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Optimal Use of Antidepressants: Focusing on SNRI, NDRI and SSRE
Optimal Use of Antidepressants: Focusing on SNRI, NDRI and SSRE
Chan-Hyung Kim, MD
Severance Mental Health Hospital
Institute of Behavioral Science in Medicine
Chan-Hyung Kim, MD
Severance Mental Health Hospital
Institute of Behavioral Science in Medicine
Selecting an Antidepressant (STEPS)
Safety
Tolerability
Efficacy
Payment
Simplicity
Others : – Previous response
– Family response
– Patient’s preferences
– Evidence
Safety
Tolerability
Efficacy
Payment
Simplicity
Others : – Previous response
– Family response
– Patient’s preferences
– Evidence
Total EffectEquation 1Effect = Pharmacodynamics X Pharmacokinetics X Interindividual variance
Equation 2Potency for site of action X Concentration at site of action X Interindividual variance
Equation 3Concentration = dosing rate (mg/day) / clearance (mL/min)
Equation 1Effect = Pharmacodynamics X Pharmacokinetics X Interindividual variance
Equation 2Potency for site of action X Concentration at site of action X Interindividual variance
Equation 3Concentration = dosing rate (mg/day) / clearance (mL/min)
Serotonin and Norepinephrine Reuptake
Inhibitors (SNRI)
Serotonin and Norepinephrine Reuptake
Inhibitors (SNRI)
Venlafaxine
Milnacipran
Duloxetine
Venlafaxine
Milnacipran
Duloxetine
Venlafaxine has a Profile Similar to Clomipramine but Without the Anti-Ch
and Anti-H EffectsNE and 5-HT reuptake inhibitorAs effective as other antidepressantsModest success with highly resistant ptsDose 75mg to 375 mg– Start at 37.5 or 18.25 mg to avoid nausea– Higher doses may be more effective than lower ones
Side effects– Nausea– Insomnia (lower doses) and sedation (higher doses)– Increased blood pressure (higher doses)– Sexual dysfunction(at > 225 mg qd)
NE and 5-HT reuptake inhibitorAs effective as other antidepressantsModest success with highly resistant ptsDose 75mg to 375 mg– Start at 37.5 or 18.25 mg to avoid nausea– Higher doses may be more effective than lower ones
Side effects– Nausea– Insomnia (lower doses) and sedation (higher doses)– Increased blood pressure (higher doses)– Sexual dysfunction(at > 225 mg qd)
Venlafaxine: Characteristics
Protein binding T1/2Venlafaxine 27 ± 2% 5hrsO-desmethyl- venlafaxine
30 ± 12% 11hrs
• Metabolized by P450 IID6• Very weak inhibitor of II D6• 87% renal excretion• O-desmethylvenlafaxine only major active
metabolite
Venlafaxine Hypertension
Placebo 75mg 150mg 225mg 375mg
Treatment emergent
hypertension
1.1% 1.1% -- 2.2% 4.5%
Sustained Dias. BP
avg. sustained = 10-
15mmHg)
2% 3% 5% 7% 13%
Average change BP -2.2 mm 0mm 0mm 0mm 7.2mm
Venlafaxine Side Effects That Decrease with Dose Increase
% Treatment Emergent
Placebo 75mg 225mg 375mg
Anxiety 4.3 11.2 4.5 2.3
Nervousness 4.3 21.3 13.5 12.5
Insomnia 9.8 22.5 20.2 13.6
Venlafaxine was Effective for Severely Refractory Depressed Patients
70 unipolarMean HDRSDocumented failure of at least:– 3 adequate antidepressant trials– 1 attempt at augmentation
Rapid titration up to 375mg32.9% responded acutely
Nierenberg et al. 1994
70 unipolarMean HDRSDocumented failure of at least:– 3 adequate antidepressant trials– 1 attempt at augmentation
Rapid titration up to 375mg32.9% responded acutely
Nierenberg et al. 1994
Venlafaxine: ProsBroad spectrum antidepressant efficacy– Looks like a TCA and SSRI combined
Does not inhibit metabolism of other drugs
Does not significantly displace other protein bound drugs (weakly bound to protein)
Effective in very treatment resistant patients
Modest sexual side effects at low doses
Broad spectrum antidepressant efficacy– Looks like a TCA and SSRI combined
Does not inhibit metabolism of other drugs
Does not significantly displace other protein bound drugs (weakly bound to protein)
Effective in very treatment resistant patients
Modest sexual side effects at low doses
Venlafaxine: ConsNausea most common cause of dropouts (esp –IR formulation)
P450 IID6 inhibitors can significantly increase venlafaxine levels
BID dosing (XR-single dosing)
High doses risk hypertension, sedation, and sexual dysfunction
Nausea most common cause of dropouts (esp –IR formulation)
P450 IID6 inhibitors can significantly increase venlafaxine levels
BID dosing (XR-single dosing)
High doses risk hypertension, sedation, and sexual dysfunction
Pharmacology of Atypical Antidepressants
½ Life Protein Binding
Enzyme Inhibition Effects*
Venlafaxine 5h 30% None
Nefazodone 3-26h 99% III-A3/4
Bupropion 4-24h 80% IIB6
VenlafaxineSSRI at low doses, SNRI only at higher doses (> 150 mg/day)requires dose-titration to bring in NA activityNA : 5-HT = 1:30
MilnacipranSNRI at all dosesinhibition of reuptake 5-HT = NAno dose-titration required for NA activityNA : 5-HT = 3:1
Milnacipran vs Venlafaxine
First line therapyAll depressed patients particularly• slowed down (low energy) patients• patients with predominant physical symptoms (pain)• elderly and polymedicated patients
Second line therapy• non-responders to SSRI (incl low-dose venlafaxine)• intolerant of SSRI (sexual effects, weight gain)• intolerant of venlafaxine (sexual effects, weight gain)• intolerant of TCA (anticholinergic or cardiac)
MilnacipranIts place in the treatment of depression
PharmacologyIndicationsEfficacySide EffectsPotential Clinical Usefulness
DuloxetineAnother SNRI? What’s New?
NE and DA Reuptake Inhibitors (NDRI)
NE and DA Reuptake Inhibitors (NDRI)
Bupropion
(Wellbutrin, Zyban)
Bupropion
(Wellbutrin, Zyban)
Bupropion Pharmacodynamics
1989: FDA approval
– seizure risk: dose-related, occur in special population)
Structually related to amphetamine: stimulating effect
Weak neuronal uptake inhibitors of DA, NE, and 5-HT
Unknown mechanism of action but believed to be NE and/or DA
Ultimately downregulates adrenergic receptors
1989: FDA approval
– seizure risk: dose-related, occur in special population)
Structually related to amphetamine: stimulating effect
Weak neuronal uptake inhibitors of DA, NE, and 5-HT
Unknown mechanism of action but believed to be NE and/or DA
Ultimately downregulates adrenergic receptors
Bupropion SR Pharmacokinetics
Metabolite T1/2(hr) Peak Level* PotencyBupropion 21 ± 9 1 1Hydroxybupropion 20 ± 5 17 times 1Theohydrobupropion 37 ± 13 1.5 times 0.1- 0.5Erythrohydrobupropion 33 ± 10 7 times 0.1- 0.5
• 3 Main Metabolites
• Bupropion metabolites produced false-positive on urine amphetamine toxicology
• Bupropion metabolized by P450 IIB6
*Proportion compared to Bupropion
Clinical IndicationsDepression: – psychomotor retardation
– esp bipolar depression: add-on to mood stabilizers
– Depression with Parkinson’s disease
Smoking cessation
ADHD: esp comorbid substance abuse
Add-on to:– AD effects of SSRIs
– SSRI induced sexual dysfunction
Chronic fatigue syndrome
Depression: – psychomotor retardation
– esp bipolar depression: add-on to mood stabilizers
– Depression with Parkinson’s disease
Smoking cessation
ADHD: esp comorbid substance abuse
Add-on to:– AD effects of SSRIs
– SSRI induced sexual dysfunction
Chronic fatigue syndrome
Bupropion for Fluoxetine Induced Sexual Dysfunction
Sexual Dysfunction = Orgasm Delay or Failure
N=39 (22 females, 17 males) with sexual dysfunction on fluoxetine; 31 completed
On bupropion:
– 26 patients(84%) – complete remission
– 3 patients (10%) – partial remission
2 had preexisting sexual dysfunction
Sexual Dysfunction = Orgasm Delay or Failure
N=39 (22 females, 17 males) with sexual dysfunction on fluoxetine; 31 completed
On bupropion:
– 26 patients(84%) – complete remission
– 3 patients (10%) – partial remission
2 had preexisting sexual dysfunction
Treatment Resistant Depression Bupropion
TCA nonresponders(n=1,301)
– 54% had good or better response to bupropion
Fluoxetine nonresponders
– 47% responded to bupropion
Bupropion’s unique mechanism of action may be an advantage
TCA nonresponders(n=1,301)
– 54% had good or better response to bupropion
Fluoxetine nonresponders
– 47% responded to bupropion
Bupropion’s unique mechanism of action may be an advantage
Bupropion - Pros
Evolution of bupropion : IR -> SR-> XRLow overall side-effects make it the lowest in drop-outs (10%)Unique (but unknown) mechanism of action makes it a high choice in treatment resistant depressionLow mania/rapid cycling inductionLow/no sexual side effectsMinimal drug metabolism interactions through P450 IIB6 metabolism– Drugs lowering seizure thresholds: clozapine, thephyline,
clomopramine, alcohol, BZP – MAOI and Bupropion: contraindicated
Evolution of bupropion : IR -> SR-> XRLow overall side-effects make it the lowest in drop-outs (10%)Unique (but unknown) mechanism of action makes it a high choice in treatment resistant depressionLow mania/rapid cycling inductionLow/no sexual side effectsMinimal drug metabolism interactions through P450 IIB6 metabolism– Drugs lowering seizure thresholds: clozapine, thephyline,
clomopramine, alcohol, BZP– MAOI and Bupropion: contraindicated
Bupropion - ProsEqually effective in:– Anxious and nonanxious depressions– Typical and atypical depressions
Low suicide riskDual effectiveness in ADHD with depressionCan reduce addiction risk (cocaine, nicotine) particularly in those with depression– Approved for nicotine dependence (10 week quit rate
– 46% on bupropion vs. 20% on placebo)
Equally effective in:– Anxious and nonanxious depressions– Typical and atypical depressions
Low suicide riskDual effectiveness in ADHD with depressionCan reduce addiction risk (cocaine, nicotine) particularly in those with depression– Approved for nicotine dependence (10 week quit rate
– 46% on bupropion vs. 20% on placebo)
Bupropion - ConsMay increase psychosis risk in psychotics and borderlines
Seizure risk significantly higher in “at risk” individuals– Bulimics, anorexia, head injury, seizure history
– Concurrent use of alcohol, stimulants, or cocaine
Seizure risk at 400mg higher than with most other antidepressants(0.4%)– At 300 mg only 0.1% seizure risk
Requires BID dosing although low seizure risk patients may try qd dosing
May increase psychosis risk in psychotics and borderlines
Seizure risk significantly higher in “at risk” individuals– Bulimics, anorexia, head injury, seizure history
– Concurrent use of alcohol, stimulants, or cocaine
Seizure risk at 400mg higher than with most other antidepressants(0.4%)– At 300 mg only 0.1% seizure risk
Requires BID dosing although low seizure risk patients may try qd dosing
Bupropion - ConsNot proven effective for panic or other anxiety disorders: unique among Ads
Most common side effects– Insomnia
–Dry mouth
– tremor
Not proven effective for panic or other anxiety disorders: unique among Ads
Most common side effects– Insomnia
–Dry mouth
– tremor
Tianeptine Basic Pharmacology
Increasing uptake of serotonin
Little affinity for D2, adrenergic, GABA, BZP, muscarinic, or histamine sites.
Do not bind to either presynaptic serotonin sites or postsynaptic 5-HT1 and 5-HT2 sites.
Two active metabolites: MC5 and MC3
Increasing uptake of serotonin
Little affinity for D2, adrenergic, GABA, BZP, muscarinic, or histamine sites.
Do not bind to either presynaptic serotonin sites or postsynaptic 5-HT1 and 5-HT2 sites.
Two active metabolites: MC5 and MC3
Tianeptine Clinical Pharmacology
Peak plasma level: within 1hr
No first-pass hepatic metabolism
Short halflife: 1.4-3.6 hr (MC5 7.2hr)
Extensive hepatic metabolism
Recommended daily dose: 12.5mg in three divided doses
Common side effects: drowsiness, irritability, and GI upset
Well tolerated in overdose
Peak plasma level: within 1hr
No first-pass hepatic metabolism
Short halflife: 1.4-3.6 hr (MC5 7.2hr)
Extensive hepatic metabolism
Recommended daily dose: 12.5mg in three divided doses
Common side effects: drowsiness, irritability, and GI upset
Well tolerated in overdose
Tianeptine Clinical Pharmacology
Peak plasma level: within 1hr
No first-pass hepatic metabolism
Short halflife: 1.4-3.6 hr (MC5 7.2hr)
Extensive hepatic metabolism
Recommended daily dose: 12.5mg in three divided doses
Common side effects: drowsiness, irritability, and GI upset
Well tolerated in overdose
Peak plasma level: within 1hr
No first-pass hepatic metabolism
Short halflife: 1.4-3.6 hr (MC5 7.2hr)
Extensive hepatic metabolism
Recommended daily dose: 12.5mg in three divided doses
Common side effects: drowsiness, irritability, and GI upset
Well tolerated in overdose
QUIZ
1. Serotonin and NE re-uptake inhibitor?
2. Is associated with eosinophilia-myalgia syndrome?
3. Contraindicated in Parkinson’s disease?
4. Effective Diabetic Pain syndrome?
1. Serotonin and NE re-uptake inhibitor?
2. Is associated with eosinophilia-myalgia syndrome?
3. Contraindicated in Parkinson’s disease?
4. Effective Diabetic Pain syndrome?
A. Citalopram B. Moclobemide C. Milnacipran D. Venlafaxine E. Mirtazapine F. Tianeptine G. L-tryptophan H. Amoxapine I. Paroxetine
J. Bupropion