Class 4- depressive disorder Flashcards
1
Q
DRUGS THAT MAY BE INVOLVED depression
A
o Anticonvulsants o Benzodiazepines o Betablockers, a lot of fatigue when you start them o Corticosteroids o Interferon alpha or beta o Isotretinoin acutnae o Opioids o Varenicline champs
2
Q
MONOAMINES HYPOTHESIS
A
- Depletion of neurotransmitters = depressive symptoms
* Does not account for delayed onset of effect on mood in relation to increased synaptic neurotransmitters concentration
3
Q
DYSREGULATION HYPOTHESIS
A
- Dysregulation of neurotransmitters = alteration in both pre- and post- synaptic receptors = depressive symptoms
- Normalization of receptors in response to antidepressant therapy is delayed in relation to change in synaptic neurotransmitter concentration
- Better accounts for delay in onset of antidepressant action
4
Q
Examples of medications to avoid, minimize or stop during ECT
A
o Anticonvulsants (e.g. divalproex): increased threshold for convulsions o Benzodiazepines: increased threshold for convulsions o Lithium (controversial): increased risk of delirium and/or prolonged seizures o High-dose bupropion? : lowering the threshold for convulsions
5
Q
SSRI – MECHANISM OF ACTION
A
• Selective inhibition of 5-HT recapture via SERT
receptor inhibition
• ↑ 5-HT in the synapse
6
Q
Prolongation of QTc interval SSRI
A
- Maximum doses of 40 mg for citalopram and 20 mg for escitalopram
- In the elderly > 60 years, maximum doses of 20 mg for citalopram and 10 mg for escitalopram
7
Q
Fluoxetine
A
Activation effect
- Possible release of DA and NA
- Taken in the morning
- Long half-life
- a lot of interactions
8
Q
Fluvoxamine
A
- Anxiolytics
- Short half-life (can be given BID)
9
Q
Sertraline
A
Take while eating for better absorption
10
Q
Paroxetine
A
Anticholinergic effects ++
- Calming and sedative effect
- More side effects
11
Q
SSRI – SIDE EFFECTS
A
• Gastrointestinal • Headache • Drowsiness or insomnia • Possible anxiety at the beginning of treatment • Sexual dysfunction • Weight gain: 5-10 lbs • Hyponatremia: in the elderly diaphoresis
12
Q
Pharmacokinetics interactions SSRI
A
• Some are at higher risk (e.g. paroxetine via CYP2D6)
13
Q
Pharmacodynamic interactions SSRI
A
- Decrease in platelet aggregation (with all antidepressants having an effect on serotonin) = increase risk of bleeding
- Clinical impact if administered with AINS? Clopidogrel?
- Examples of risk factors: thrombopenia, H. Pylori
14
Q
SNRI – MECHANISM OF ACTION
A
• Selective inhibition of 5-HT and NE recapture via
inhibition of SERT and NET receptors
• ↑ 5-HT and NE in the synapse
15
Q
SNRI
Lots of similarities with SSRIs, benefits for some indications:
A
o Pain
o Vasomotor symptoms of menopause (small doses; e.g. venlafaxine XR)
16
Q
Venlafaxine
Effexor XRTM
A
5-HT > NE
- First IRSN on the market
- The higher the dose, the more you have an effect on NE
17
Q
Desvenlafaxine
A
5-HT > NE
- Not covered by RAMQ
18
Q
Duloxetine
A
5-HT > NE - Also indicated in treatment of : • Neuropathic pain secondary to diabetes • Fibromyalgia • Low back pain
19
Q
Levomilnacipran
A
NE > 5-HT
- New drug
- Not covered by RAMQ
- contra-indicated if heart problems
20
Q
SNRI – SIDE EFFECTS
A
Similar to SSRIs, + : • Constipation • Dry mouth • Sweating • Increased blood pressure (mostly) Few drug interactions
21
Q
BUPROPION – MECHANISM OF ACTION
A
• Selective inhibition of NE and DA recapture via
inhibition of DAT and NET receptors
• ↑ NE and DA in synapse
22
Q
BUPROPION
Also indicated in :
A
o Seasonal depression
o Smoking cessation
23
Q
BUPROPION – SIDE EFFECTS
A
• Agitation
• Insomnia
• Gastrointestinal effects
• Decrease in convulsion threshold
Ø Caution if uncontrolled epilepsy, eating disorders, electrolytic disorders
• Less weight gain or sexual dysfunction than SSRIs and IRSNs
Some drug interactions via CYP2D6
24
Q
MIRTAZAPINE – MECHANISM OF ACTION
A
- Alpha2 receptor antagonist
- 5-HT2A/2C receptor antagonist
- 5-HT3 receptor antagonist
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• Alpha2 receptor antagonist
Alpha2 receptor: It is a self-receptor, its stimulation is a "brake" to the release of NE
Alpha2 receptor antagonist: - Blocking this receptor increases the release of NE
- The increase in NE also acts on alpha receptors located on serotonin neurons, thus increasing the transmission of 5-HT
FINAL EFFECT = ↑ NE and 5-HT
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5-HT2 receptor antagonist
- Contributes to the antidepressant effect
- Decreased anxiety
- Weight gain/drowsiness
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H1 receptor antagonist
- Antihistamine effect
- More drowsiness or weight gain
- Useful if patient has insomnia or has little appetite
More present in small doses
- e.g. 7.5 or 15 mg
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MIRTAZAPINE – SIDE EFFECTS
• Sedation
• Weight gain/increased appetite
• Dry mouth
• Hypercholesterolemia
• Fewer sexual dysfunctions than SSRIs and NSRIs
• Less nausea (via the 5-HT3 antagonistic effect)= tolerate effexor better
Few drug interactions
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VORTIOXETINE
• Inhibition of serotonin reuptake (such
as SSRIs)
• Partial agonist 5-HT1A• Inhibition of serotonin reuptake (such as SSRIs)
• Partial agonist 5-HT1A
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VILAZODONE
• Inhibition of serotonin reuptake (such
as SSRIs)
• Partial agonist 5-HT1A, 5-HT1B
• Antagonist 5-HT3, 5-HT1D
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MULTIMODAL ANTIDEPRESSANTS; mechanism
Mechanism of action is similar to SSRIs
o Clinical effect on other receptors is not very clear
o Possible advantage of vortioxetine over cognitive functions
o Vilazodone should be taken with food
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MULTIMODAL ANTIDEPRESSANTS: s/e
* Similar to SSRIs
| * Vilazodone should be titled very slowly to avoid gastrointestinal effects
33
TRAZODONE – MECHANISM OF ACTION
• 5-HT2 and alpha1 receptor antagonist
• Low inhibition of serotonin and norepinephrine reuptake
• Antihistaminic effect at low dose
Rarely used as an antidepressant
o Especially used in the treatment of insomnia at a smaller dose
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TRAZODONE S/E
```
oDifficult to tolerate :
• Orthostatic hypotension
• Drowsiness, sedation
• Cognitive disorders
• Increased risk of heart disease
• Priapism (rare)
```
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TCA – MECHANISM OF ACTION
• Selective inhibition of 5-HT and NE recapture via
inhibition of SERT and NET receptors
• ↑ 5-HT and NE in the synapse
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Secondary amines
Better tolerated
(desipramine, nortriptyline)
NE > 5-HT
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Tertiary amines
(amitriptyline, clomipramine, doxepine, imipramine,
trimipramine)
5-HT > NE
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TCA – SIDE EFFECTS
```
• Anticholinergiques ++
Ø Blurred vision, sedation, urinary retention, dry mouth, constipation, orthostatic hypotension, tachycardia, cognitive impairments
• Weight gain
• Sexual dysfunction
• Decrease in convulsion threshold
• Overdose toxicity (arrhythmias)
```
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Pharmacokinetic interactions TCA
* Very high interaction potential
| * Via CYP1A2 and CYP2D6
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Pharmacodynamic interactions TCA
• Combination with other anticholinergic drugs
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ATC – THERAPEUTIC MONITORING
FOR SAFETY
o Risk of toxicity in overdose
o Risk of arrhythmias and convulsions
o Significant anticholinergic effects (confusion, blurred vision)
o Sedation
** Dosing should be taken 12 hours post dose
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MAO – A
Plays a more important role in the degradation of
| 5-HT and NE and tyramine in the gut
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MAO – B
Plays a more important role in the degradation of
| DA
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MOCLOBEMIDE
- Reversible
| - Specific to MAO-A
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TRANYLCYPROMINE
| PHENELZINE
- Irreversible: binds to receptor and doesn't move
| - Non-specific (inhibits MAO-A and MAO-B)
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MAOI – SIDE EFFECTS
```
o Weight gain
o Sexual dysfunction
o Orthostatic hypotension
o Edema
o Insomnia (tranylcypromine) or drowsiness (phenelzine)
o Short half time so BID
HYPERTENSIVE CRISIS
```
47
HYPERTENSIVE CRISIS
- Dangerous increase in blood pressure with diastolic > 120 mmHg
- Inhibition of MAO allows the absorption of exogenous tyramine which causes overstimulation of NE receptors, which can cause an increase in blood pressure
-To minimize the risk: avoid food containing tyramine (nutritionist)
-Worse with irreversible MAOIs
-It may also be the result of interaction with drugs that increase NE
• Oral decongestants
• Stimulants
• Antidepressants inhibiting NE reuptake (e.g. SNRIs)
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Pharmacokinetic interactions MAOI
Some via the CYP2C19
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Pharmacodynamic interactions MAOI
o Risk of serotonin syndrome (see section on management of adverse events)
o Risk of hypertensive crisis
50
QUETIAPINE XR – MECHANISM OF ACTION
* 5-HT2C and 5-HT2A receptor antagonist
* 5-HT1A partial agonist
* possible inhibition of NE reuptake (norquetiapine)
51
QUETIAPINE XR – SIDE EFFECTS
o Metabolic side effects: Weight gain, increased blood pressure, dyslipidemia, insulin resistance
o Sedation
o Orthostatic hypotension
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ESKETAMINE –
| MECHANISM OF ACTION
NMDA RECEPTOR ANTAGONIST
o Increased glutamate release
o AMPA activation
o↑ Synaptogenesis
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ESKETAMINE – SIDE EFFECTS
- Dizziness
- Sedation
- Gastrointestinal (nausea, vomiting, dry mouth)
- Dissociation (derealization, depersonalization, distortion of time and space)
- Increased blood pressure
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ESKETAMINE- CONSIDER
```
INTRA-NASAL ADMINISTRATION
• 1 – 2 times/week
CONSIDER
• Costs
• Side effects
• Treatment/availability supervision
```
55
ADJUNCTIVE TREATMENTS 1st line
ATYPICAL ANTIPSYCHOTICS
Olanzapine, risperidone, quetiapine, aripiprazole
o Lower doses than in mania or schizophrenia
o Consider the risk of metabolic syndrome and extrapyramidal reactions
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ADJUNCTIVE TREATMENTS 2nd line
LITHIUM
o Aim for a lower serum concentration than
bipolar affective disease
o Risk of side effects and interactions
STIMULANTS: don't treat, only decrease fatigue
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ST. JOHN’S WORT
o Demonstrated in the treatment of mild to moderate depression
Unknown mechanism of action
o Non-standardized and preparations available often vary
Side effects
o Gastric irritation, headache, anxiety
Drug interactions:
o High inducor of CYP3A4
o Reduces the effectiveness of many drugs!!
58
OMEGA-3 FATTY ACIDS
Adjunct
Unknown required doses
Side effects: residual taste in the mouth, dyspepsia and increased risk of bleeding
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Recovery
No symptoms x 12 months
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Substitute the antidepressant
- First antidepressant treatment
- Intolerance to initial treatment
- Non-response to initial treatment (< 25% improvement)
- Less severe depression and less functional impairment
- Patient prefers to change antidepressant
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Add an agent
- ≥ 2 antidepressant treatments attempted
- Well-tolerated initial treatment
- Partial response to initial treatment (> 25%
improvement)
- Residual symptoms or specific side effects that
may be targeted
- More severe depression and significant functional
impairment
- Patient prefers to add another drug
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COMBINATIONS OF ANTIDEPRESSANTS
```
SSRI + bupropion
SSRI + mirtazapine
SSRI + TCA
SNRI + bupropion
venlafaxine + mirtazapine
Antidepressant + trazodone
```
63
SNRI +
| bupropion
- Complementary mechanisms of action and synergistic effect on NE
- Increase doses gradually to avoid side effects (e.g. restlessness, anxiety)
- Monitor blood pressure and pulse
- Decrease in sexual effects associated with venlafaxine
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venlafaxoine
| + mirtazapine
- Complementary mechanisms of action and synergistic effect on neurotransmitters
- Reaches higher doses of venlafaxine, as mirtazapine blocks side effects of SNRI
65
Antidepressant
| + trazodone
- Improved sleep if small-dose trazodone is used
| - Possible combination with all antidepressants, but it is best to avoid association with irreversible MAOIs
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SSRI +
| bupropion
- Complementary mechanisms of action
- Decrease in sexual effects associated with SSRIs
- Adding bupropion can worsen insomnia if already present
67
SSRI +
| mirtazapine
- Complementary mechanisms of action
- Improved sleep
- Decrease in sexual effects associated with SSRIs
- More weight gain
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SSRI + TCA
- Use of a secondary amine that primarily inhibits NE reuptake to have complementary mechanisms of action
- Small dose of TCA would be sufficient
- Higher risk of side effects
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RESISTANCE TO TREATMENT
No response to 2 antidepressant treatments
• appropriate dose and duration of treatment
ESKETAMINE
• Indicated in the treatment of resistant depression, as an adjunctive treatment to an
antidepressant
• Not covered by RAMQ (refusal by INESS)
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SUBSTITUTION OF ANTIDEPRESSANTS
In most cases :
Withdrawal the first drug over a period of one to two weeks and then gradually introduce
the new drug simultaneously
Exception
MAOI involved: withdrawal the first drug completely and wait for 2 weeks (or longer if long
half-life) before the introduction of the second
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DURATION OF TREATMENT
- 6 – 9 months
```
- 2 years or more if :
• Recurrent or frequent episodes
• Severe episodes
• Chronic episodes
• Presence of psychiatric or physical comorbidities
• Residual symptoms
• Difficult-to-treat episodes
```
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CESSATION OF TREATMENT
Gradual withdrawal over a few weeks
o Allows to detect the recurrence of symptoms and facilitate a return to initial treatment as required
o Reduces the risk of withdrawal symptoms
• Especially for medicines with short half-lifes (paroxetine, venlafaxine)
• Anxiety, irritability, insomnia, headache, nausea
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Sexual side effects
- Reduce dose if possible
- Add bupropion or mirtazapine
- Substitute the antidepressant
- Consider taking a PDE5 inhibitor (e.g. sildenafil)
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SEROTONIN TOXICITY SYMPTOMS
```
o Altered mental status and/or agitation
o Autonomic instability
• Hypertension, tachycardia, diaphoresis
o Neuromuscular changes
• Clonus, tremors, hyperreflexia
o Gastrointestinal symptoms
o Hyperthermia
```
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SEROTONIN TOXICITY
- Potentially fatal side effect-
- Especially at risk of occurring in the presence of a drug that increases serotonin levels with a drug that decreases its metabolism (e.g. SSRI and MAOI)
* Beware of secret IMAOs (e.g. linezolide)
76
SEROTONIN TOXICITY MANAGEMENT
o Discontinuer the drug in question
| o Support therapy according to severity
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OTHER TREATMENTS / FUTURE TREATMENTS?
o Ketamine IV
o Brexanolone
o Botox?
