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