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Depression Today
Diagnostic Criteria
DSM-IV criteria of Major Depressive Episode
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.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition,
Text Revision. DSM-IV TR. Washington : APA 2000.
3
Depression Today
Physiopathology
The aminergic theory of depression
A depletion or reduced activity of cerebral noradrenaline and serotonin
Symptoms of depression
Serotonergic
Noradrenergic
- Agitation
- Loss of appetite
- Decreased libido
- Suicidal ideation
- Depressed
mood
- Loss of interest or
pleasure
- Decreased
concentration
- Insomnia or hypersomnia
- Retardation
- Loss of energy
- Lassitude
- Aggressive
- Feeling of worthlessness
- Tiredness
behaviour
- Anxiety
(oral or physical)
- Reduced self-care
- Pessimism
(hygiene)
- Irritability
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.
7
Pharmacology
and Pharmacokinetics
Milnacipran's Pharmacology and Pharmacokinetics
Mechanism of action
A well balanced SNRI
TCAs
1
H1
ACh
tolerance (+)
TCA
5-HT
to Mono selective drugs
SSRI
NA
efficacy (-)
5-HT
to Dual Action Drugs
SNRI
Milnacipran
5-HT
NA
16
Milnacipran's Pharmacology and Pharmacokinetics
Mechanism of action
A well balanced SNRI
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
* Selectivity ratios for reuptake inhibitors measured in vitro
Tran PV et al. Dual monoamine modulation for improved treatment of major depressive disorder.
J Clin Psychopharmacology 2003;23:78-86.
17
Milnacipran's Pharmacology and Pharmacokinetics
Mechanism of action
A selective mechanism of action
Absence of binding to post-synaptic receptors
Milnacipran IC50 >10 000 nM on over 40 receptors studied
IC50 (nM)
muscarinic
alpha1
H1
Milnacipran
> 10 000
> 10 000
>10 000
Imipramine
46
32
37
Affinity for monoamine receptors
Puozzo C et al. Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol 2002;
17(Suppl 1):S25-S35.
25
Milnacipran's Pharmacology and Pharmacokinetics
Mechanism of action
A selective mechanism of action
Absence of binding to post-synaptic receptors
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
26
Milnacipran's Pharmacology and Pharmacokinetics
Pharmacokinetics
Excellent oral absorption (> 90%)
No effect of meals on absorption
Linear relationship dose - plasma levels
Ease 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
28
Milnacipran's Pharmacology and Pharmacokinetics
Pharmacokinetics
No liver metabolism by cytochrome P-450
Inhibition of
CYP 450
subtypes
FLUV
1A2
+++
2C19
PAROX
SERT
VENLA
DULOX
MILNA
Substrate
0
+
0
0
0
0
theophylline, TCAs,
melatonin, clozapine,
haloperidol
+++
++
+
0
0
0
0
benzodiazepines,
propranolol, TCAs,
proton pump inhibitor
2C9
++
0
+
++
0
0
0
NSAIDs
2D6
+
0
+++
0
+
++
0
TCAs,
antipsychotics, betablockers, antiarrhythmics
3A4
+++
++
+
0
+
0
0
antibiotics, antivirals,
benzodiazepines,
calcium antagonists
FLUOX/
NORFLUOX
FLUV: fluvoxamine; FLUOX/NORFLUOX: fluoxetine/norfluoxetine; PAROX: paroxetine; SERT: sertraline; VENLA: venlafaxine;
MILNA: milnacipran; DULOX: duloxetine
(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®.
31
Efficacy
in Major Depression
Milnacipran's Efficacy in Major Depression
Efficacy vs SSRIs
Comparative studies vs SSRIs
in moderate to severe depression
2 major double-blind studies
comparing Milnacipran with SSRIs in major depression
Population
 Adults
 Inpatients
SSRIs
Fluoxetine, 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 Depression
Efficacy vs SSRIs
Meta-analysis of double-blind studies
in moderate to severe depression
Change in total HDRS score between baseline and endpoint
HDRS
Milnacipran
SSRIs
(n=150)
(n=156)
at baseline
27.0
26.5
at endpoint
11.9
14.3
-15.1*
-12.2
 at endpoint
* p<0.05
Milnacipran : a superior improvement in HDRS score
Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression.
Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46.
52
Milnacipran's Efficacy in Major Depression
Efficacy vs SSRIs
Meta-analysis of double-blind studies
in moderate to severe depression
Higher response and remission rates vs SSRIs
80
70
% patients
60
50
64%*
Milnacipran 50 mg BID (n=150)
50%
39%
40
28%
30
20
* p<0.01
10
0
SSRIs (fluvoxamine 100 mg BID
or fluoxetine 20 mg OD) (n=156)
Responders
Remitted
Response : reduction in HDRS score of at least 50%.
Remission : total HDRS score  7 at endpoint
Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression.
Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46.
53
Milnacipran's Efficacy in Major Depression
Efficacy vs SSRIs
Comparative study vs Paroxetine
in 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
Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression.
J Affect Disord 2004;83:233-36.
60
Milnacipran's Efficacy in Major Depression
Efficacy vs SSRIs
Comparative study vs Paroxetine
in ambulatory patients with mild to moderate depression
25
HDRS17 score
20
Milnacipran
15
(n=148)
Paroxetine
(n=151)
10
5
(ITT population-LOCF)
0
Baseline
7
14
21
28
35
42
days
Change in total HDRS score between baseline and endpoint
Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression.
J Affect Disord 2004;83:233-36.
61
Milnacipran's Efficacy in Major Depression
Efficacy vs SSRIs
Comparative study vs Paroxetine
in ambulatory patients with mild to moderate depression
70
p=0.70
p=0.71
60
% responders
50
40
30
Milnacipran 50 mg BID
20
Paroxetine 20 mg OD
10
0
HDRS17
MADRS
Response : reduction in HDRS or MADRS score of at least 50%
Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression.
J Affect Disord 2004;83:233-36.
62
Milnacipran's Efficacy in Major Depression
Efficacy vs SSRIs
Comparative study vs Paroxetine
in ambulatory patients with mild to moderate depression
Predictive factors of Milnacipran CGI responder rate according
to psychomotor retardation at baseline
p=0.047
% CGI responders
100
Milnacipran 50 mg BID
Paroxetine 20 mg OD
80
60
40
20
0
ALL
<1
<2
<3
HDRS Retardation item 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.
63
Milnacipran's Efficacy in Major Depression
Efficacy vs Venlafaxine
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
(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.
66
Tolerance and Safety
Milnacipran's Tolerance and Safety
Overall tolerability
A good tolerance profile
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)
No weight modification
Minimal sexual dysfunction
No effect on cardiac conduction or ventricular depolarisation
(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).
81
Milnacipran's Tolerance and Safety
Sexual function
Minimal sexual dysfunction
associated with milnacipran therapy
 very low (< 2%) spontaneous reports of sexual dysfunction
in clinical trials
 very low frequency suggested by feedback from prescribing
clinicians
Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9.
83
Milnacipran's Tolerance and Safety
Cardiovascular safety
Cardiovascular safety
associated with milnacipran therapy
No effect on cardiac conduction or ventricular depolarisation
During clinical trials :
 a mean increase in heart rate of approximately
3 beats per minute
 negligible changes in arterial blood pressure
84
Milnacipran's Tolerance and Safety
Dysuria
Dysuria
All patients
Males
Females
(n=1871)
(n=529)
(n=1342)
Dysuria
44 (2.35%)
42 (7.94%)
2 (0.15%)
Retention
12 (0.64%)
11 (2.08%)
1 (0.07%)
 >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
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.
85
Milnacipran's Tolerance and Safety
Sleep
A significant improvement of objective sleep parameters
 associated with the clinical improvement of depression
Polysomnographic results
Baseline
Days 4-6
Days 26-28
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
74.0
83.4*
84.5*
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
Total sleep time (min)
Sleep efficiency index
Sleep latency (min)
*p<0.05; **p<0.01 vs baseline (Student’s t-test); (a) at least 1 minute in ‘awake’ sleep stage
Lemoine P, Faivre Th. Subjective and polysomnographic effects of milnacipran on sleep in depressed patients.
Hum Psychopharmacl Clin Exp 2004;19:1-5.
86
Milnacipran's Tolerance and Safety
Driving vigilance
No effects on vigilance as evaluated by laboratory tests
 visual and auditory vigilance tests
Before
treatment
Milnacipran
Placebo
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
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
Visual vigilance
Auditory vigilance
Values are means ± SD
Richet F et al. Effects of milnacipran on driving vigilance. Int J Psych Clin Pract 2004;8:109-115.
87
Milnacipran's Tolerance and Safety
Driving vigilance
No effects on vigilance in a real driving situation
 evaluation of driving tests by instructor
Before
treatment
Milnacipran
Placebo
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
199.1 ± 39.1
197.8 ± 30.6
192.9 ± 23.1
Adaptation to driving
(160 points)
Global note
(320 points)
Values are means ± SD
Richet F et al. Effects of milnacipran on driving vigilance. Int J Psych Clin Pract 2004;8:109-115.
88
Milnacipran's Tolerance and Safety
Adverse events vs SSRIs
Incidence of adverse events
Lower with milnacipran than SSRIs
Nausea
Headache
Dry mouth
Abdominal pain
Constipation
Anxiety
Vomiting
Milnacipran
Fatigue
SSRIs
Somnolence
0
5
10
15
20
% occurrence
Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression.
Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46.
92
Milnacipran's Tolerance and Safety
Adverse events vs SSRIs
Incidence of treatment discontinuation emergent symptoms
Lower with milnacipran than paroxetine
Patients with at least one symptom :
Milnacipran 13% vs Paroxetine 31.8%
(p=0.032)
Anxiety
Insomnia
Milnacipran (n=46)
Nervousness
Paroxetine (n=44)
Aggravated depression
Depression
Paranoia
Dizziness
Convulsions
0
2.5
5
7.5
10
% occurrence
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.
94
Milnacipran's Tolerance and Safety
Adverse events vs Venlafaxine
Incidence of adverse events
Lower with milnacipran than venlafaxine
Nausea
Somnolence
Dry mouth
Dizziness/Vertigo
Constipation
Drowsiness
Milnacipran
Nervousness
Venlafaxine
Sweating
0
10
20
30
40
% occurrence
(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
Milnacipran's Tolerance and Safety
Long-term tolerability
Incidence of adverse events
A reduction over time
0-3 months (n=1010)
3-6 months (n=1010)
6-9 months (n=715)
9-12 months (n=237)
>12 months (n=189)
15
% occurrence
12
9
6
3
0
Data on file.
96
Milnacipran's Tolerance and Safety
Conclusions
Improved tolerance profile versus other classes
TCAs
SSRIs
Venlafaxine
Milnacipran
Nausea
Sexual dysfunction
Weight gain
Sedation
+
++
++
++
++
++
-
+
+
+
-
+
-
Sweating
Constipation
++
++
+
-
++
-
+
-
++
+
YES
NO
+
YES
+
NO
YES
YES
21-33%
NO
NO
12-20%
YES
YES
11-19%
NO
NO
7.6%
Dry mouth
Dysuria
Sustained hypertension
Orthostatic intolerance
QT Prolongation
Treatment discontinuation
for adverse events
(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.
99
Milnacipran's Tolerance and Safety
Safety in overdose
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
Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol
2002;17(Suppl 1):S43-S50.
101
Special Patient Profiles
Milnacipran and Special Patient Profiles
Depression symptoms
A quick onset of action on all symptoms of depression
80
70
% improvement
60
50
Anxiety
40
Sleep
30
Cognitive symptoms
20
Psychomotor retardation
10
Core symptoms
0
0
1
2
3
4
5
6
7
8
Weeks
(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.
104
Milnacipran and Special Patient Profiles
Retarded depression
A significantly higher probability of response vs paroxetine
in depressed patients with psychomotor retardation
% responders
100
*
50
* p=0.047
Milnacipran
50 mg BID
Paroxetine
20 mg OD
Responder rate in depressed patients with a HDRS retardation score > 3 at study entry
Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants.
Int Clin Psychopharmacol 17 (Suppl 1):S43-S50.
105
Milnacipran and Special Patient Profiles
Suicidal risk
Less suicide attempts and completed suicides
Patients exposure years (n)
[log scale]
1
Suicide attempts
Completed suicides
0.1
0.01
Placebo
TCAs
SSRIs
Milnacipran
Treatment
Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9.
107
Milnacipran and Special Patient Profiles
Young active patients
Milnacipran advantages in patients with active lifestyle
 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
(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;49:118125. (3) Richet F et al. Effects of milnacipran on driving vigilance. Int J Psychiatr Clin Pract 2004 (in press).
108
Milnacipran and Special Patient Profiles
Elderly depressed patients
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.
109
Milnacipran and Special Patient Profiles
Elderly depressed patients
Milnacipran advantages in elderly patients (aged  50 years)
% responding patients at w10
A better response to milnacipran than to SSRI
100
80
80%
64%
60
52%
40
20
0
Milnacipran
Fluvoxamine
Paroxetine
(n=55 ; 30-100 mg/day)
(n=42 ; 75-150 mg/day)
(n=62 ; 20-40 mg/day)
Response : reduction in HDRS score of at least 50%
Morishita S, Arita S. Comparison of milnacipran and SSRIs, especially in age. Abstr 2004.
111
Milnacipran and Special Patient Profiles
Depressed patients with sleep disorders
Improvement of sleep
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
(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.
112
Milnacipran and Special Patient Profiles
Preferential response to milnacipran
Differential effects of Milnacipran and SSRIs
Improved response in agitated and inhibited depression
100
% response at w2
Inhibited depression
80
Agitated depression
60
40
20
0
Milnacipran
Fluvoxamine
Paroxetine
(n=55 ; 50-100 mg/day)
(n=42 ; 75-150 mg/day)
(n=55 ; 20-40 mg/day)
Response : reduction in HDRS score of at least 50%
Morishita S, Arita S. Differential response of milnacipran and SSRIs for inhibition and agitation. Abstr 2004.
113
Milnacipran and Special Patient Profiles
Switch to mania
% patients with manic change
Less switch to mania or hypomania than with SSRIs
10
8.86%
8
6
4.90%
4
2
1.47%
0
Milnacipran
Fluvoxamine
Paroxetine
(n=68 ; 14-150 mg/day)
(n=122 ; 25-225 mg/day)
(n=79 ; 10-40 mg/day)
Retrospective cohort analysis of outpatients major depression disorder or bipolar disorder depression
Morishita S, Arita S. Prevalence of switch mania in patients with milnacipran or SSRIs. Abstr 2004.
114
Milnacipran's place in major depression
A better quality of life
A tremendous improvement of quality of life
Over 63% improvement
100
90
80
70
60
50
40
30
20
10
0
% score improvement in DIP* score month 6 vs baseline
80.5%
76.3%
Home assistance
Sleep
72.4% 72.0%
Mobility
70.5%
69.7%
68.1%
69.0%
62.2%
62.2%
Communication
Psycho-social score
Recreation
Total score
Emotional
Social
Alertness
* DIP : Disability and Impact Profile, a quality of life questionnaire
Rouillon F et al. Prevention of recurrent depressive episodes with milnacipran : consequences on quality of life.
J Affect Disord 2000;58:171-180.
120
In other pathologies
Milnacipran in other pathologies
Anxiety Disorders
=> Generalised Anxiety Disorder (GAD)
=> Panic Disorder (PD)
=> Fibromyalgia (FMS)
=> Social Anxiety Disorder (Social Phobia)
=> Post-Traumatic Stress Disorder (PTSD)
122
Milnacipran in other pathologies
Anxiety Disorders
Generalised Anxiety Disorder
HAM-A Total score
30
25
20
15
Milnacipran 45–150 mg/day
10
5
0
0
1
2
3
4
5
6
7
8 Weeks
Open study
Tsukamoto T et al. Usefulness of milnacipran in the treatment of Generalized Anxiety Disorder. Abstr 2003.
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Milnacipran in other pathologies
Anxiety Disorders
Social Phobia
LSAS (Liebowitz Scale) score
100
90
80
Milnacipran 50–150
mg/day
70
60
50
p<0.001
40
0
4
8
12
Weeks
Open trial (n=12) in patients with Taijin-Kyofusho (DSM-IV Social Phobia criteria)
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.
124
Milnacipran in other pathologies
Chronic Pain
Chronic abdominal, back, chest and glossal pain
VAS pain score
A significant improvement in pain
100
90
80
70
60
50
40
30
20
10
0
88.2
32.8
Baseline
Endpoint
(w12)
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
Milnacipran in other pathologies
Chronic Pain
Chronic orthopaedic pain (including degenerative spondylosis)
A significant improvement in pain
100
Pain VAS
80
60
Milnacipran
15 - 75 mg BID
40
20
0
0
1
2
3
4
5
6
7
8
Weeks
Open trial (n=17) in patients suffering from pain in the trunk and/or extremities due to degenerative spondylosis
Tanikawa H. Efficacy or milnacipran in patients with chronic orthopedic pain including degenerative spondylosis.
Abstr 2003.
126
Milnacipran in other pathologies
Chronic Pain
Fibromyalgia (FMS) - related pain
% patients
A significant improvement in pain
100
90
80
70
60
50
75%**
37%*
40
38%
Placebo
Milnacipran
* p=0.0395
** p=0.004
30
20
10
0
14%
> 50% reduction
in pain intensity
Improvement
Results of a US phase II double-blind placebo-controlled trial
Milnacipran vs Placebo (4 weeks dose escalation + 8 weeks fixed dose) ; 84% of patients at 200 mg/day
Cypress Bioscience Inc. 2003 (www.cypressbio.com).
127
Milnacipran in other pathologies
Chronic Pain
Fibromyalgia (FMS) - related pain in patients with depressive symptoms
VAS pain score
A significant improvement in pain
associated with relief from depressive symptomatology
100
90
80
70
60
50
40
30
20
10
0
77.6
p<0.01
50.0
Baseline
Endpoint
(w12)
Patients (n=11) with no significant depressive symptomatology at endpoint
Open-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.
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Milnacipran in other pathologies
Depression in schizophrenia spectrum disorders
Schizophrenia, delusional and schizoaffective disorders
with depressive symptoms
A significant improvement of depressive symptomatology
SDS* Score
60
58.3
±8.1
p=0.008
42.4
40
±9.6
20
0
Baseline
Endpoint (w8)
*Self-rating Depression Scale
Open-label study, milnacipran up to 45-75 mg/day
Nakanishi S et al. Efficacy of milnacipran for depressive symptoms in schizophrenia spectrum disorders.
Psychiatry Clin Neurosci 2004;58(2):226-7.
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How to prescribe
How to prescribe milnacipran
Dosing schedule
 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)
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