Depression duloxetine

The position of the regulatory authorities is best illustrated by a recent Marketing Authorisation Application by Eli Lilly (www.emea.europa.eu/ humandocs/PDFs/EPAR/cymbalta/19256704en6.pdf) for their anti-depressant duloxetine. The phase III protocols specified a repeated measures ANOVA as the primary method of analysis and the regulatory submission was based on such analyses. The CPMP, however, asked for an additional simpler analysis based on change from baseline as the outcome measure and using LOCF. 

Thiophene seems to be very popular in Li Lilly drugs. Its dual selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for depression, duloxetine (Cymbalta), contains a thiophene. And its atypical antipsychotic drug olanzapine (Zyprexa) has a fused thiophene as its core structure. 

More recently, an analysis of pooled data from seven safety and efficacy trials of duloxetine did not find any differences in efficacy in depressed Hispanics compared with Whites (Lewis-Fernandez etal, 2006). Unfortunately, the sample size for the Hispanic group was very small in comparison to the White cohort (n = 58 White, n = 748), and most likely underpowered to detect any differences. Also, the Hispanic group included Mexicans and Mexican Americans along with Central and South Americans (percentage breakdown is unknown). 

Lewis-Fernandez, R., Blanco, C., Mallinkcrodt, C. H., Wohlreich, M. M. et al. (2006). Duloxetine in the treatment ofmajor depressive disorder comparisons of safety and efficacy in US Hispanic and majority Caucasian patients. /. Clin. Psychiatry, 67, 1379-90. 

Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake indicated for depression and painful diabetic neuropathy, is expected to become first-line therapy for SUI. Duloxetine is thought to facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase. 

There are three approved drugs, venlafaxine (16), duloxetine (17) and milnacipran (18), in the serotonin-norepinephrine reuptake inhibitor (SNRI) class. Whereas milnacipran blocks 5-HT and NE reuptake with almost equal potency, venlafaxine and duloxetine block 5-HT reuptake preferentially [39-41]. Clinical evidence shows that SNRIs have comparable efficacy in the treatment of MDD compared with antidepressants in the SSRI class. An advantage with SNRIs appears to be the ability of alleviating chronic pain associated with, and independent of depression [42-44],... 

Antidepressants. The most widely used psychiatric medicines with the broadest range of application in TBI patients are undoubtedly the SSRI antidepressants. They are well tolerated, unlikely to worsen any of the preexisting deficits associated with TBI, and offer relief from not only depression but also impulsivity and virtually all variants of anxiety in these patients. As such, SSRIs are the preferred first-line treatment for all anxiety disorders after TBI. Other newer antidepressants that also work (at least in part) by boosting serotonin activity, namely, mirtazapine (Remeron), nefazodone (Serzone), venlafaxine (Effexor XR), and duloxetine (Cymbalta) can also be considered, but they have not been well studied in patients with TBI. In... 

Duloxetine Blocks NE reuptake 1T Serotonin Depression Anxiety disorders ( )... 

Duloxetine hydrochloride, a novel anti-depressive, is known to be acid labile and, consequently, it has been formulated as an enteric-coated tablet. Interestingly, Jansen et al. [97] subsequently found that the drug was destabilised by degradation products within these enteric polymers. The authors found that succinyl and phthalyl residues from the hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) formed... 

Suicidality in children and adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of duloxetine or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. 

Side effects, mainly due to serotonin reuptake inhibition include G1 upset, nervousness, and sexual dysfunction. SSRls are associated with an increased risk of falls. Hyponatraemia due to SIADH is an uncommon, but important side effect in elderly patients. Selective serotonin and norepinephrine reuptake inhibitors (S SNRls) such as venlafaxine and duloxetine are also useful in older patients. Other heterocyclic antidepressants of importance in older patients because of relative safety include bupro-prion and mirtazepine. They are reserved for patients with resistance to or intolerance of SSRls. Currently, trazodone is used mostly for sleep disturbance in depression in doses of 50-100 mg at bedtime. The monoamine oxidase inhibitors phenelzine. 

Geriatric Considerations - Summary Compared to placebo, duloxetine is effective for the treatent of depression and painful diabetic neuropathy Few head-to-head studies are available comparing duloxetine to other agents in the treatment of depression or painful neuropathy. Because this agent may increase urethral sphincter activity, it is now being assessed as an agent for the treatment of stress urinary incontinence. This same property may increase the risk of urinary retention, although this has not been well documented. Duloxetine has not been well studied with respect to falls. 

Kirwin JL, Goren JL. Duloxetine a dual serotonin-norepinephrine reuptake inhibitor for treatment of major depressive disorder. Pharmacotherapy 2005 25 396-410. 

Hepatotoxicity. Duloxetine is rarely associated with increases in serum transaminase levels, typically in the first 2 months of treatment. In controlled trials in major depressive disorder, elevations of alanine aminotransferase (ALT) to greater than three times the upper limit of normal occurred in 0.9% (8 of 930) of the duloxetine-treated patients and in 0.3% (2 of 652) of the placebo-treated patients. Current product labeling contains a caution regarding the use of duloxetine in patients with significant alcohol use or chronic liver disease. Postmarketing reports have indicated that increases in transaminases have occurred in some patients with chronic liver disease (Cymbalta 2005). 

Sexual dysfunction. The controlled clinical trials of duloxetine in the treatment of major depression used a rating scale to assess prospectively treatment-emergent sexual dysfunction. As with... 

Arnold LM, Lu Y, Crofford LJ, et al A douhle-hlind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 50 2974— 2984, 2004... 

Goldstein, D.J., Mallickrodt, C., Lu, Y., Demitrack, MA Duloxetine in the treatment of major depressive disorder, a double blind clinical trial. J. Clin Psychiatry 63,225— 231.2002. 

The SNRIs include venlafaxine, its metabolite desvenlafaxine, and duloxetine. Another SNRI, milnacipran, is in late clinical trials in the USA but has been available in Europe for several years. In addition to their use in major depression, other applications of the SNRIs include the treatment of pain disorders including neuropathies and fibromyalgia. SNRIs are also used in the treatment of generalized anxiety, stress urinary incontinence, and vasomotor symptoms of menopause. 

Duloxetine Moderately selective blockade of NET and SERT Acute increase in serotonergic and adrenergic synaptic activity otherwise like SSRIs Major depression, chronic pain disorders fibromyalgia, perimenopausal symptoms Toxicity Anticholinergic, sedation, hypertension (venlafaxine) Interactions Some CYP2D6 inhibition (duloxetine, desvenlafaxine)... 

Gupta S, Nihalani N, Masand P Duloxetine Review of its pharmacology, and therapeutic use in depression and other psychiatric disorders. Ann Clin Psychiatry 2007 19(2) 125. [PMID 17612852]... 

Additional dual 5HT-NE reuptake inhibitors include sibutramine, which is approved for the treatment of obesity but not depression. Tramadol is a kappa opiate agonist approved for the treatment of pain, but it also has serotonin and norepinephrine reuptake inhibitor properties. Dual reuptake inhibitors in clinical testing as antidepressants include milnacipran and duloxetine. 

Atypical antidepressants represent a heterogeneous group comprising agents that interfere only weakly or not at all with monoamine reuptake (trazodone, nefazo-done, bupropion, mirtazapine), preferentially block reuptake of norepinephrine (re-boxetine), or act as dual inhibitors of 5-HT and norepinephrine reuptake (venlafaxine, milnacipran, duloxetine). Venlafaxine appears to be as effective as tricyclic antidepressants in severe depression. 

Cowen PJ, Ogilvie AD, Gama J. Efficacy, safety and tolerability of duloxetine 60 mg once daily in major depression. Curr Med Res Opin 2005 3 345-55. 

Adding other agents to duloxetine for treating depression could follow fhe same pracfice for augmenfing SSRIs or ofher SNRIs if done by experts while monitoring carefully in difficulf cases... 

Duloxetine has well-documented efficacy for the physical symptoms of depression... 

Detke MJ, Lu Y, Goldstein DJ, Flayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder a randomized double-blind placebo-controlled trial. J Clin Psychiatry 2002 63(4) 308-15. 

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