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

Diagnostic Criteria Pyramid

Etiologic

Pathophysiologic

Syndromic

Symptomatic

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

5-HT Reuptake Enhancer (SSRE)

5-HT Reuptake Enhancer (SSRE)

TianeptineTianeptine

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