Enhances serotonergic tone / activity throughout the body: - Gut = nausea, GI upset, diarrhea - CNS:spinal cord and above = diminished sexual function and interest - HIS: Inhibits serotonin reuptake into platelets, reduced coagulation, increased risk of bleeding - CVS:Inhibits nitric oxide synthase = favors vasoconstriction

L50 – Anti-depressants Flashcards by Max Kam

List 7 signs and symptoms of depression.

Feelings of sadness, emptiness, hopelessness
diminished pleasure in life activities
Significant changes in appetite, body weight
Feelings of self-loathing / worthlessness / guilt
Changes in your sleep pattern
Increased anger / irritability
Fatigue / loss of energy

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Classify different severity of depression? How to Dx?

Major depression disorder:

At least 5 that interfere with patient’s ability to function
> 2 weeks

Dysthymic disorder (dysthymia)

At least 2 sym./signs
> 2 years

Minor disorder

At least 2 sym/signs
about 2 weeks

Dx by clinical interview and tests: Stroop test, Beck Depression inventory, Hamilton depression scale

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2 hypothesis in changes in brain chemistry causing depression disorder?

Monoamine hypothesis

Neurotropic hypothesis

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Outline the monoamine hypothesis

Depression is caused by low level or a deficit in function of neurotransmitters
All antidepressants enhance synaptic availability of serotonin, norepinephrine or dopamine

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Shortcomings of monoamine hypothesis

Many depressed patients do not have alterations in function or levels of monoamines
Benefits of monoamine anti-depressants take time to work, feel worse during first week
Removal of serotonin precursor doesn’t lead to depression

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Outline the neurotrophic hypothesis?

impaired growth of neurons is associated with depression
Loss of volume in hippocampus causes decrease Brain-derived neurotropic factor (BDNF): regulate neural plasticity, neurogenesis, emotions
Antidepressants increase BDNF and neuron growth

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Shortcomings of neurotrophic hypothesis?

BDNF knockout mice do not have increase in depressive or anxious behaviors.
Social-stressed animals showed increase BDNF levels rather than a decrease

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Principal mechanism of all anti-depressive medication?

increasing the amount of neurotransmitters in the brain:

preventing them being broken down or
prevent “reuptake” into the cells

Different anti-depressants affect one or more neurotransmitters to different extent

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Which patients are at highest risk to anti-depressive drugs?

children, teens, young adults

Increase the risk of suicidality in patients < age 25
» All antidepressants must include FDA black box warning

No risk in older patients >65

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What are the ABCDEF anti-depressant withdrawal symptoms?

 A: Agitation, anxiety  
 B: Balance problems, bad dreams  
 C: Concentration problems 
 D: Dizziness, diarrhea, nausea, vomiting  
 E: Electric shock-like sensations  
 F: Flu-like symptoms

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How to withdraw anti-depressants?

Doses should be gradually reduced over at least a 4-week period

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List some other disorders that can be treated with anti-depressants?

Panic disorder
General anxiety disorder
PTSD
OCD
Bulimia
Pain disorders

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What is the effectiveness of anti-depressants in patients with various severity of depression?

Mild to moderate dpression: Nonexistent to negligible difference between placebos and antidepressants

Severe depression: significantly effective

> > should only be given when the risk of untreated depression far outweighs that of antidepressant mediations

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Why do anti-depressants work as effectively as placebos in many patients?

People’s belief in the power of anti-depressants

> > overcome any actual pharmacological response

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List 2 ways to treat depression without using medication?

Cognitive –behavioural/ psychotherapy (find out cause): as effective in mild/ moderate depression
Interpersonal therapy (teach communication to improve relationship)

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MoA of SSRI? Give 3 examples.

Selective serotonin reuptake inhibitor (SSRI): Fluoxetine (Prozac), Fluvoxamine,
Paroxetine

inhibits ~80% activity of serotonin transporter

> > blocks reuptake of serotonin by presynaptic neuron

> > maintains high levels of 5-HT in the synapse

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D/D interaction of SSRIs?

Fluxoetine + TCA: Fluxoetine = potential inhibitors of CYP2D6 isoenzyme, unpredictable elevations of TCA levels

Fluxoetine + Diltiazem:
Fluxoetine = CYP3A4 inhibitor, use with diltiazem (= calcium channel blocker) cause bradycardia / hypotension

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ADR of SSRI?

Enhances serotonergic tone / activity throughout the body:

Gut = nausea, GI upset, diarrhea
CNS:spinal cord and above = diminished sexual function and interest
HIS: Inhibits serotonin reuptake into platelets, reduced coagulation, increased risk of bleeding
CVS:Inhibits nitric oxide synthase = favors vasoconstriction

C/O of SSRI?

Inhibits nitric oxide synthase = favors vasoconstriction

Contradicted for pregnant women with hypertension / preeclampsia (can lead to fetal prematurity)

Why is SSRI 1st line treatment against other anti-depressants?

 Fewest side effects (mild to moderate, transitory) among anti-depressants
 Safety in overdose
 Low cost/ cost effective

MoA of NRI, give 2 examples?

Binds to noradrenaline transporter on pre-synapse&raquo_space; selectively blocks reuptake of NA
» increases NA concentration in synaptic cleft

 Atomoxetine
 Maprotiline

ADR of NRI?

 Acts on α receptors on pacemaker cells in heart = increase heart rate and blood pressure

 CNS activation (e.g. insomnia, anxiety, agitation)

MoA of SNRI? 2 examples?

Serotonin-norepinephrine reuptake inhibitors (SNRI)

 Bupropion
 Mirtazapine

Binds to both serotonin and norepinephrine transporters > blocks serotonin and nonepinephrine reuptake

Low affinity for other receptors, e.g. histamine receptor, mucarinic acetylcholine receptor (unlike TCA)

ADR of SNRI?

 Have serotonergic adverse affects as serotonin selective reuptake inhibitor

 Have noradrenergic effects as norepinephrine reuptake inhibitor

MoA of TCA? Name one

Tricyclic antidepressants (TCA): Amitriptyline Affect the uptake of all 3 neurotransmitters associated with mood: 1. Serotonin: obsessions, compulsions, memory 2. Norepinephrine: alertness, concentration, energy 3. Dopamine: pleasure, reward, motivation/drive

ADR of TCA?

BLurred vision, Drowsiness, Loss of libido Constipation, dry mouth, Postural hypertension, urinary retention (similar to muscarinic receptor antagonist ADRs)

Why is TCA now rarely used?

 Poor tolerability  Difficult to use  Lethal in overdose  Serious drug interactions Nowadays only used in patients who do not response to SSRI

Triple MoA of SARI? Name one.

Serotonin antagonist-reuptake inhibition (SARI): Trazodone 1. Antagonizes 5-HT2A receptors (increased receptor number in depression) (= most potent): increases release of neurotransmitter 2. Blocks serotonin reuptake transporter (SERT) (100-fold less potent) 3. Agonizes 5-HT1A receptors: Converted into meta-chloro-phenylpiperazine (mCPP) to activates 5-HT2C >>> cause downstream activation of 5-HT1A = Anti-depressive

ADR of SARI?

Agonist actions of serotonin at other subtypes:  Sexual dysfunction  Insomnia  Anxiety + desensitization over time

MoA of NASA? Name one.

α2 adrenoceptor antagonist (NASA): Mianserin 1) Blocks α2 presynaptic autoreceptor (not transporter) (exam) >> remove negative feedback on presynaptic neuron >> enhances noradrenaline release 2) 5-HT2A antagonist

ADR of NASA?

 Sedation  Dry mouth  Dizziness  Vertigo

Classify MAOI (Monoamine oxidase inhibitor) anti-depressants? Give examples of each.

Non-selective MAOI:  Phenelzine  Tranylcypromine Selective MAOAI:  Moclobemide

MoA of MAOI (Monoamine oxidase inhibitor)?

Inhibit monoamine oxidase: = decrease degradation enzyme of excessive serotonin, norepinephrine, dopamine 2 isoforms: 1) MAOA metabolizes 5-HT, noradrenaline, adrenaline, dopamine, tyramine 2) MAOB metabolizes dopamine, phenylethylamine, tyramine >> MOAI Increase levels of all 3 major neurotransmitters in synaptic cleft

Why is MAOI rarely used?

Potentially fatal interaction with certain food and drugs: cause hypertensive crisis, stroke, death

Explain the interaction between MAOI and certain foods?

MAOI inhibit breakdown of tyramine from food (e.g. avocados, bananas, pineapple, eggplants) >> accumulated tyramine cause increase release of stored monoamine neurotransmitters (e.g. dopamine, norepinephrine, epinephrine) >> increases blood pressure and heart rate >> hypertensive crisis

Explain some D/D interactions of MAOI?

MAOI + serotonergic agent (SSRI / SNRI / TCA) may lead to serotonin syndrome (life-threatening): Caused by overstimulation of 5-HT receptors in the brain, potentially lethal

Guidelines on switching between MAOI and serotonergic agents?

Before starting MAOI, discontinue serotonergic antidepressants for at least 2 weeks Fluoxetine has long half-life = discontinued for 4-5 weeks Before starting a serotonergic agent, must discontinue MAOI for at least 2 weeks

ADR of MAOI?

 Orthostatic hypotension  Weight gain  Insomnia, Restlessness  Confusion

MoA of Melatonin receptor agoinst?

Acts on:  Melatonin receptor  Serotonin receptor (5-HT2C receptors): Does not increase serotonin level, but increases concentrations of dopamine, norepinephrine in brain

Name one melatonin receptor agoinst

Agomelatine (Valdoxan) = synthetic melatonin

What is the physiological function of melatonin?

important for regulating sleep Released in response to darkness by the pineal gland: Levels vary according to the circadian rhythm In tune: helps us sleep and wake Out of whack: disrupts energy, alertness, mood)

ADR of melatonin receptor agonist?

Derangement in liver function requires regular liver function monitoring

Which serotonin receptors are acted on by SARI?

Serotonin antagonist-reuptake inhibitor (SARI) Antagonist for 5-HT2A receptor while agonist for 5HT-1A receptor. It also blocks serotonin reuptake transporter SERT.

List some synmptoms of serotonin syndrome caused by MAOI?

Minor: Agitation, insomnia, nervousness, BP change, Diarrhea, Akathisia, Mydriasis ... Major: Coma, confusion, fever, tremors, rigidity ...