PDA III - Exam 3: Antidepressants and Depression - RW

What type of antidepressant is Fluoxetine?

SSRI

What makes Fluoxetine unique in terms of selectivity?

It's an SSRI, without high SERT selectivity

It's active metabolite, Norfluoxetine, is a potent SERT inhibitor

Why dose Fluoxetine, an SSRI, not have high SERT selectivity?

Due to stereochemistry and active metabolites

How does stereochemistry affect Fluoxetines SERT selectivity?

Fluoxetine is a racemic mixture of R- and S-enantiomers

Only the S-enantiomer is highly selective for SERT

What is the active metabolite of fluoxetine?

Norfluoxetine

Which TCAs are more selective for SERT?

Tertiary amine TCAs

Imipramine, Amitriptyline, Doxepin, Clomipramine

How do active metabolites affect Fluoxetines SERT selectivity?

S-norfluoxetine is a potent and highly selective SERT inhibitor

S-enantiomer is stereo-selectively created by metabolism at a higher rate than the R-enantiomer

So, once Fluoxetine is metabolized it becomes SERT selective

Which TCAs are more selective for NET?

Secondary amine TCAs

Desipramine, Nortriptyline, Protriptyline

What is the common ring structure TCAs share?

6-7-6 tricyclic ring structure

What are characteristics of the TCA ring structure?

Not required for binding with SERT or NET

Adds lipophilicity

Needed for CNS active drugs to reach the CNS

What structural characteristic of TCAs are essential for activity?

3-carbon spacer between the N on the ring and the N on the side chain

What effect does side chain chemistry have on TCAs selectivity?

Tertiary amine TCAs are more selective for SERT

Secondary TCAs are more selective for NET

What tertiary amine is the exception to the rule, and is more selective for NET?

Doxepin

What are characteristics of tertiary amine TCAs structures?

N bonded to 3 carbons

What are characteristics of secondary amine TCAs structures?

N bonded to 2 carbons

Which TCAs are tertiary amines?

Imipramine

Amitriptyline

Doxepin

Clomipramine

Which TCAs are secondary amines?

Desipramine

Nortriptyline

Protriptyline

How are TCAs metabolized?

Extensively metabolized by CYP450

Via demethylation and hydroxylation

How do TCAs block SERT/NET activity?

TCA's bind to a distinct site on the transporter

(diff than NT and other ADs)

Binding causes conformational change

Reduces NT binding affinity for the transporter

What structural characteristic of TCAs causes them to bind extensively to receptors?

Planar structure

Able to fit into sterically tight binding sites

Which TCA side chain chemistry is associated with more side effects?

Tertiary amines

Do tertiary or secondary amine TCAs cause more side effects?

Tertiary amines

Are more SERT selective or more NET selective TCAs associated with more side effects?

More side effects with SERT selective drugs (tertiary amines)

What receptor is associated with sedation side effects?

H1

What receptor is associated with orthostatic hypotension side effects?

a1

What receptor is associated with dry mouth side effects?

M1

What receptor is associated with urinary retention side effects?

M1

What receptor is associated with constipation side effects?

M1

What side effects are associated with TCAs?

Sedation

Orthostatic hypotension

Dry mouth

Urinary retention

Constipation

More SEs w/tertiary amines

What factors limit the use of TCAs?

Lots of ADRs

Overdose may be lethal (CV SEs)

Since tertiary amine TCAs cause more SEs, why would they ever be used?

Sedation beneficial in insomnia

Some pt.'s may respond better to tertiary amines

Are SSRIs more selective for SERT or NET?

SERT

What is the common structural characteristic of SSRIs?

All have ionizable amine

Why do all SSRIs have an ionizable amine?

Contributes to binding with target site

Via ionic binding with basic amino acid residues

Which SSRIs are single isomers?

Escitalopram

Paroxetine

Sertraline

What is the definition of enantiopure?

Only contains one enantiomer

What is the definition of diasteriopure?

Drug with 2 chiral centers, that are diaseromers

Are SNRIs more selective for SERT or NET?

Close to equal selectivity for SERT and NET

What are structural characteristics of Arylpiperazine antidepressants?

All contain piperazine ring

Attached to an aryl (aromatic ring) group

Which drugs are examples of Arylpiperazine antidepressants?

Trazodone

Vilazodone

Vortioxetine

"Atypical ADs"

What is meant by the term "atypical" antidepressaants?

Mechanism involves something other than just inhibiting NT reuptake

What are characteristics of Trazodones binding profile?

Weak SERT Inhibitor

Antagonist at 5-HT1A receptors

What are characteristics of Vilazodone binding profile?

Inhibits SERT

Partial agonist at 5-HT1A receptors

What are characteristics of Vortioxetine binding profile?

Inhibits SERT

Antagonist at multiple 5-HT receptors

What are common characteristics of antidepressant metabolism?

ADs are extensively metabolism

Many have active metabolites that extend their DOA

CYP inhibition is common

What is the primary CYP isoform metabolizing TCAs and a majority of other ADs?

CYP2D6

Which CYP isoforms are major contributors to AD metabolism?

**2D6

3A4

1A2

C19

2B6

Metabolism of which 2 ADs is distinct?

Bupropion and desvenlafaxine

What is different about the metabolism of Bupropion?

Metabolized to hydroxy-bupropion and tow diastereoisomers

What is different about the metabolism of Desvenleflaxine?

Metabolized by UGT

How is fluoxetine metabolized?

Metabolized by CYP2D6

Norfluoxetine is the most common metabolite

Active as an SSRI

How is trazodone metabolized?

Metabolized by CYP3A4

To an active (MCPP) and inactive metabolite

Minor pathway involves metabolism to a reactive metabolite that causes hepatotoxicity

What is depression defined as?

A disorder of mood ann emotion

What are the types of depression?

Major (unipolar) depression

Bipolar depression

Reactive (exogenous/secondary) depression

What is major depression defined as?

Recurring episodes of dysphoria (sadness) and negative thinking

Due to biochemical deficits in the brain

What is bipolar depression defined as?

Episodes that cycle between depression and mania

What is reactive depression defined as?

Normal state of sadness, felt in response to loss or disappointment

Not a mental illness, unless it is disproportionate or prolonged

How many symptoms are required for major depression diagnosis?

At least 5 symptoms for at least 2 weeks

1 of the 5 has to be depressed mood or anhedonia

What are criteria for major depression diagnosis?

≥5 symp for ≥2 weeks

Symp. severe enough to disrupt life

Not caused by drug abuse, medication, or illness

Can be w/ or w/o psychosis

What is described by Atypical depression?

Increased appetite

Hypersomnia

What are symptoms of major depression?

*Depressed mood

*Anhedonia (inability to experience pleasure)

Inc. or dec. in appetite

Insomnia or hypersomnia

Inc. or dec. in psychomotor (physical) activity

Fatigue

Loss of self-esteem

Diminished ability to think, concentrate, and make decisions

Suicidal thinking

Will untreated depression resolve on it's own?

Untreated depression resolves in 6-9 months

But episodes will continue to occur with increasing frequency and intensity

What usually precedes the first episode of depression?

Stress

Later episodes can occur w/o stress

What is described by the Monoamine Hypothesis of major depression?

Depression is a result of low monoamine levels

Which NTs are monoamines?

NE

5-HT

DA

Which monoamines are the main ones thought to be involved in depression?

NE and 5-HT

Where did the Monoamine Hypothesis of major depression originate from?

Reserpine

An irreversible VMAT inhibitor that prevents monoamine storage in vesicles, leading to dec. levels

SE of this drug was depression

Thought to be due to monoamine depletion

What evidence supports the Monoamine Hypothesis of major depression?

ADs work by increasing monoamine signaling

Depressed patients have low levels of NE and 5-HT metabolites

(suggesting low utilization)

What is a shortcoming of the Monoamine Hypothesis of major depression?

ADs that target monoamine systems have clinical lag

Despite causing an immediate inc. in NT signaling

What activates the HPA axis?

Stress

What normally occurs in the HPA axis once it is activated by stress?

Hypothalamus releases CRF/CRH

CRH acts at the pituitary and causes ACTH release

ACTH acts at adrenal gland and causes cortisol release

What is the effect of cortisol release in the HPA axis?

Exerts negative feedback on the hypothalamus and hippocampus

Preventing further cortisol release

(and toxic cortisol buildup)

What happens to the HPA axis in depressed patients?

All stress hormones are higher in the HPA

What happens to stress hormone levels in the HPA axis in patients with depression?

High CRF levels

Which causes high ACTH levels

Which causes high cortisol levels

What happens to the pituitary and adrenals in depression patients?

Pituitary and adrenals are enlarged

Due to hypersecretion of stress hormones

What is the cause of the dysfunction in the HPA axis in patients with depression?

Abnormalities in the hypothalamus

What hypothalamus abnormalities cause HPA axis dysfunction?

Too many CRF producing cells, producing too much CRF

Not responding to negative feedback

What is a possible cause of hypothalamus abnormalities in depression?

Genetic variation

Causing an increased number of CRF producing cells in the hypothalamus

Pt. more prone to developing major depression

What are characteristics of the normal circadian rhythm of cortisol?

Cortisol begins to increase at 6 am and peaks in the early morning

Then decreases until the next morning, when the cycle restarts

What is the effect of depression on the circadian rhythm of cortisol?

Circadian rhythm of cortisol is flatter and higher in depression

High cortisol all day every day in depression patients

What is described by the Glucocorticoid Hypothesis of major depression?

Depression due to atrophy of dendrites and spines in the PFC/hippocampus and decrease neurogenesis in the hippocampus

Why is stress thought to cause depression, based on the Glucocorticoid Hypothesis of major depression?

Prolonged high glucocorticoid levels cause hippocampal neurons to become damaged and unresponsive

What is the effect of the hippocampus on CRF release?

Hippocampus inhibits CRF release by the hypothalamus

Via glucocorticoid receptors

(which respond to cortisol)

What is the effect of cortisol induced damage to hippocampal neurons?

Damaged hippocampal neurons become unresponsive to cortisol

Can't perform negative feedback on hypothalamus

Hypothalamus continues to release ACTH

More and more cortisol is released

Causing more damage

What is the effect of cortisol (stress) on hippocampal neurons?

Cortisol causes atrophy of hippocampal neurons

Loss of dendrites and spines

What is the effect of loss of dendrites, due to atrophy, in the hippocampus?

Neuron's function is impaired

Hippocampus can't inhibit hypothalamus

In what areas of the brain does cortisol (stress) cause loss of dendrites and spines?

Hippocampus and pre-frontal cortex

What are the two effects of cortisol (stress) in the hippocampus)

Loss of dendrites and spines

Dec. neurogenesis

Where does neurogenesis occur?

Hippocampus

Does neurogenesis occur in the PFC?

NO

Why are neurons not able to replace the neurons lost to cortisol atrophy?

Neurons are post-mitotic

Can't undergo mitosis to replace lost neurons

What cells are able to perform neurogenesis?

Neural progenitors (aka neuronal precursors)

What happens during neurogenesis?

Neural progenitors undergo mitosis

Differentiate into a new neuron

Why are neuronal progenitors able to perform neurogenesis?

Not yet differentiated into neurons

Still mitotic

What is the effect of stress (cortisol) on neurogenesis?

Cortisol inhibits neurogenesis

How does cortisol inhibit neurogenesis?

Either kills neuronal progenitors, or prevents them from becoming neurons

How does Glucocorticoid Hypothesis of major depression explain the clinical lag of antidpressants?

Takes time to develop dendrites

(spines develop quickly)

Takes time for neural progenitor cells to undergo neurogenesis, and then exert an effect

What evidence supports the Glucocorticoid Hypothesis of major depression?

Depressed patients have decreased hippocampal vol.

Due to loss of neurons

Both ADs and ECT decrease CRF levels

(hippocampus inhibiting the hypothalamus after therapy)

What are neurotrophins?

Short peptides

Stimulate migration, development, and survival of neurons

What is BDNF?

brain derived neurotrophic factor