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American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition, Text Revision. DSM-IV TR. Washington : APA 2000.
DSM-IV criteria of Major Depressive Episode
3
Depression TodayDiagnostic Criteria
1. Depressed mood
2. Loss of interest or pleasure in all, or almost all, usual activities
3. Significant weight loss or weight gain
4. Insomnia or hypersomnia
5. Psychomotor agitation or retardation
6. Fatigue or loss of energy
7. Feelings of worthlessness or excessive or inappropriate guilt
8. Diminished ability to think or concentrate or indecisiveness
9. Recurrent thoughts of death or suicide
Five (or more) symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
Healy D, McMonagle T. The enhancement of social functioning as a therapeutic principle in the management of depression. J Psychopharmacol 1997;11(4, Suppl):S25-S31.
A depletion or reduced activity of cerebral noradrenaline and serotonin
Symptoms of depression
Serotonergic NoradrenergicANDAND
- Agitation
- Loss of appetite
- Decreased libido
- Suicidal ideation
- Aggressive behaviour (oral or physical)
- Irritability
- Depressed mood
- Loss of interest or pleasure
- Insomnia or hypersomnia
- Feeling of worthlessness
- Anxiety
- Pessimism
- Decreased concentration
- Retardation
- Loss of energy
- Lassitude
- Tiredness
- Reduced self-care (hygiene)
Depression TodayPhysiopathology
The aminergic theory of depression
7
Pharmacology
and Pharmacokinetics
15
Milnacipran's Pharmacology and PharmacokineticsWhat is milnacipran ?
(1RS) Z-2aminomethyl – 1 – phenyl – N , N – diethylcyclopropane - carboxamide hydrochloride
O
N
N H2H C l
Milnacipran hydrochloride
Milnacipran's Pharmacology and PharmacokineticsMechanism of action
A well balanced SNRI
16
to Dual Action Drugs
efficacy (-)
tolerance (+)
TCAsto Mono selective drugs
TCANA5-HT
1 H1 ACh
SSRI5-HT
SNRIMilnacipran
NA5-HT
efficacy (+)to
lerance (+
)
* Selectivity ratios for reuptake inhibitors measured in vitro
17
A well balanced SNRI
Tran PV et al. Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacology 2003;23:78-86.
Compound Ratio NA / 5-HT*
Mirtazapine 0.05
Desipramine 0.05
Milnacipran 1.6
Amitriptyline 8.1
Duloxetine 9.4
Imipramine 26.4
Venlafaxine 30.2
Clomipramine 135.7
Fluoxetine 296.3
Milnacipran's Pharmacology and PharmacokineticsMechanism of action
A selective mechanism of action
25
Absence of binding to post-synaptic receptors Milnacipran IC50 >10 000 nM on over 40 receptors studied
Puozzo C et al. Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol 2002;17(Suppl 1):S25-S35.
Milnacipran's Pharmacology and PharmacokineticsMechanism of action
Affinity for monoamine receptors
IC50 (nM) muscarinic alpha1 H1
Milnacipran > 10 000 > 10 000 >10 000
Imipramine 46 32 37
A selective mechanism of action
Absence of binding to post-synaptic receptors
26
Receptor Clinical benefit in case of absence of binding to receptor
Alpha and beta adrenergic Cardiovascular safety
Cholinergic No anticholinergic effects
(constipation and dry mouth)
Histaminergic H1 No sedation and weight gain
Milnacipran's Pharmacology and PharmacokineticsMechanism of action
28
Excellent oral absorption (> 90%)No effect of meals on absorption
Linear relationship dose - plasma levelsEase of dose adjustment
Relatively short half-life (8 h)Rapid establishment of steady-state levels
Low protein binding (13%)Rare drug interactions
Low inter-individual variation
Milnacipran's Pharmacology and PharmacokineticsPharmacokinetics
31
Inhibition of CYP 450 subtypes
FLUV FLUOX/NORFLUOX
PAROX SERT VENLA DULOX MILNA Substrate
1A2 +++ 0 + 0 0 0 0 theophylline, TCAs, melatonin, clozapine, haloperidol
2C19 +++ ++ + 0 0 0 0 benzodiazepines, propranolol, TCAs, proton pump inhibitor
2C9 ++ 0 + ++ 0 0 0 NSAIDs
2D6 + 0 +++ 0 + ++ 0 TCAs, antipsychotics, beta-blockers, anti-arrhythmics
3A4 +++ ++ + 0 + 0 0 antibiotics, antivirals, benzodiazepines, calcium antagonists
No liver metabolism by cytochrome P-450
(1) Yamane K. Clinical efficacy of the SNRI milnacipran on a depressive state in a department of neurology. 2003. Abstr. (2) http:/medicine.iupui.edu/flockhart (3) Cupp MJ, Tracy TS. Cytochrome P450 : new nomenclature and clinical implications. Am Fam Physician 1998;57(1):107-16. (4) Prescribing Information Cymbalta®.
Milnacipran's Pharmacology and PharmacokineticsPharmacokinetics
FLUV: fluvoxamine; FLUOX/NORFLUOX: fluoxetine/norfluoxetine; PAROX: paroxetine; SERT: sertraline; VENLA: venlafaxine; MILNA: milnacipran; DULOX: duloxetine
Efficacy
in Major Depression
Comparative studies vs SSRIsin moderate to severe depression
2 major double-blind studiescomparing Milnacipran with SSRIs in major depression
Population Adults Inpatients
SSRIsFluoxetine, Fluvoxamine
Studies carried out in Europe
Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46. 51
Milnacipran's Efficacy in Major DepressionEfficacy vs SSRIs
52Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46.
Meta-analysis of double-blind studies in moderate to severe depression
Change in total HDRS score between baseline and endpoint
* p<0.05
HDRS Milnacipran(n=150)
SSRIs(n=156)
at baseline 27.0 26.5
at endpoint 11.9 14.3
at endpoint -15.1* -12.2
Milnacipran's Efficacy in Major DepressionEfficacy vs SSRIs
Milnacipran : a superior improvement in HDRS score
53Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46.
Milnacipran's Efficacy in Major DepressionEfficacy vs SSRIs
Meta-analysis of double-blind studies in moderate to severe depression
Response : reduction in HDRS score of at least 50%. Remission : total HDRS score 7 at endpoint
Responders Remitted
* p<0.01
SSRIs (fluvoxamine 100 mg BID or fluoxetine 20 mg OD) (n=156)
Milnacipran 50 mg BID (n=150)
% p
atie
nts
0
10
20
30
40
50
60
70
80
64%*
50%39%
28%
Higher response and remission rates vs SSRIs
60
Comparative study vs Paroxetinein ambulatory patients with mild to moderate depression
Depressed outpatients
Major depression (DSM-IV)
2 parallel groups
Milnacipran 50 mg BID (n=150)
Paroxetine 20 mg OD (n=153)
Measures
HDRS17, MADRS, predictors of response, discontinuation emergent symptoms
Follow-up : 6 weeks
Milnacipran's Efficacy in Major DepressionEfficacy vs SSRIs
Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83:233-36.
61
Change in total HDRS score between baseline and endpoint
(ITT population-LOCF)
Baseline 7 14 21 28 35 42
0
5
10
15
20
25
HD
RS
17 s
core Milnacipran
(n=148)Paroxetine
(n=151)
days
Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83:233-36.
Milnacipran's Efficacy in Major DepressionEfficacy vs SSRIs
Comparative study vs Paroxetinein ambulatory patients with mild to moderate depression
62
Response : reduction in HDRS or MADRS score of at least 50%
Paroxetine 20 mg OD
Milnacipran 50 mg BID
HDRS17 MADRS
p=0.70p=0.71
% r
espo
nder
s
0
10
20
30
40
50
60
70
Milnacipran's Efficacy in Major DepressionEfficacy vs SSRIs
Comparative study vs Paroxetinein ambulatory patients with mild to moderate depression
Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83:233-36.
63
Predictive factors of Milnacipran CGI responder rate according to psychomotor retardation at baseline
(1) Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83:233-36. (2) Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 17 (Suppl 1):S43-S50.
HDRS Retardation item at baseline
ALL <1 < 2 <3
% C
GI r
espo
nder
s Paroxetine 20 mg OD
Milnacipran 50 mg BID p=0.047
0
20
40
60
80
100
Milnacipran's Efficacy in Major DepressionEfficacy vs SSRIs
Comparative study vs Paroxetinein ambulatory patients with mild to moderate depression
Venlafaxine
=> SSRI at low doses, SNRI only at higher doses (> 150 mg/day)
=> requires dose-titration to bring in NA activity
and true SNRI dose less well tolerated than SSRIs
Milnacipran
=> SNRI at all doses
(well balanced reuptake inhibition of 5-HT and NA whatever the dose)
=> no dose-titration required for NA activity
and all doses as well tolerated as SSRIs
66
(1) Puozzo C et al. Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol 2002;17(Suppl 1):S25-S35. (2) Briley M. The logical evolution towards dual action antidepressants. Drugs in Focus 2001;3:5-10. (3) Moret C, Briley M. Effects of milnacipran and pindolol on extracellular noradrenaline and serotonin levels in guinea pig hypothalamus. J Neurochem 1997;69:815-822.
Milnacipran's Efficacy in Major DepressionEfficacy vs Venlafaxine
Tolerance and Safety
No stimulant or sedative effect
Positive effect on vigilance and cognition
No alteration of ability to drive a car
No potentiation of alcohol effects
No effect on seizure threshold
No alteration sleep pattern (EEG)
A good tolerance profile
81
(1) Hindmarch I et al. Pharmacodynamics of milnacipran in young and elderly volunteers. Br J Clin Pharmacol 2000;49:118-125. (2) Richet F et al. Effects of milnacipran on driving vigilance. Int J Psychiatr Clin Pract 2004 (in press).
Milnacipran's Tolerance and SafetyOverall tolerability
No weight modification
Minimal sexual dysfunction
No effect on cardiac conduction or ventricular depolarisation
associated with milnacipran therapy
83
Minimal sexual dysfunction
Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9.
Milnacipran's Tolerance and SafetySexual function
very low (< 2%) spontaneous reports of sexual dysfunction
in clinical trials
very low frequency suggested by feedback from prescribing
clinicians
84
No effect on cardiac conduction or ventricular depolarisation
During clinical trials :
associated with milnacipran therapy
Cardiovascular safety
Milnacipran's Tolerance and SafetyCardiovascular safety
a mean increase in heart rate of approximately 3 beats per minute
negligible changes in arterial blood pressure
>70% of events rated as mild to moderate
67% of affected patients continued treatment in spite of adverse effects
Clinical experience has shown that symptoms of male dysuria can be adequately controlled by using an α1-blocker
85
Dysuria
All patients
(n=1871)
Males
(n=529)
Females
(n=1342)
Dysuria 44 (2.35%) 42 (7.94%) 2 (0.15%)
Retention 12 (0.64%) 11 (2.08%) 1 (0.07%)
Puech A et al. Milnacipran, a new serotonin and noradrenaline reuptake inhibitor : an overview of its antidepressant activity and clinical tolerability. Int Clin Psychopharmacol 1997;12:99-108.
Milnacipran's Tolerance and SafetyDysuria
86
A significant improvement of objective sleep parameters
Lemoine P, Faivre Th. Subjective and polysomnographic effects of milnacipran on sleep in depressed patients. Hum Psychopharmacl Clin Exp 2004;19:1-5.
Milnacipran's Tolerance and SafetySleep
associated with the clinical improvement of depression
Polysomnographic results Baseline Days 4-6 Days 26-28
Total sleep time (min) 331 375 403*
Stage I sleep (min) (% of total sleep) 44 (13.3%) 44 (11.7%) 49 (12.2%)
Stage II sleep (min) (% of total sleep) 190 (57.4%) 240** (64.0%) 243* (60.3%)
Stage III and IV(slow wave) sleep (min) (% of total sleep)
27 (8.2%) 33 (8.8%) 42 (10.4%)
REM sleep (min) (% of total sleep) 70 (21.2%) 58 (15.5%**) 69 (17.1%*)
REM latency (min) 43 77** 80**
Mean REM episode duration (min) 20 18 19
Sleep efficiency index 74.0 83.4* 84.5*
Sleep latency (min) 43 24** 27
Intrasleep awake time (min/h) 13.8 7.2 6.0
Number of awakenings(a) per hour 1.9 2 1.8*p<0.05; **p<0.01 vs baseline (Student’s t-test); (a) at least 1 minute in ‘awake’ sleep stage
visual and auditory vigilance tests
87
No effects on vigilance as evaluated by laboratory tests
Richet F et al. Effects of milnacipran on driving vigilance. Int J Psych Clin Pract 2004;8:109-115.
Milnacipran's Tolerance and SafetyDriving vigilance
Before
treatment
Milnacipran Placebo
Visual vigilance
Number of good responses (to 45
stimuli)
43.6 ± 1.4 43.8 ± 1.3 44.3 ± 0.8
Mean time of good responses (1/100 s) 63.0 ± 17.4 57.6 ± 21.0 61.7 ± 17.0
Tiredness index -0.92 ± 16.9 1.58 ± 20.6 2.92 ± 14.5
Auditory vigilance
Number of good responses (to 45
stimuli)
43.2 ± 2.4 43.0 ± 1.9 43.8 ± 1.2
Mean time of good responses (1/100 s) 96.1 ± 25.3 84.2 ± 30.3 92.8 ± 24.9
Tiredness index -11.5 ± 14.7 -12.8 ± 26.9 -9.8 ± 27.4
Values are means ± SD
88
No effects on vigilance in a real driving situation
Richet F et al. Effects of milnacipran on driving vigilance. Int J Psych Clin Pract 2004;8:109-115.
Milnacipran's Tolerance and SafetyDriving vigilance
evaluation of driving tests by instructor
Values are means ± SD
Before treatment
Milnacipran Placebo
Adaptation to driving (160 points)
103.3 ± 19.7 103.3 ± 19.7 103.3 ± 17.3
Adaptation to the size of vehicle (60 points)
38.8 ± 6.8 37.5 ± 5.8 36.3 ± 4.3
Adaptation to traffic conditions(80 points)
45.0 ± 13.8 45.0 ± 9.0 45.0 ± 9.0
Attitude and behaviour at the steering-wheel (20 points)
12.0 ± 2.9 12.0 ± 2.4 11.7 ± 2.1
Global note(320 points)
199.1 ± 39.1 197.8 ± 30.6 192.9 ± 23.1
92
Lower with milnacipran than SSRIs
Incidence of adverse events
Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46.
% occurrence
Milnacipran's Tolerance and SafetyAdverse events vs SSRIs
0 5 10 15 20
Milnacipran
SSRIsSomnolence
Fatigue
Vomiting
Anxiety
Constipation
Abdominal pain
Dry mouth
Headache
Nausea
94
Incidence of treatment discontinuation emergent symptoms
Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83(2-3):233-236.
Milnacipran's Tolerance and SafetyAdverse events vs SSRIs
Lower with milnacipran than paroxetine
% occurrence0 2.5 5 7.5 10
Milnacipran (n=46)
Paroxetine (n=44)
Dizziness
Paranoia
Depression
Aggravated depression
Nervousness
Insomnia
Anxiety
Convulsions
Patients with at least one symptom :Milnacipran 13% vs Paroxetine 31.8%(p=0.032)
(1) Kasper S et al. Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression : a summary of clinical trials. Int Clin Psychopharmacol 1996;11(4):35-39. (2) Feighner JP. The role of venlafaxine in rational antidepressant therapy. J Clin Psychiatry 1994;55 Suppl A:62-8. 95
Lower with milnacipran than venlafaxine
Incidence of adverse events
Milnacipran's Tolerance and SafetyAdverse events vs Venlafaxine
% occurrence0 10 20 30 40
Milnacipran
VenlafaxineSweating
Nervousness
Drowsiness
Constipation
Dizziness/Vertigo
Dry mouth
Somnolence
Nausea
96
A reduction over time
Incidence of adverse events
0-3 months (n=1010)
3-6 months (n=1010)
6-9 months (n=715)
9-12 months (n=237)
>12 months (n=189)
0
3
6
9
12
15
NauseaHeadache
Constipation
Dry mouth
Perspiration
Insomnia
Abdominal painVertigo
% o
ccu
rre
nce
Data on file.
Milnacipran's Tolerance and SafetyLong-term tolerability
TCAs SSRIs Venlafaxine Milnacipran
Nausea + ++ + +
Sexual dysfunction ++ ++ + -
Weight gain ++ - + -
Sedation ++ - - -
Sweating ++ + ++ +
Constipation ++ - - -
Dry mouth ++ - - -
Dysuria + - + +
Sustained hypertension YES NO YES NO
Orthostatic intolerance YES NO YES NO
QT Prolongation YES NO YES NO
Treatment discontinuation for adverse events
21-33% 12-20% 11-19% 7.6%
99
Improved tolerance profile versus other classes
(1) Deakin B, Dursun S. Optimizing antidepressant treatment : efficacy and tolerability. Int Clin Psychopharmacol 2002;17(Suppl 1):S13-S24. (2) Tran PV et al. Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacology 2003;23:78-86.
Milnacipran's Tolerance and SafetyConclusions
Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 2002;17(Suppl 1):S43-S50. 101
No lethal danger due to voluntary overdose
In doses up to 28 times the recommended daily dose
no fatal case
no cardiac rhythm abnormalities or coma
patients restored without sequelae
Milnacipran's Tolerance and SafetySafety in overdose
Special Patient Profiles
Milnacipran and Special Patient ProfilesDepression symptoms
104
A quick onset of action on all symptoms of depression
(1) Montgomery S. Dual action antidepressants in clinical practice. Drugs 2001;3(1):43-49. (2) Costa e Silva JA. The effect of milnacipran on depressive symptoms. Int J Psych Clin Pract 1999;3(Suppl 2):S21-S27.
Weeks
% im
prov
emen
t
0
10
20
30
40
50
60
70
80
0 1 2 3 4 5 6 7 8
Anxiety
Sleep
Cognitive symptoms
Psychomotor retardation
Core symptoms
Milnacipran and Special Patient ProfilesRetarded depression
105
A significantly higher probability of response vs paroxetine in depressed patients with psychomotor retardation
Responder rate in depressed patients with a HDRS retardation score > 3 at study entry
* p=0.047
50
100
Paroxetine 20 mg OD
Milnacipran 50 mg BID
% r
espo
nder
s
*
Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 17 (Suppl 1):S43-S50.
Milnacipran and Special Patient ProfilesSuicidal risk
Less suicide attempts and completed suicides
107Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9.
Suicide attempts
Completed suicides
Pat
ient
s ex
posu
re y
ears
(n)
[log
scal
e]
0.01
0.1
1
Placebo TCAs SSRIs Milnacipran
Treatment
Milnacipran and Special Patient ProfilesYoung active patients
Little effect on vigilance and cognition
No subjective sedation
No enhancement of sedative effects of alcohol
No effect on a battery of psychomotor tests measuring reaction time, learning and recall tasks, visuospatial memory (up to 100 mg as a single dose)
No alteration of ability to drive a car
Other benefits : - no weight modification - minimal sexual dysfunction
108
Milnacipran advantages in patients with active lifestyle
(1) Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9. (2) Hindmarch I et al. Pharmacodynamics of milnacipran in young and elderly volunteers. Br J Clin Pharmacol 2000;49:118- 125. (3) Richet F et al. Effects of milnacipran on driving vigilance. Int J Psychiatr Clin Pract 2004 (in press).
Milnacipran and Special Patient ProfilesElderly depressed patients
109
Milnacipran advantages in elderly patients
Pharmacokinetic parameters not significantly altered in elderly
patients (except in case of renal failure)
Limited drug interactions
Broad-spectrum efficacy across depressive symptoms
Favourable safety profile
(less sedation, less cardiovascular events…)
(1) Lecrubier Y. Milnacipran : the clinical properties of a selective serotonin and noradrenaline reuptake inhibitor (SNRI). Hum Psychopharmacol 1997;12:S127-S134. (2) Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9.
Milnacipran and Special Patient ProfilesElderly depressed patients
111
Milnacipran advantages in elderly patients (aged 50 years)
Morishita S, Arita S. Comparison of milnacipran and SSRIs, especially in age. Abstr 2004.
0
20
40
60
80
100
% r
espo
ndin
g pa
tient
s at
w10
Milnacipran(n=55 ; 30-100 mg/day)
Fluvoxamine(n=42 ; 75-150 mg/day)
Paroxetine(n=62 ; 20-40 mg/day)
80%
52%64%
Response : reduction in HDRS score of at least 50%
A better response to milnacipran than to SSRI
Improvement of sleep patterns (despite being non-sedative)
Improvement of sleep latency and number of nocturnal awakenings
Increase of latency of rapid eye movement (REM) sleep
Milnacipran and Special Patient ProfilesDepressed patients with sleep disorders
112
(1) Puech A et al. Milnacipran, a new serotonin and noradrenaline reuptake inhibitor : an overview of its antidepressant activity and clinical tolerability. Int Clin Psychopharmacol 1997;12:99-108. (2) Poirier MF et al. Double-blind comparative study of the action of repeated administration of milnacipran versus placebo on cognitive functions in healthy volunteers. Hum Psychopharmacol Clin Exp 2004;19:1-7.
Improvement of sleep
113
Response : reduction in HDRS score of at least 50%
Milnacipran and Special Patient ProfilesPreferential response to milnacipran
Differential effects of Milnacipran and SSRIs
Improved response in agitated and inhibited depression
0
20
40
60
80
100
% r
espo
nse
at w
2
Milnacipran(n=55 ; 50-100 mg/day)
Inhibited depression
Agitated depression
Fluvoxamine(n=42 ; 75-150 mg/day)
Paroxetine(n=55 ; 20-40 mg/day)
Morishita S, Arita S. Differential response of milnacipran and SSRIs for inhibition and agitation. Abstr 2004.
114
Milnacipran and Special Patient ProfilesSwitch to mania
Less switch to mania or hypomania than with SSRIs
Morishita S, Arita S. Prevalence of switch mania in patients with milnacipran or SSRIs. Abstr 2004.
Retrospective cohort analysis of outpatients major depression disorder or bipolar disorder depression
0
2
4
6
8
10
% p
atie
nts
with
man
ic c
hang
e
Milnacipran(n=68 ; 14-150 mg/day)
Fluvoxamine(n=122 ; 25-225 mg/day)
Paroxetine(n=79 ; 10-40 mg/day)
1.47%
4.90%
8.86%
Rouillon F et al. Prevention of recurrent depressive episodes with milnacipran : consequences on quality of life. J Affect Disord 2000;58:171-180.
Milnacipran's place in major depressionA better quality of life
120
A tremendous improvement of quality of life
Over 63% improvement
% score improvement in DIP* score month 6 vs baseline
0
10
20
30
40
50
60
70
80
90
100
76.3%72.0%
80.5%72.4% 69.7%
62.2%70.5%
62.2%68.1% 69.0%
* DIP : Disability and Impact Profile, a quality of life questionnaire
Sleep Emotional Home assistance Mobility
Social Alertness Communication Recreation Psycho-social score
Total score
In other pathologies
Milnacipran in other pathologiesAnxiety Disorders
=> Generalised Anxiety Disorder (GAD)
=> Panic Disorder (PD) => Fibromyalgia (FMS) => Social Anxiety Disorder (Social Phobia)
=> Post-Traumatic Stress Disorder (PTSD)
122
Tsukamoto T et al. Usefulness of milnacipran in the treatment of Generalized Anxiety Disorder. Abstr 2003.
Milnacipran in other pathologiesAnxiety Disorders
Generalised Anxiety Disorder
123
0
5
10
15
20
25
30
0 1 2 3 4 5 6 7 8 Weeks
HA
M-A
Tot
al s
core
Milnacipran 45–150 mg/day
Open study
Nagata T et al. Open trial of milnacipran for Taijin-Kyofusho in Japanese patients with Social Anxiety Disorder. Int J Psych Clin Pract 2003;00:1-6.
Milnacipran in other pathologiesAnxiety Disorders
Social Phobia
124
Open trial (n=12) in patients with Taijin-Kyofusho (DSM-IV Social Phobia criteria)
40
50
60
70
80
90
100
Milnacipran 50–150 mg/day
0 4 8 Weeks12
LSA
S (L
iebo
witz
Sca
le) s
core
p<0.001
Five outpatients suffering from chronic pain since 17.8 months (mean) treated with milnacipran 50 - 150 mg/day for 12 weeks.
Kamata M et al. Efficacy of milnacipran for the treatment of chronic pain patients. Abstr 2004.125
Endpoint (w12)
VA
S p
ain
scor
e
Baseline
88.2
32.8
0102030405060708090
100
Milnacipran in other pathologiesChronic Pain
Chronic abdominal, back, chest and glossal pain
A significant improvement in pain
Tanikawa H. Efficacy or milnacipran in patients with chronic orthopedic pain including degenerative spondylosis. Abstr 2003.
Milnacipran in other pathologiesChronic Pain
Chronic orthopaedic pain (including degenerative spondylosis)
126
Open trial (n=17) in patients suffering from pain in the trunk and/or extremities due to degenerative spondylosis
A significant improvement in pain
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 Weeks
Pai
n V
AS
Milnacipran 15 - 75 mg BID
Results of a US phase II double-blind placebo-controlled trialMilnacipran vs Placebo (4 weeks dose escalation + 8 weeks fixed dose) ; 84% of patients at 200 mg/day
Cypress Bioscience Inc. 2003 (www.cypressbio.com).
Milnacipran in other pathologiesChronic Pain
Fibromyalgia (FMS) - related pain
127
A significant improvement in pain
* p=0.0395 ** p=0.004
% p
atie
nts
Placebo
Milnacipran
> 50% reduction in pain intensity
14%
37%*
0
10
20
30
40
50
60
70
80
90
100
Improvement
38%
75%**
Patients (n=11) with no significant depressive symptomatology at endpointOpen-label trial, patients with fibromyalgia and a depressive state score of 50 on the Zung Self-rating Depression Scale; milnacipran dose-escaladation up to 100 mg/day for 12 weeks.
Nagaoka S et al. An open-label clinical trial of milnacipran in fibromyalgia syndrome with co-morbid depressive symptoms. Int J Psych Clin Pract 2003;1-5.
Milnacipran in other pathologiesChronic Pain
Fibromyalgia (FMS) - related pain in patients with depressive symptoms
128
A significant improvement in painassociated with relief from depressive symptomatology
p<0.01
VA
S p
ain
scor
e
Baseline Endpoint (w12)
77.6
50.0
0102030405060708090
100
Nakanishi S et al. Efficacy of milnacipran for depressive symptoms in schizophrenia spectrum disorders. Psychiatry Clin Neurosci 2004;58(2):226-7.
Milnacipran in other pathologiesDepression in schizophrenia spectrum disorders
Schizophrenia, delusional and schizoaffective disorders with depressive symptoms
129
A significant improvement of depressive symptomatology
*Self-rating Depression ScaleOpen-label study, milnacipran up to 45-75 mg/day
p=0.008
Baseline Endpoint (w8)
58.3±8.1
0
20
40
60
SD
S*
Sco
re
42.4±9.6
How to prescribe
How to prescribe milnacipranDosing schedule
131
It is advisable to start with a low dose of 25 mg twice daily or 50 mg
once daily of milnacipran
The dose should then be progressively increased to 100 mg/day
Recommended (optimum) dosage :
100 mg a day in two 50 mg doses, 1 capsule morning and evening
Doses up to 200 mg/day can be safely given where further efficacy
is required
Milnacipran can be taken with food (food does not modify the pharmacokinetics of milnacipran ; nevertheless, less nausea is observed
when administered with food, and it is recommended that milnacipran be taken during meals)
:איקסל נמצא בקופות החולים
השתתפות המטופל 50%מכבי -
השתתפות המטופל15%מאוחדת -
השתתפות המטופל60%לאומית -
₪ לחודש טיפול במינון 185חיר שוק פרטי - מ
מ"ג ליום100של
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