inhibit reuptake of serotonin
• block postsynaptic serotonin receptors of subtype 2a
• subtype 2a: bad serotonin receptors activation, contribute to depression
• Antagonize histaminic H1 and adrenergic alpha-1 receptors
• sedative effects 

Vilazodone 

• serotonin partial agonist reuptake inhibitor
• it partially stimulates serotonin receptors and it inhibits reuptake of serotonin

Vortioxetine

• mechanism of action that is still a little unclear
• but it is believed to be related to its ability to 
• inhibit serotonin reuptake 
• activate and block different subtypes of serotonin receptors involved in mood regulation

5. Lithium

• mood stabilizing drug
• initially for depression, but currently for bipolar disorders
• Unfortunately Lithium has a fairly narrow therapeutic index
• minor changes in dose or its blood levels can lead to toxicity
• Mechanism of action of Lithium as a mood stabilizer is still not entirely known, but a few mechanisms of action have been proposed one in particular that has been extensively
• studied states that Lithium inhibits the recycling of neuronal membrane inositol lipids

In the inositol lipid pathway, 

• G-protein coupled receptors such as serotonin receptors activate phospholipase-C (PLC)
• cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to the signaling molecules
• diacylglycerol (DAG)
• inositol 1,4,5-trisphosphate (IP3)
• IP3's action is terminated by conversion to inositol 4,5-bisphosphate (IP2)
• enzyme inositol phosphatase comes around and dephosphorylates (IP2) to inositol phosphate (IP1)
• another inositol phosphatase dephosphorylates IP1 to free inositol which is necessary for the regeneration of PIP2 

More about inositol lipid pathway: 【Covid-19】Causes & mechanisms that promote thromboinflammation in COVID-19 3e. Purinergic signaling

Lithium action

• inhibits both inositol phosphatase enzymes 
• thus decreases cellular responses to neurotransmitters that are linked to this second messenger system
• was found to inhibit glycogen-synthase-kinase-3 (GSK3) mimicking the Wnt protein signaling pathway
• Wnt proteins: secreted glycoproteins acting as a signaling molecules
• GSK3: regulates critical processes such as axon remodelling synapse formation plasticity and neurogenesis
• When they bind to receptors of frizzled family, 
• they induce certain reactions which ultimately result in inhibition of GSK3
• Abnormal activation of GSK3
• associated with several neurological and psychiatric disorders such as bipolar disorder
• as Lithium inhibits GSK3 directly and non-directly

Related link: 【Neuro】23 rare behavioral and mental disorders

6. Reference

https://youtu.be/T25jvLC6X0w

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