Depression Today Diagnostic Criteria

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 Depression is a complex disease characterised by a cluster of symptoms, although not all symptoms are necessarily present in all depressed profiles. Today, in order to define and classify mental disorders, psychiatrists refer most often to the diagnostic criteria established by the American Psychiatric Association (APA : Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition, DSM-IV). According to these criteria, the Major Depressive Episode is characterised by the following features : - the person must have for at least a two-week period either a depressed mood or loss of pleasure or interest in almost all activities (i.e. anhedonia), - and, in addition, at least three/four other depressive symptoms among the following: significant weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness, recurrent thoughts of death or suicide, In all, five depressive symptoms have to be present, the overall condition representing a change from previous functioning. 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 Serotonergic Noradrenergic
The aminergic theory of depression A depletion or reduced activity of cerebral noradrenaline and serotonin Symptoms of depression Serotonergic Noradrenergic AND - Agitation - Decreased concentration - Depressed mood - Loss of appetite - Retardation - Decreased libido - Loss of interest or pleasure - Loss of energy - Suicidal ideation - Insomnia or hypersomnia Psychopharmacology has numerous biochemical hypotheses with respect to the physiopharmacology of depression. However, today it does appear to be a broad acceptance of the aminergic theory of depression. This concerns itself with the depletion or reduced activity of cerebral monoamines, in particular noradrenaline and serotonin. According to this theory, for example, decreased serotonergic function results in problems of impulse control, aggressive behaviour, irritability, whereas decreased noradrenergic activity basically results in loss of energy or tiredness. Other aspects of human functioning lie at the intersection of these two neurotransmitter systems. - Lassitude - Feeling of worthlessness - Aggressive behaviour (oral or physical) - Tiredness - Anxiety - Reduced self-care (hygiene) - Pessimism - 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 What is milnacipran ?
Milnacipran hydrochloride (1RS) Z-2aminomethyl – 1 – phenyl – N , N – diethylcyclopropane - carboxamide hydrochloride N H H C l 2 O Drawing on both pharmacological and clinical research, the Pierre Fabre Research Centre focused its efforts on promoting a new class of antidepressants called Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs), in developing a dual action antidepressant which inhibited specifically the reuptake of both serotonin and noradrenaline and which lacked affinity for postsynaptic receptors. This led to the synthesis of the antidepressant (1RS) Z-2 aminomethyl-1-phenyl-N,N-diethylcyclopropane-carboxamide hydrochloride, whose international non-proprietary name is milnacipran hydrochloride. N 15

to Mono selective drugs
Milnacipran's Pharmacology and Pharmacokinetics Mechanism of action A well balanced SNRI to Dual Action Drugs efficacy (-) tolerance (+) TCAs to Mono selective drugs TCA NA 5-HT 1 H1 ACh SSRI SNRI Milnacipran efficacy (+) Considering the aminergic theory of depression, which hypothesises that depression is essentially due to the depletion or reduced activity of cerebral monoamines, in particular noradrenaline and serotonin, a logical goal of psychopharmacological research was to identify antidepressant drugs which act on both serotonergic and noradrenergic pathways – like the TCAs – but which lack affinity for postsynaptic receptors - like the SSRIs. By inhibiting the reuptake of both serotonin and noradrenaline, milnacipran is as effective as TCAs, the reference dual antidepressants, whilst being better tolerated, thanks to their lack of affinity for postsynaptic receptors strongly related to the occurrence of side-effects. Thus milnacipran's dual action fits clinical reality, with a full efficacy and a full safety that guarantees the best efficacy/tolerance ratio. 16

Milnacipran's Pharmacology and Pharmacokinetics Mechanism of action
A well balanced SNRI Compound Ratio NA / 5-HT* Mirtazapine 0.05 Desipramine Milnacipran 1.6 Amitriptyline 8.1 Duloxetine 9.4 Imipramine 26.4 Venlafaxine 30.2 Clomipramine 135.7 Fluoxetine 296.3 Several findings supporting the view that combined serotonin and noradrenaline enhancement has greater therapeutic efficacy compared with the enhancement of either neurotransmitter alone, it is important to develop antidepressants achieving a well-balanced inhibition of the reuptake of both these monoamines. This is the case with milnacipran, whose noradrenaline/serotonin inhibition ratio is close to 1. * 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

Affinity for monoamine receptors
Milnacipran's Pharmacology and Pharmacokinetics Mechanism of action A selective mechanism of action Absence of binding to post-synaptic receptors Milnacipran IC50 > nM on over 40 receptors studied Affinity for monoamine receptors IC50 (nM) muscarinic alpha H1 Milnacipran > > >10 000 Imipramine Unlike many antidepressants, such as TCA imipramine for example, milnacipran has a selective mechanism of action, with no affinity for post-synaptic receptors. Indeed, its IC50 is superior to nM on over 40 receptors including muscarinic, alpha1-adrenergic and histaminergic. 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 It is commonly admitted that the affinity of many antidepressants, and first of all tricyclic antidepressants, for certain postsynaptic neurotransmitter receptors may be responsible for some, if not all of their side effects. Anti-adrenergic properties are responsible for orthostatic hypotension, cardiac arrhythmias and a range of autonomic disturbances. Anticholinergic properties contribute to constipation, dry mouth and other autonomic symptoms, sedation and impact on cognitive function. The principal consequence of antihistamine activity is sedation. Having no affinity for these receptors, milnacipran shows a favourable tolerance profile, with a good cardiovascular tolerance, a lack of anticholinergic effects, of sedation and of 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 Milnacipran's pharmacokinetic profile in humans is particularly favourable. Milnacipran is rapidly and widely absorbed with a high bioavailability and a peak reached in 1/2 to 4 hours; its absorption is not affected by food intake. Plasma levels of milnacipran are predictable because of the drug’s linear pharmacokinetics, a very important characteristic in case of dose adjustment. The relatively short half-life of milnacipran (8 h) offers flexibility in administration, with a rapid establishment of steady-state levels when dose is increased or decreased, whilst ensuring that the drug is rapidly eliminated from the body when treatment is stopped. The weak protein-binding of milnacipran (13%) and a low inter-individual variation are other important features of milnacipran's pharmacokinetics. 28

Milnacipran's Pharmacology and Pharmacokinetics Pharmacokinetics
No liver metabolism by cytochrome P-450 Inhibition of CYP 450 subtypes FLUV FLUOX/ NORFLUOX PAROX SERT VENLA DULOX MILNA Substrate 1A2 +++ + theophylline, TCAs, melatonin, clozapine, haloperidol 2C19 ++ benzodiazepines, propranolol, TCAs, proton pump inhibitor 2C9 NSAIDs 2D6 TCAs, antipsychotics, beta-blockers, anti-arrhythmics 3A4 antibiotics, antivirals, benzodiazepines, calcium antagonists The limited role of cytochrome P450 (CYP 450) enzymes in the transformation of milnacipran confers additional flexibility in the use of the drug, which is not sensitive, as is the case for most other antidepressants, to genetic factors in metabolism. Therefore, there is a limited risk of metabolic competition modifying the pharmacokinetics of milnacipran in patients who are taking drug combinations. Thus, unlike most other antidepressants, the CYP2D6 isoenzyme of cytochrome P450, which is responsible for the biotransformation of most drugs including the majority of antidepressants, has no impact on the metabolism of milnacipran in vivo. The pharmacokinetics of milnacipran are not modified in subjects who are deficient in the CYP2D6 isoenzyme (slow sparteine-like metabolisers). Furthermore, milnacipran does not interfere in vivo with the other isoenzymes of cytochrome P450, CYP1A2 (whose substrates are : theophylline, TCAs, melatonin, clozapine, haloperidol), CYPI2C19 (substrates : benzodiazepines, propranolol, TCAs, proton pump inhibitors), CYP2C9 (substrates : NSAIDs) and CYP3A4 (substrates : antibiotics, antivirals, benzodiazepines, calcium antagonists). 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 Abstr. (2) (3) Cupp MJ, Tracy TS. Cytochrome P450 : new nomenclature and clinical implications. Am Fam Physician 1998;57(1): (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 A superior efficacy of milnacipran versus SSRIs, has been demonstrated in a meta-analysis of clinical trials vs SSRIs. Two multicentre, randomised, double-blind parallel-group studies involving a total of 306 adult inpatients have compared milnacipran 50 mg twice a day with the SSRIs fluoxetine and fluvoxamine. In both studies depression was moderate to severe, i.e. defined in the study protocols as a score of 25 or above on the Montgomery Asberg Depression Rating Scale (MADRS) or score of 3 or above on the Clinical Global Depression (CGI) Scale. 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

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 (n=150) SSRIs (n=156) at baseline 27.0 26.5 at endpoint 11.9 14.3  at endpoint -15.1* -12.2 This meta-analysis demonstrated that milnacipran 50 mg BID is more effective than SSRIs as assessed by the improvement in the HDRS scores between baseline and endpoint (p<0.05). * 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

Efficacy vs SSRIs Meta-analysis of double-blind studies in moderate to severe depression Higher response and remission rates vs SSRIs 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) % patients 10 20 30 40 50 60 70 80 64%* 50% 39% 28% Milnacipran's superiority over SSRIs was particularly marked when more rigorous criteria, such as response (reduction in HDRS or MADRS score of at least 50%) and remission rates (total HDRS score  7 at endpoint) were used, with 64% and 50% responders on the HDRS and 39% and 28% remitted patients with milnacipran and SSRIs respectively (p<0.01). Lopez-Ibor J et al. Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996;11(Suppl 4):S41-S46. 53

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 A multicentre double-blind placebo-controlled study compared milnacipran with paroxetine in depressed outpatients (DSM-IV criteria). The patients were randomly assigned to 2 treatment groups, receiving either milnacipran 50 mg twice a day (n=150) or paroxetine 20 mg once a day (n=153) for 6 weeks. Outcome measures included HDRS17 and MADRS scores, predictors of response and frequence of discontinuation emergent symptoms. Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83: 60

Efficacy vs SSRIs Comparative study vs Paroxetine in ambulatory patients with mild to moderate depression (ITT population-LOCF) Baseline 7 14 21 28 35 42 5 10 15 20 25 HDRS17 score Milnacipran (n=148) Paroxetine (n=151) days The efficacy analysis was based on data from 299 patients (148 in the milnacipran group and 151 in the paroxetine group). The mean baseline HAMD17 and MADRS scores were similar in both treatment arms and reflected a mild to moderate depressive state in most patients. Between baseline and endpoint, the main HAMD17 score decreased in a clinically significant manner in both groups : from 23.7 to 11.9 in the milnacipran group and from 23.4 to 11.4 in the paroxetine group (without any statistically significant difference between the two groups, p= 0.85). Similarly, the mean MADRS score decreased significantly in both groups (with no difference between the two groups, p=0.66). 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: 61

Efficacy vs SSRIs Comparative study vs Paroxetine in ambulatory patients with mild to moderate depression Response : reduction in HDRS or MADRS score of at least 50% Paroxetine 20 mg OD Milnacipran 50 mg BID HDRS17 MADRS p=0.70 p=0.71 % responders 10 20 30 40 50 60 70 Responder rates (reduction in MADRS or HDRS score of at least 50%) at endpoint were similar from a clinical and statistical viewpoint in both groups (HAMD17 responder rates : 58.1% and 60.3% respectively, p = 0.70 and MADRS responder rates : 62.8% and 64.9% respectively, p = 0.71). Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83: 62

HDRS Retardation item at baseline
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 ALL <1 < 2 <3 % CGI responders Paroxetine 20 mg OD Milnacipran 50 mg BID p=0.047 20 40 60 80 100 In this study, determinants of treatment response among the different baseline clinical variables (scores on the individual items of the 17-item HDRS) were assessed. In the milnacipran-treated group, there was a statistically significant relationship between degree of psychomotor retardation at baseline and CGI treatment response (p=0.047, Fisher’s exact test), with the most retarded patients at baseline having a higher probability of response, higher than those receiving paroxetine. 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: (2) Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 17 (Suppl 1):S43-S50. 63

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 Serotonin and Noradrenaline Reuptake Inhibitors (SRNIs) show a full efficacy in depression, comparable to the reference antidepressants which are the TCAs, because of their a dual action on both serotonin and noradrenaline. It is therefore important that this balanced dual mechanism be maintained whatever the dose. It has been shown that with SNRI venlafaxine the two effects - on serotonin and noradrenaline - are of different magnitude at different doses. Indeed, at low doses, venlafaxine is some fifteen times more potent on the serotonin system than on the noradrenaline system, acting actually like a SSRI. In consequence, venlafaxine requires dose-titration to bring in noradrenaline activity. On the other hand, at true SNRI dose, venlafaxine is less well tolerated than an SSRI. As it has been shown, milnacipran is, in fact, the only non tricyclic antidepressant that has such a balanced dual action in vivo over the entire dosing range. Therefore, it doesn't need any dose-titration in order to obtain noradrenaline activity. (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: 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 Milnacipran has a good overall tolerability being better tolerated than other classes of antidepressants. The reason is that, unlike other antidepressants such as TCAs, it does not bind to post-synaptic receptors (α1-adrenergic, cholinergic and histaminergic) that are implicated in the typical adverse effects of these drugs. Thus : - in classical tests, milnacipran was found to be neither stimulant nor sedative; - extensive series of studies assessing the potential impact of milnacipran on cognitive function have shown that single doses of milnacipran up to 100 mg had no effect on a battery of cognitive tests in healthy volunteers and can even have a positive impact on cognition and vigilance; - tests have shown that milnacipran does not alter the ability to drive a car; - milnacipran does not potentiate the effects of alcohol; - it is unlikely that convulsions appear during treatment with milnacipran, this drug having no effect on seizure threshold; - EEG studies have also shown that milnacipran doesn’t alter sleep pattern. Moreover, a treatment with milnacipran : - causes no change in body weight; - does not modify significantly sexual function; - has 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: (2) Richet F et al. Effects of milnacipran on driving vigilance. Int J Psychiatr Clin Pract 2004 (in press). 81

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 Disturbances in sexual function, particularly dysorgasmia and anorgasmia, are common and may be most distressing side effects observed with SSRIs. Sexual dysfunction has not been systematically investigated in the milnacipran clinical development programme. However, pooled data from clinical trials imply that incidence of sexual dysfunction is very low with milnacipran (less than 2%). These very low incidence rates are confirmed by feedback from prescribing clinicians. Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9. 83

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 Milnacipran doesn't display any sodium channel blocking activity and is devoid of effect at potassium and calcium channels. This might explain why milnacipran has no effect on cardiac conduction or ventricular depolarization. During clinical trials, the mean increase in heart rate was approximately 3 beats per minute, and changes in arterial blood pressure were negligible. 84

Dysuria 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%)  >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 Even it occurs more frequently during therapy with milnacipran than during the administration of placebo, TCAs or SSRIs, dysuria associated with milnacipran therapy is relatively rare. It concerns about 2.35% of all patients and is seen more frequently in men. More than 70% of events are rated as mild to moderate and 67% of affected patients are continuing the treatment in spite of this adverse event. Dysuria appears to be related to the noradrenergic tropism of milnacipran which is not counter-balanced by α-adrenolytic effects. It is therefore possible to control symptoms of male dysuria using an α1-blocker. However, although dysuria is relatively rare, close monitoring of high risk patients, e.g. those with prostate disorders, is advisable. 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: 85

Sleep A significant improvement of objective sleep parameters  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) 24** 27 Intrasleep awake time (min/h) 13.8 7.2 6.0 Number of awakenings(a) per hour 1.9 2 1.8 The clinical improvement of depression during treatment with IXEL is accompanied by a significant improvement of objective sleep parameters, such as :  an improvement of the total duration of sleep (principally due to a major increase in stage II sleep significant from D4-6),  a significant reduction, within 4-6 days, of the sleep latency,  a significant increase in sleep efficiency as soon as D4-6. *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

Driving vigilance No effects on vigilance as evaluated by laboratory tests  visual and auditory vigilance tests 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 43.2 ± 2.4 43.0 ± 1.9 43.8 ± 1.2 96.1 ± 25.3 84.2 ± 30.3 92.8 ± 24.9 -11.5 ± 14.7 -12.8 ± 26.9 -9.8 ± 27.4 A recent double-blind, placebo-controlled four-sequence cross-over trial tried to investigate the effects of milnacipran on the sensory and psychomotor skills implicated in car driving and to determine any possible interactions with the effect of alcohol. The results of laboratory tests (vigilance and postural stability tests) were not significantly different between groups receiving milnacipran compared to placebo. Thus, it can be stated that milnacipran has no significant effects on vigilance as evaluated by laboratory tests. Values are means ± SD Richet F et al. Effects of milnacipran on driving vigilance. Int J Psych Clin Pract 2004;8: 87

Driving vigilance No effects on vigilance in a real driving situation  evaluation of driving tests by instructor Before treatment Milnacipran Placebo Adaptation to driving (160 points) 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 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 Furthermore, there was any significant difference in the results of real on-road driving situation tests between groups receiving milnacipran compared to placebo. It is thus clear that milnacipran does not modify the psychomotor skills required for driving. Moreover, it has been shown that with milnacipran, there is no accentuation of the negative effects of alcohol intake, the effects of the association of milnacipran with alcohol being not different from those of the association of placebo with alcohol in any test. Values are means ± SD Richet F et al. Effects of milnacipran on driving vigilance. Int J Psych Clin Pract 2004;8: 88

Adverse events vs SSRIs Incidence of adverse events Lower with milnacipran than SSRIs 5 10 15 20 Milnacipran SSRIs Somnolence Fatigue Vomiting Anxiety Constipation Abdominal pain Dry mouth Headache Nausea Milnacipran is at least as well tolerated as SSRIs, if not better, as it has been shown in a meta-analysis of studies comparing milnacipran to SSRIs. Milnacipran is better tolerated than SSRIs especially in terms of gastrointestinal adverse effects (nausea, vomiting and abdominal pain). % 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

Adverse events vs SSRIs Incidence of treatment discontinuation emergent symptoms Lower with milnacipran than paroxetine % occurrence 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) In a study comparing milnacipran versus paroxetine in ambulatory patients with predominantly mild to moderate depression, after treatment discontinuation, milnacipran was associated with significantly less emergent symptoms than paroxetine. Emergent symptoms were observed in only 13% of milnacipran treated patients compared to 31,8% in paroxetine treated patients (p = 0.032). Most of the discontinuation emergent symptoms affected the central nervous system. Sechter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004;83(2-3): 94

Adverse events vs Venlafaxine Incidence of adverse events Lower with milnacipran than venlafaxine % occurrence 10 20 30 40 Milnacipran Venlafaxine Sweating Nervousness Drowsiness Constipation Dizziness/Vertigo Dry mouth Somnolence Nausea Milnacipran 100 mg/day is better tolerated than venlafaxine causing, for example, less nausea, somnolence, dry mouth, vertigo or constipation. (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): (2) Feighner JP. The role of venlafaxine in rational antidepressant therapy. J Clin Psychiatry 1994;55 Suppl A:62-8. 95

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) 3 6 9 12 15 Nausea Headache Constipation Dry mouth Perspiration Insomnia Abdominal pain Vertigo % occurrence Long-term tolerability data were available from 1,010 patients who had received milnacipran for at least three months. No significant difference in the incidence or spectrum of adverse events were found between milnacipran-treated patients and those receiving placebo. The incidence of the most frequent adverse events diminish with time particularly after the first three months of treatment. The long-term data, up to more than 1 year of treatment, indicate that the tolerability of milnacipran improves with extended treatment. Data on file. 96

Conclusions Improved tolerance profile versus other classes TCAs SSRIs Venlafaxine Milnacipran Nausea + ++ Sexual dysfunction - Weight gain Sedation Sweating Constipation Dry mouth Dysuria Sustained hypertension YES NO Orthostatic intolerance QT Prolongation Treatment discontinuation for adverse events 21-33% 12-20% 11-19% 7.6% Milnacipran has an improved tolerance profile versus other classes. Milnacipran's excellent tolerance profile is a result of its lack of interaction with postsynaptic receptors. Overall, milnacipran does not induce any more adverse effects than placebo. The incidence of adverse effects which occur more frequently with milnacipran than with placebo is less than 5% - these include nausea, sweating and dysuria. All these indesirable events remit rapidly and long-term tolerance is good. Milnacipran is undoubtedly better tolerated than TCAs - especially in regards to anticholinergic (e.g. dry mouth, constipation) or antihistaminergic side effects (e.g. fatigue, drowsiness, weight gain)-, than venlafaxine and even than SSRIs. Major advantages of milnacipran are its absence of cardiotoxicity, a limited change in body weight (no weight gain is observed in 9 patients out of 10), a relative absence of sexual dysfunction, as well as lack of sedative effects or of alteration of cognitive dysfunction. Overall, this leads to better compliance to milnacipran treatment and to less treatment discontinuations due to 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

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 Since drug overdose is a common method of attempting suicide, it is important that an antidepressant agent should be relatively harmless when taken in overdose. Fifteen cases of overdose with milnacipran were reported : they involved the ingestion of quantities up to 2800 mg of milnacipran (1 month’s treatment) alone or combined with other therapeutic agents. None of the patients died, no cardiac rhythm abnormalities and no coma has been reported and each case had a good outcome, patients being 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 Weeks % improvement 10 20 30 40 50 60 70 80 1 2 3 4 5 6 7 8 Anxiety Sleep Cognitive symptoms Psychomotor retardation Core symptoms Analysis of the qualitative nature of the antidepressant efficacy of milnacipran has shown that it acts consistently on the major symptoms of depression. All symptoms respond rapidly to treatment with milnacipran to a similar extent, and across a similar timeframe. Such a broad-spectrum effect on symptoms may be attributed to the dual action of milnacipran on noradrenaline and on serotonin, and it contrasts with what has been observed with SSRIs, which appear to improve some symptoms more or less rapidly than others. (1) Montgomery S. Dual action antidepressants in clinical practice. Drugs 2001;3(1): (2) Costa e Silva JA. The effect of milnacipran on depressive symptoms. Int J Psych Clin Pract 1999;3(Suppl 2):S21-S27. 104

Retarded depression A significantly higher probability of response vs paroxetine in depressed patients with psychomotor retardation 100 * % responders 50 * p=0.047 Patients with high levels of retardation may derive more benefit from an antidepressants which acts on the noradrenergic as well as the serotoninergic systems. This has been shown in a study comparing milnacipran and paroxetine assessing determinants of treatment response among different baseline clinical variables (scores on the individual items of the 17-item HDRS). In the milnacipran-treated group, there was a statistically significant relationship between degree of psychomotor retardation at baseline and CGI treatment response (p=0.047, Fisher’s exact test), with the most retarded patients (HDRS retardation score > 3 at study entry) at baseline having a higher probability of response, higher than those receiving paroxetine. 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

Patients exposure years (n)
Milnacipran and Special Patient Profiles Suicidal risk Less suicide attempts and completed suicides Suicide attempts Completed suicides Patients exposure years (n) [log scale] 0.01 0.1 1 Placebo TCAs SSRIs Milnacipran Treatment Absolute number of suicides and suicide attempts in patients treated with milnacipran are low. The incidence of suicide attempts is of about 4.9 cases per 100 patient exposure years, slightly less than with TCAs and markedly less than in patients treated with SSRIs or in placebo-treated patients (respectively 20 and 16 cases/100 patient exposure years). In terms of the actual number of completed suicides, rates in milnacipran treated patients were approximately 3 times lower than in patients on placebo. Montgomery SA. The place of milnacipran in clinical practice. Int Clin Psychopharmacol 2003;18(Suppl 1):S1-S9. 107

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 The pronounced antihistaminergic and anticholinergic activity of TCAs is responsible for their sedative properties. Such deleterious drug effects on arousal and cognitive function are a major inconvenient for active patients undertaking routine tasks requiring dexterity and concentration. Milnacipran has little effect on cognitive function or psychomotor performance and is not associated with subjective sedation. It does not enhance the sedative effects of alcohol. In healthy volunteers, milnacipran - up to 100 mg as a single dose - has no effect on a battery of psychomotor tests measuring reaction time, learning and recall tasks, visuospatial memory. In car-driving tasks, milnacipran has no effect on vigilance or performance levels. As such, milnacipran is thus suitable for use in patients with an 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). 108

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…) In elderly patients, the treatment of depression faces specific challenges, concerning first at all age-related changes in drug metabolism and in sensitivity to psychotropic drugs. Moreover, the elderly patients are also more likely than younger ones to receive treatment for multiple illnesses, thus increasing the potential for serious drug interactions and are more vulnerable to treatment side effects. Last but not least, difficulties may be related to the specific symptom profile seen in the elderly patients. Milnacipran possesses a number of advantages in this population : its pharmacokinetic parameters are not significantly altered in the elderly patients (except in case of renal failure), it has a limited potential for drug interactions, a broad-spectrum efficacy across depressive symptoms and a favourable safety profile (less sedation, less cardiovascular events etc.). (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

% responding patients at w10
Milnacipran and Special Patient Profiles Elderly depressed patients Milnacipran advantages in elderly patients (aged  50 years) A better response to milnacipran than to SSRI 20 40 60 80 100 % responding patients at w10 Milnacipran (n=55 ; mg/day) Fluvoxamine (n=42 ; mg/day) Paroxetine (n=62 ; mg/day) 80% 52% 64% A main advantage of milnacipran in elderly patients is the better response to this treatment than to SSRIs. Thus, a retrospective cohort analysis of outpatients treated for depression between January and December 2001 showed that in patients 50 years and older, response rate (i.e. the reduction of HDRS score of at least 50%) to milnacipran (80%) was far better than the rates for paroxetine (64%) and fluvoxamine (52%). Response : reduction in HDRS score of at least 50% Morishita S, Arita S. Comparison of milnacipran and SSRIs, especially in age. Abstr 2004. 111

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 Sleep, as a symptom of depression, responds rapidly to treatment with milnacipran, to a similar extent and across a similar timeframe as the core symptoms of depression. Thus, milnacipran improves sleep quality : it decreases sleep latency, reduces the frequency of nocturnal awakenings and increases the latency of onset of REM sleep. On the other hand, milnacipran has no sedative effect and doesn’t alter the cognitive functions. (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: (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

Preferential response to milnacipran Differential effects of Milnacipran and SSRIs Improved response in agitated and inhibited depression 20 40 60 80 100 % response at w2 Milnacipran (n=55 ; mg/day) Inhibited depression Agitated depression Fluvoxamine (n=42 ; mg/day) Paroxetine (n=55 ; mg/day) A retrospective cohort analysis of outpatients treated for depression between January and December 2001 explored the effect of three different antidepressant drugs with regard to the type of depression (inhibited or agitated). At the end of a two-week treatment period, patients receiving milnacipran treatment showed a better response than paroxetine and fluvoxamine in both agitated and inhibited depression. However, the response rate in milnacipran-treated patients with agitated depression was higher than the rate in patients with inhibited depression. 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

% patients with manic change
Milnacipran and Special Patient Profiles Switch to mania Less switch to mania or hypomania than with SSRIs 2 4 6 8 10 % patients with manic change Milnacipran (n=68 ; mg/day) Fluvoxamine (n=122 ; mg/day) Paroxetine (n=79 ; mg/day) 1.47% 4.90% 8.86% Antidepressants have been recognized as potential inducers of mania since their introduction in the 1950s. In depressed patients treated with TCAs or MAOIs, reported incidence of mania or hypomania can reach up to 10% of subjects. But not all antidepressants are equivalent in this regard. If we compare milnacipran to paroxetine and fluvoxamine using data of a retrospective cohort analysis of patients treated for depression between December 2000 and November 2001, we can see that with milnacipran there is less switch to mania or hypomania (1.47%) than with SSRIs (4.9% and 8.86% with fluvoxamine and paroxetine respectively). 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 % score improvement in DIP* score month 6 vs baseline 10 20 30 40 50 60 70 80 90 100 76.3% 72.0% 80.5% 72.4% 69.7% 62.2% 70.5% 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 Globally, treatment with milnacipran leads to a tremendous improvement of quality of life. Thus, in a long-term study, responders who continued treatment with milnacipran had an over 69% improvement in DIP-quality of life total score, every sub-score being improved by at least 63%. Rouillon F et al. Prevention of recurrent depressive episodes with milnacipran : consequences on quality of life. J Affect Disord 2000;58: 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) Milnacipran has been shown to be efficient in a number of other pathologies, such as anxiety disorders, which are strongly related to depression (strong comorbidity, common physiopathological pathways etc.). Today, there exists evidence supporting milnacipran's efficacy in : - Generalised Anxiety Disorder (GAD), - Panic Disorder (PD), - Obsessive Compulsive Disorder (OCD), - Social Anxiety Disorder (Social Phobia), - Post-Traumatic Stress Disorder (PTSD). 122

Anxiety Disorders Generalised Anxiety Disorder 5 10 15 20 25 30 1 2 3 4 6 7 8 Weeks HAM-A Total score Milnacipran 45–150 mg/day The results of an 8-week open study in patients with Generalized Anxiety Disorder (GAD) suggest that milnacipran is effective in the treatment of this disease. HAMA (Hamilton Anxiety Rating Scale) score was markedly reduced vs baseline as soon as week 1 and all patients achieved remission (i.e. absence or near absence of symptoms) at 8 weeks. Open study Tsukamoto T et al. Usefulness of milnacipran in the treatment of Generalized Anxiety Disorder. Abstr 2003. 123

LSAS (Liebowitz Scale) score
Milnacipran in other pathologies Anxiety Disorders Social Phobia 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 4 8 Weeks 12 LSAS (Liebowitz Scale) score p<0.001 A recent open trial in 12 patients with Taijin-Kyofusho (the Japanese designation of DSM-IV Social Phobia) suggest that milnacipran may be helpful in the treatment of social phobia. 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

Chronic Pain Chronic abdominal, back, chest and glossal pain A significant improvement in pain VAS pain score Baseline 88.2 32.8 10 20 30 40 50 60 70 80 90 100 Milnacipran appears to be a useful agent in the management of chronic pain. Thus, in patients suffering of chronic abdominal, back, chest and glossal pain, milnacipran showed a significant improvement in pain reducing the VAS pain score by 55.4 points after 12 weeks of treatment. Endpoint (w12) Five outpatients suffering from chronic pain since 17.8 months (mean) treated with milnacipran mg/day for 12 weeks. Kamata M et al. Efficacy of milnacipran for the treatment of chronic pain patients. Abstr 2004. 125

Chronic Pain Chronic orthopaedic pain (including degenerative spondylosis) A significant improvement in pain 20 40 60 80 100 1 2 3 4 5 6 7 8 Weeks Pain VAS Milnacipran mg BID It has been found empirically in the orthopaedic field that antidepressants are effective for pain disorders such as phantom pain after limb amputation, peripheral neuritis etc. The results of an 8-week open study in 17 subjects suffering from pain in the trunk and/or extremities due to degenerative spondylosis suggest that milnacipran is very effective in the treatment of chronic orthopaedic pain. Thus, the mean VAS (Visual Analogue Scale) for pain was markedly reduced at the end of the study. 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

Chronic Pain Fibromyalgia (FMS) - related pain A significant improvement in pain * p=0.0395 ** p=0.004 % patients Placebo Milnacipran > 50% reduction in pain intensity 14% 37%* 10 20 30 40 50 60 70 80 90 100 Improvement 38% 75%** Milnacipran was shown to significantly improve a number of primary and secondary hallmark symptoms of fibromyalgia syndrome (FMS). In a double-blind placebo-controlled trial, milnacipran-treated patients (4 weeks dose escalation + 8 weeks fixed dose) showed a statistically significant improvement in pain compared to those who received placebo. Further, 37% reported at least a 50% reduction in the intensity of their pain, compared to just 14% of placebo patients (p=0.0395, intention-to-treat analysis) and 75% of all milnacipran-treated patients reported overall improvement compared to 38% in the placebo-group (p=0.004). 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 ( 127

Chronic Pain Fibromyalgia (FMS) - related pain in patients with depressive symptoms A significant improvement in pain associated with relief from depressive symptomatology p<0.01 VAS pain score Baseline Endpoint (w12) 77.6 50.0 10 20 30 40 50 60 70 80 90 100 In patients with depressive symptoms, the significant improvement in pain observed under milnacipran treatment is associated with relief from depressive symptomatology, as it was shown in an open-label study in patients with fibromyalgia and a depressive state score of  50 on the Zung Self-rating Depression Scale and who were treated with milnacipran up to 100 mg/day for 12 weeks. 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

Depression in schizophrenia spectrum disorders Schizophrenia, delusional and schizoaffective disorders with depressive symptoms A significant improvement of depressive symptomatology p=0.008 Baseline Endpoint (w8) 58.3 ±8.1 20 40 60 SDS* Score 42.4 ±9.6 Patients with schizophrenia often manifest depressive symptoms, and these patients comprise approximately 25% of all schizophrenic patients. A recent open-label study in such patients – with schizophrenia, delusional and schizoaffective disorders with depressive symptoms - has shown that milnacipran is highly beneficial, improving significantly the depressive symptomatology. This is important to know because, unlike milnacipran, some antidepressants (e.g. tricyclics) for schizophrenia spectrum patients increases the seriousness of anticholinergic side-effects, as they are already exposed to antipsychotics for the treatment of their original illness, or to anticholinergic agents for the control of extrapyramidal side-effects of antipsychotics. *Self-rating Depression Scale Open-label study, milnacipran up to 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

100 mg a day in two 50 mg doses, 1 capsule morning and evening
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) Milnacipran is well tolerated, but it is advisable to start with a low dose of 25 mg twice daily or 50 mg once daily; the dose should then be progressively increased to 100 mg/day over 2-3 weeks. The recommended (optimum) dosage is 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, because food does not modify the pharmacokinetics of milnacipran. Nevertheless, the safety profile of the drug is improved (i.e. less nausea is observed) when administered with food, and it is recommended that milnacipran be taken during meals. 131

איקסל נמצא בקופות החולים:
השתתפות המטופל מכבי - 50% מאוחדת - 15% השתתפות המטופל לאומית - 60% השתתפות המטופל מחיר שוק פרטי ₪ לחודש טיפול במינון של 100 מ"ג ליום

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