1
Q
SSRI
A
Antidepressant
First Line
2
Q
SNRIs
A
Antidepressant
First Line
3
Q
Bupropion
A
Antidepressant
First Line
4
Q
Mirtazapine
A
Antidepressant
First Line
5
Q
TCAs
A
Antidepressant
Second Line/Alternative Agent
6
Q
MAOIs
A
Antidepressant
Second Line/Alternative Agent
7
Q
Major Depressive Disorder
A
5+ for atleast 2 weeks
- DEPRESSED MOOD
- DIMINISHED INTEREST/PLEASURE (anhedonia)
- significant weight loss/gain
- insomnia or hypersomnia
- psychomotor agitation/retardation
- fatigue or loss of energy
- feelings of worthlessness or excessive guilt
- diminished ability to think or concentrate; indecisivenss
- recurrent thoughts of death; suicidal ideation or attempt
8
Q
The Monoamine Hypothesis
A
- depressed mood results from decreased monoamine neurotransmission
- major classes of clinically useful drugs INCREASE monoamine neurotransmission by LIMITING THE REUPTAKE OF MONOAMINE NEUROTRANSMITTERS or by preventing their breakdown
9
Q
Process of release/effect of NT
A
Neurotransmitters:
- synthesized from amino acid precursors in specific neurons
- packaged into vesicles
- released in response to stimulus
- bind postsynaptic receptors
- subject to reuptake by presynaptic transporters
10
Q
Catecholamines from Tyrosine
A
Monoamine Neurotransmitters
- epinephrine
- dopamine
- norepinephrine
11
Q
Tryptamines from Tryptophan
A
Monoamine Neurotransmitter
- serotonin
12
Q
Reserpine
A
inhibits VMAT
13
Q
SSRI Site of Action
A
- block reuptake of serotonin
- serotonin left in extracellular space left to interact with receptors for longer period of time
14
Q
SNRI Site of Action
A
- block reuptake of serotonin and norepinephrine
- same as TCAs
- serotonin and norepi left in extracellular space left to interact with receptors for a longer period of time
- ** MORE SELECTIVE THAT TCAs***
15
Q
TCAs Site of Action
A
- block reuptake of serotonin and norepinephrine
- same as SNRIs
- serotonin and norepi left in extracellular space left to interact with receptors for a longer period of time
- ** INTERACT WITH A WHOLE BUNCH OF OTHER RECEPTORS AS WELL ***
16
Q
MAOIs Site of Action
A
- prevent breakdown of monoamines in presynaptic cell
- inhibit MAO; prevents breakdown of NT, increasing amount in extracellular space
- ACT INTRACELLULARLY
17
Q
Bupropion Site of Action
A
- blocks reuptake of DOPAMINE and norepinephrine
- acts on dopaminergic neuron
18
Q
Mirtazapine Site of Action
A
- blocks presynaptic a2 receptors and some 5-HT2/3 receptors
- antagonist of presynaptic a2 autoreceptor, which ENHANCES RELEASE OF NE and 5-HT
- block binding of NT to presynaptic recpetor
19
Q
Limitations to Monoamine Hypothesis
A
- clinically useful antidepressants act rapidly at pharmacologic sites of action, yet clinical effects require 3+ weeks of therapy
- while reserpine rapidly depletes neurotransmitter, several weeks of treatment are required to induce depression
20
Q
Major Antidepressant Site of Action Targets
A
Neurotransmitter reuptake transporters
* activity limited by reuptake rate*
21
Q
Autoreceptors
A
- found on presynaptic cell
- respond to level of neurotransmitter
- when reuptake is blocked, elevated NT in synapse leads to down-regulation of synthesis and release of additional NT
- upon chronic use, autoreceptors may be down regulated, thereby relieving inhibition of NT synthesis and release, and enhancement of neurotransmission
- receptors constantly bound to ligand, receptor downregulated and removed from cell surface
- MAY ACCOUNT FOR LIMITATIONS OF HYPOTHESIS
22
Q
SSRI uses
A
- MAJOR DEPRESSION
- anxiety disorder
- OCD
- PTSD
- PMDD
23
Q
SNRI uses
A
- major depression
- anxiety disorder
- chronic pain
- fibromyalgia
24
Q
Bupropion uses
A
- major depression*
- *first-line alternative to SSRI or SNRI when anxiety is not a prominent symptom
- smoking cessation
25
Mirtazapine uses
- major depression*
| - * particularly useful in patients with insomnia or marked weight loss
26
TCAs uses
- alternative agent
| - major depression (when unresponsive to other drugs)
27
MAOIs
- alternative agent
| - major depression (when unresponsive to other drugs)
28
Anti-depressant Boxed Warning
SUICIDE RISK
29
Antidepressant Adverse Events (All)
- suicide risk
| - mania (most often in patients with undiagnosed bipolar disorder)
30
SSRIs Adverse Events
- inhibit 5-HT reuptake SELECTIVELY compared to NE reuptake; side effects limited to effects on 5-HT mediated responses
Adverse Events:
- nausea
- headache
- anxiety
- agitation
- insomnia
- sexual dysfunction
- seizures with gross overdose
31
SNRIs Adverse Events
- inhibit reuptake of both 5-HT and NE; side effects due to excess of both serotonin and norepi
```
Adverse Events:
__________________________
- nausea
- headache
- anxiety
- agitation ........................... same as SSRIs
- insomnia
- sexual dysfunction
seizures with gross overdose
__________________________
- anticholinergic
- sedation
- hypertension (veniafaxine)
```
32
Bupropion Adverse Events
- inhibits reuptake transporters for NE and dopamine
- resembles amphetamine
* ** especially helpful in patients with impaired concentration ***
* ** alternative for patients with antidepressant-induced sexual dysfunction ***
Adverse Events:
- nausea
- headache
- anxiety
- irritability
- insomnia
- mild hypertension and tachycardia
- tremor
- appetite suppression
- dose related seizures (minimized with EXT release formulation)
33
Why Sexual Dysfunction with SSRIs and SNRIs but not Bupropion?
- sexual dysfunction associated with SSRIs and SNRIs due to stimulation of 5-HT receptor subtypes in the brain and spinal cord
34
Mirtazapine Adverse Events
- antagonist of a2 autoreceptor; enhances release of NE and 5-HT
- antagonist at 5-HT 2/3 receptors
* ** particularly useful in patients with INSOMNIA or marked WEIGHT LOSS***
* ** helpful in patients who experience nausea with SSRIs, SNRIs, or bupropion ***
Adverse Events:
- sedation
- weight gain
- dizziness
- dry mouth
- constipation
35
When beneficial for Bupropion Use?
- patients with impaired concentration
| - alternative for patients with antidepressant-induced sexual dysfunction
36
When beneficial for Mirtazapine Use?
- patients with insomnia or marked weight loss
| - helpful in patients who experience nausea with SSRIs, SNRIs, or bupropion
37
Tricyclic Antidepressants Site of Action
- inhibit reuptake transporters for BOTH NE and 5-HT (like SNRIs)
- *** tend to interact with a variety of OTHER receptors, therefore have a broader range of side effects than SNRIs***
38
Tricyclic Antidepressant Adverse Events
Those for SNRIs
- nausea
- headache
- anxiety
- agitation
- insomnia
- sexual dysfunction
- extrapyramidal effects (early in treatment)
- seizures with gross overdose
- serotonin syndrome with MAOI
- anticholinergic
- sedation
************************************************
PLUS
- orthostatic hypotention
- weight gain
- arrhythmias
************************************************
39
Reuptake Blockers SNRI & TCAs
venlafaxine (SNRI)
imipramine (TCA)
amitriptyline (TCA)
SNRI & TCAs 5-HT ++ NE +
SAME mechanism of action; same effect on 5-HT and NE differ in spectrum of side effects
IMIPRAMINE AND AMITRIPTYLINE ACTIVATE MANY OTHER RECEPTORS which are why they are problematic to take
40
Reuptake Blockers SSRIs
fluoxetine
paroxetine
sertraline
ALL: 5-HT +++
fluoxetine: NE 0
paroxetine: NE +
sertraline: NE 0
41
MAOIs site of action
phenelzine
tranylcypromine
- inhibit Monoamine Oxidase (MAO)
- phenelzine combines IRREVERSIBLY with MAO to provide long-lasting inhibition
- tranylcypromine does not bind irreversibly, but still has prolonged effect
42
MAOIs Adverse Events
- hypertensive reactions in response to INDIRECTLY ACTING SYMPATHOMIMETICS (otherwise typically lower blood pressure)
- hypertensive crisis with tyramine containing foods
- hyperthermia
- CNS stimulation leading to agitation and convulsions
- seizures with overdose
- serotonin syndrome with SSRIs/SNRIs
43
Pharmacokinetics of Antidepressant Agents
```
In general most:
- have rapid oral absorption
- reach peak plasma concentration in 2-3 hours
- have t1/2 of .5-1 day
are tightly bound to plasma proteins
- metabolized by liver
- eliminated by kidney
```
44
Pharmacokinetics of specific drugs may influence choice of agent: SSRIs; escitalopram and citalopram
- several SSRIs are moderate to strong inhibitors of CYP2D6
| - escitalopram and citalopram exhibit age-dependent decrease in CYP2C19 metabolism (use with care in elderly)
45
Fluoxetine half life
7-10 days *much longer than most*
| avg .5-1 day
46
Drug Interactions
| SNRIs, TCAs, Mirtazapine, Trazodone
- additive with other sedatives, particularly alcohol and benzodiazepines
47
SSRIs Drug Interactions
- additive effects on QT interval and torsade de pointes with other QT-interval prolonging drugs
48
SSRIs and SNRIs Drug Interactions
- increased risk of bleeding with antiplatelet or anticoagulant drug (SSRIs and SNRIs)
- risk of serotonin syndrome with MAOIs
49
Serotonin Syndrome
- can be caused by all serotonergic drugs; rare but potentially life-threatening triad of abnormalities consisting of cognitive, autonomic and somatic effects due to excess serotonin
- can progress toward coma and death
Management: sedation (benzodiazepines), paralysis, intubation and ventilation
50
Overdoses TCAs
- extremely dangerous; prescribed on "no refill basis", small quantities
51
Overdoses MAOIs
- intoxication rare, requires supportive treatment
52
Overdoses SSRIs
- OD fatalities rare
| - intoxication requires supportive treatment
53
Overdoses Bupropion
- seizures
54
Overdoses Mirtazapine
- disorientation, tachycardia
55
Overdoses of Antidepressants Newer Agents
- often involves other drugs, including alcohol
