Optimal Use of Antidepressants: Focusing on SNRI, NDRI and SSRE

Transcription

1 Optimal Use of Antidepressants: Focusing on SNRI, NDRI and SSRE Chan-Hyung Kim, MD Severance Mental Health Hospital Institute of Behavioral Science in Medicine

2 Diagnostic Criteria Pyramid Etiologic Pathophysiologic Syndromic Symptomatic

3 Selecting an Antidepressant (STEPS) Safety Tolerability Efficacy Payment Simplicity Others : Previous response Family response Patient s preferences Evidence

4 Total Effect Equation 1 Effect = Pharmacodynamics X Pharmacokinetics X Interindividual variance Equation 2 Potency for site of action X Concentration at site of action X Interindividual variance Equation 3 Concentration = dosing rate (mg/day) / clearance (ml/min)

5 Serotonin and Norepinephrine Reuptake Inhibitors (SNRI) Venlafaxine Milnacipran Duloxetine

6 Venlafaxine has a Profile Similar to Clomipramine but Without the Anti-Ch and Anti-H Effects NE and 5-HT reuptake inhibitor As effective as other antidepressants Modest success with highly resistant pts Dose 75mg to 375 mg Start at 37.5 or 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)

7 Venlafaxine: Characteristics Metabolized by P450 IID6 Very weak inhibitor of II D6 87% renal excretion O-desmethylvenlafaxine only major active metabolite Protein binding T1/2 Venlafaxine 27 ± 2% 5hrs O-desmethylvenlafaxine 30 ± 12% 11hrs

8 Venlafaxine Hypertension Placebo 75mg 150mg 225mg 375mg Treatment emergent hypertension Sustained Dias. BP avg. sustained = 10-15mmHg) 1.1% 1.1% % 4.5% 2% 3% 5% 7% 13% Average change BP -2.2 mm 0mm 0mm 0mm 7.2mm

9 Venlafaxine Side Effects That Decrease with Dose Increase % Treatment Emergent Placebo 75mg 225mg 375mg Anxiety Nervousness Insomnia

10 Venlafaxine was Effective for Severely Refractory Depressed Patients 70 unipolar Mean HDRS Documented failure of at least: 3 adequate antidepressant trials 1 attempt at augmentation Rapid titration up to 375mg 32.9% responded acutely Nierenberg et al. 1994

11 Venlafaxine: Pros 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

12 Venlafaxine: Cons 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

13 Pharmacology of Atypical Antidepressants ½Life Protein Binding Enzyme Inhibition Effects* Venlafaxine 5h 30% None Nefazodone 3-26h 99% III-A3/4 Bupropion 4-24h 80% IIB6

14 Milnacipran vs Venlafaxine Venlafaxine SSRI at low doses, SNRI only at higher doses (> 150 mg/day) requires dose-titration to bring in NA activity NA : 5-HT = 1:30 Milnacipran SNRI at all doses inhibition of reuptake 5-HT = NA no dose-titration required for NA activity NA : 5-HT = 3:1

15 Milnacipran Its place in the treatment of depression First line therapy All 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)

16 Duloxetine Another SNRI? What s New? Pharmacology Indications Efficacy Side Effects Potential Clinical Usefulness

17 NE and DA Reuptake Inhibitors (NDRI) Bupropion (Wellbutrin, Zyban)

18 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

19 3 Main Metabolites Bupropion SR Pharmacokinetics Bupropion metabolites produced false-positive on urine amphetamine toxicology Bupropion metabolized by P450 IIB6 Metabolite T1/2(hr) Peak Level* Potency Bupropion 21 ± Hydroxybupropion 20 ± 5 17 times 1 Theohydrobupropion 37 ± times Erythrohydrobupropion 33 ± 10 7 times *Proportion compared to Bupropion

20 Clinical Indications 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

21 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

22 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

23 Bupropion - Pros Evolution of bupropion : IR -> SR-> XR Low 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 depression Low mania/rapid cycling induction Low/no sexual side effects Minimal drug metabolism interactions through P450 IIB6 metabolism Drugs lowering seizure thresholds: clozapine, thephyline, clomopramine, alcohol, BZP MAOI and Bupropion: contraindicated

24 Bupropion - Pros Equally effective in: Anxious and nonanxious depressions Typical and atypical depressions Low suicide risk Dual effectiveness in ADHD with depression Can 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)

25 Bupropion - Cons 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

26 Bupropion - Cons Not proven effective for panic or other anxiety disorders: unique among Ads Most common side effects Insomnia Dry mouth tremor

27 5-HT Reuptake Enhancer (SSRE) Tianeptine

28 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

29 Tianeptine Clinical Pharmacology Peak plasma level: within 1hr No first-pass hepatic metabolism Short halflife: 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

30 Tianeptine Clinical Pharmacology Peak plasma level: within 1hr No first-pass hepatic metabolism Short halflife: 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

31 QUIZ A. Citalopram B. Moclobemide C. Milnacipran D. Venlafaxine E. Mirtazapine F. Tianeptine G. L-tryptophan H. Amoxapine I. Paroxetine J. Bupropion 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?