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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. 123 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. 128 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. 129 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) 131