OJD  Vol.2 No.4 , November 2013
A Review of the Serotonin-Norepinephrine Reuptake Inhibitors: Pharmacologic Aspects and Clinical Implications for Treatment of Major Depressive Disorder and Associated Painful Physical Symptoms
Abstract: Background: Depression is characterized by low mood, low self-esteem, and loss of interest or pleasure. Painful physical symptoms (PPS) associated with depression have a negative impact on the probability of remission. Because both norepinephrine and serotonin are involved with the central regulation of pain, the serotonin-norepinephrine reuptake inhibitors (SNRIs) may have more success than the selective serotonin reuptake inhibitors (SSRIs) in impacting PPS as well as the core emotional symptoms of depression. Methods: Published preclinical and clinical data on the SNRIs (i.e., milnacipran, venlafaxine, and duloxetine) have been reviewed, paying special attention to the differentiation of the pharmacological aspects of the SNRIs. The efficacy and safety results on depression and associated PPS have also been summarized. Results: Each of the SNRIs has different profiles regarding the inhibition of binding to human serotonin and norepinephrine uptake transporters and clinical pharmacokinetics. All SNRIs have data for alleviating the core symptoms of depression; duloxetine and venlafaxine show efficacy for PPS associated with depression. There are also differences in tolerability and adverse events profiles. Conclusions: Although all SNRIs have the same dual mechanism of action for the treatment of depression, they have different pharmacologic profiles that may impact clinical outcomes.
Cite this paper: Alev, L. , Lenox-Smith, A. , Altin, M. & Dueñas, H. (2013). A Review of the Serotonin-Norepinephrine Reuptake Inhibitors: Pharmacologic Aspects and Clinical Implications for Treatment of Major Depressive Disorder and Associated Painful Physical Symptoms. Open Journal of Depression, 2, 54-63. doi: 10.4236/ojd.2013.24011.

[1]   American Psychiatric Association (APA) (2000). Diagnostic and statistical manual of mental disorders (4th ed.). Washington DC: American Psychiatric Association.

[2]   Abdelmawla, A. H., Langley, R. W., Szabadi, E., & Bradshaw, C. M. (1999). Comparison of the effects of venlafaxine, desipramine, and paroxetine on noradrenaline and methoxamine-evoked constriction of the dorsal hand vein. British Journal of Clnical Pharmacology, 48, 345-354.

[3]   Ansseau, M., Papart, P., Troisfontaines, B., Bartholome, F., Bataille, M., Charles, G. et al. (1994). Controlled comparison of milnacipran and fluoxetine in major depression. Psychopharmacology (Berl), 114, 131-137.

[4]   Bair, M. J., Robinson, R. L., Katon, W., & Kroenke, K. (2003). Depression and pain comorbidity: A literature review. Archives of Internal Medicine, 163, 2433-2445.

[5]   Bair, M. J., Robinson, R. L., Eckert, G. J., Stang, P. E., Croghan, T. W., & Kroenke, K. (2004). Impact of pain on depression treatment response in primary care. Psychosomatic Medicine, 66, 17-22.

[6]   Baldwin, D., Moreno, R. A., & Briley, M. (2008). Resolution of sexual dysfunction during acute treatment of major depression with milnacipran. Human Psychopharmacology, 23, 527-532.

[7]   Benarroch, E. E. (2008). Descending monoaminergic pain modulation: Bidirectional control and clinical relevance. Neurology, 71, 217-221.

[8]   Bradley, R. H., Barkin, R. L., Jerome, J., DeYoung, K., & Dodge, C. W. (2003) Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder. American Journal of Therapeutics, 10, 318-323.

[9]   Brannan, S. K., Mallinckrodt, C. H., Brown, E. B., Wohlreich, M. M., Watkin, J. G., & Schatzberg, A. F. (2005). Duloxetine 60 mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder. Journal of Psychiatric Research, 39, 43-53.

[10]   Brecht, S., Courtecuisse, C., Debieuvre, C., Croenlein, J., Desaiah, D., Raskin, J. et al. (2007). Efficacy and safety of duloxetine 60 mg once daily in the treatment of pain in patients with major depressive disorder and at least moderate pain of unknown etiology: A randomized controlled trial. Journal of Clinical Psychiatry, 68, 1707-1716.

[11]   Bymaster, F. P., Dreshfield-Ahmad, L. J., Threlkeld, P. G., Shaw, J. L., Thompson, L., Nelson, D. L. et al. (2001). Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology, 25, 871-880.

[12]   Chang, T. T., Leng, C. H., Wu, J. Y., Lee, S. Y., Wang, Y. S., Chen, Y. C., Lu, R. B. et al. (2008). Lower side effects of milnacipran than paroxetine in the treatment of major depression disorder among Han Chinese in Taiwan. Chinese Journal of Physiology, 51, 387-393.

[13]   Cipriani, A., Furukawa, T. A., Salanti, G., Geddes, J. R., Higgins, J. P., Churchill, R. et al. (2009). Comparative efficacy and acceptability of 12 new-generation antidepressants: A multiple-treatments meta-analysis. Lancet, 373, 746-758.

[14]   Clauw, D. J., Mease, P., Palmer, R. H., Gendreau, R. M., & Wang, Y. (2008). Milnacipran for the treatment of fibromyalgia in adults: A 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clinical Therapeutics, 30, 1988-2004.

[15]   Clerc, G. (2001). Antidepressant efficacy and tolerability of milnacipran, a dual serotonin and noradrenaline reuptake inhibitor: A comparison with fluvoxamine. International Clinical Psychopharmacology, 16, 145-151.

[16]   Cymbalta (Package Insert) (2012). Indianapolis, Indiana: Eli Lilly and Company.

[17]   Danish University Antidepressant Group (1986). Citalopram: Clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology (Berl), 90, 131-138.

[18]   Davidson, J., Watkins, L., Owens, M., Krulewicz, S., Connor, K., Carpenter, D. et al. (2005). Effects of paroxetine and venlafaxine XR on heart rate variability in depression. Journal of Clinical Psychopharmacology, 25, 480-484.

[19]   Delgado, P. L., Brannan, S. K., Mallinckrodt, C. H., Tran, P. V., Mc-Namara, R. K., Wang, F. et al. (2005). Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder. Journal of Clinical Psychiatry, 66, 686-692.

[20]   Delgado, P. L., Charney, D. S., Price, L. H., Aghajanian, G. K., Landis, H., & Heninger, G. R. (1990). Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Archives of General Psychiatry, 47, 411-418.

[21]   Delgado, P. L., Miller, H. L., Salomon, R. M., Licinio, J., Heninger, G. R., Gelenberg, A. J., Charney, D. S. et al. (1993). Monoamines and the mechanism of antidepressant action: Effects of catecholamine depletion on mood of patients treated with antidepressants. Psychopharmacology Bulletin, 29, 389-396.

[22]   Delgado, P. L., Moreno, F., Potter, R., & Gelenberg, A. J. (1997). Norepinephrine and serotonin in antidepressant action: Evidence from neurotransmitter depletion studies. In: M. Briley (Ed.), Antidepressant therapy at the dawn of the third millennium (pp. 141-163). London: Martin Dunitz, Ltd.

[23]   Detke, M. J., Lu, Y., Goldstein, D. J., Hayes, J. R., & Demitrack, M. A. (2002). Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. Journal of Clinical Psychiatry, 63, 308-315.

[24]   Detke, M. J., Lu, Y., Goldstein, D. J., McNamara, R. K., & Demitrack, M. A. (2002). Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. Journal of Psychiatric Research, 36, 383-390.

[25]   DeVeaugh-Geiss, A. M., West, S. L., Miller, W. C., Sleath, B., Gaynes, B. N., & Kroenke, K. (2010). The adverse effects of comorbid pain on depression outcomes in primary care patients: Results from the ARTIST trial. Pain Medicine, 11, 732-741.

[26]   Duenas, H., Brnabic, A. J., Lee, A., Montejo, A. L., Prakash, S., Casimiro-Querubin, M. L. et al. (2011). Treatment-emergent sexual dysfunction with SSRIs and duloxetine: Effectiveness and functional outcomes over a 6-month observational period. International Journal of Psychiatry in Clinical Practice, 15, 242-254.

[27]   Effexor XR (Package Insert) (2012). Collegeville, PA: Wyeth Pharmaceuticals, Inc.

[28]   English, C., Rey, J. A., & Rufin, C. (2010). Milacipran (Savella), a treatment option for fibromyalgia. Drug Forecast, 35, 261-266.

[29]   Fava, M., Mallinckrodt, C. H., Detke, M. J., Watkin, J. G., & Wohlreich, M. M. (2004). The effect of duloxetine on painful physical symptoms in depressed patients: Do improvements in these symptoms result in higher remission rates? Journal of Clinical Psychiatry, 65, 521-530.

[30]   Feighner, J. P. (1995). Cardiovascular safety in depressed patients: Focus on venlafaxine. Journal of Clinical Psychiatry, 56, 574-579.

[31]   Fields, H. L., Heinricher, M. M., & Mason, P. (1991). Neurotransmitters in nociceptive modulatory circuits. Annual Review of Neuroscience, 14, 219-245.

[32]   Goldstein, D. J., Lu, Y., Detke, M. J., Hudson, J., Iyengar, S., & Demitrack, M. A. (2004). Effects of duloxetine on painful physical symptoms associated with depression. Psychosomatics, 45, 17-28.

[33]   Goldstein, D. J., Mallinckrodt, C., Lu, Y., & Demitrack, M. A. (2002). Duloxetine in the treatment of major depressive disorder: A double-blind clinical trial. Journal of Clinical Psychiatry, 63, 225-231.

[34]   Greco, T., Eckert, G., & Kroenke, K. (2004). The outcome of physical symptoms with treatment of depression. Journal of General Internal Medicine, 19, 813-818.

[35]   Guelfi, J. D., Ansseau, M., Corruble, E., Samuelian, J. C., Tonelli, I., Tournoux, A., Plétan, Y. et al. (1998). A double-blind comparison of the efficacy and safety of milnacipran and fluoxetine in depressed inpatients. International Clinical Psychopharmacology, 13, 121-128.

[36]   Hudson, J. I., Wohlreich, M. M., Kajdasz, D. K., Mallinckrodt, C. H., Watkin, J. G., & Martynov, O. V. (2005). Safety and tolerability of duloxetine in the treatment of major depressive disorder: Analysis of pooled data from eight placebo-controlled clinical trials. Human Psychopharmacology, 20, 327-341.

[37]   Ibor, J. J., Carrasco, J. L., Prieto, R., & Garcia-Calvo, C. (2008). Effectiveness and safety of venlafaxine extended release in elderly depressed patients. Archives of Gerontology and Geriatrics, 46, 317-326.

[38]   Iyengar, S., Webster, A. A., Hemrick-Luecke, S. K., Xu, J. Y., & Simmons, R. M. A. (2004). Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. Journal of Pharmacological Experimental Therapeutics, 311, 576-584.

[39]   Kelin, K., Berk, M., Spann, M., Sagman, D., Raskin, J., Walker, D., & Perahia, D. (2010). Duloxetine 60 mg/day for the prevention of depressive recurrences: Post hoc analyses from a recurrence prevention study. International Journal of Clinical Practice, 64, 719-726.

[40]   Kihara, T., & Ikeda, M. (1995). Effects of duloxetine, a new serotonin and norepinephrine uptake inhibitor, on extracellular monoamine levels in rat frontal cortex. Journal of Pharmacology and Experimental Therapeutics, 272, 177-183.

[41]   Knadler, M. P., Lobo, E., Chappell, J., & Bergstrom, R. (2011). Duloxetine: Clinical pharmacokinetics and drug interactions. Clinical Pharmacokinetics, 50, 281-294.

[42]   Koch, S., Hemrick-Luecke, S. K., Thompson, L. K., Evans, D. C., Threlkeld, P. G., Nelson, D. L., Perry, K. W., & Bymaster, F. P. (2003). Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats. Neuropharmacology, 45, 935-944.

[43]   Koch, S., Perry, K. W., Nelson, D. L., Conway, R. G., Threlkeld, P. G., & Bymaster, F. P. (2001). R-Fluoxetine increases extracellular DA, NE, as well as 5-HT in rat prefrontal cortex and hypothalamus: An in Vivo microdialysis and receptor binding study. Neuropsychopharmacology, 27, 949-959.

[44]   Kornstein, S. G. (2008). Maintenance therapy to prevent recurrence of depression: Summary and implications of the PREVENT study. Expert Review of Neurotherapeutics, 8, 737-742.

[45]   Lecrubier, Y., Pletan, Y., Solles, A., Tournoux, A., & Magne, V. (1996). Clinical efficacy of milnacipran: Placebo-controlled trials. International Clinical Psychopharmacology, 11, 29-33.

[46]   Lee, K. U., Lee, Y. M., Nam, J. M., Lee, H. K., Kweon, Y. S., Lee, C. T., & Jun, T. Y. (2010). Antidepressant-Induced sexual dysfunction among newer antidepressants in a naturalistic setting. Psychiatry Investigation, 7, 55-59.

[47]   Lee, M. S., Ahn, Y. M., Chung, S., Walton, R., Raskin, J., & Kim, M. S. (2012). The effect of initial duloxetine dosing strategy on nausea in korean patients with major depressive disorder. Psychiatry Investigation, 9, 391-399.

[48]   Lee, M. S., Ham, B. J., Kee, B. S., Kim, J. B., Yeon, B. K., Oh, K. S., Ohg, B. H., Leeh, C., Jungi, H. Y., Cheej, I.S., Choek, B. M., & Paik, I. H. (2005). Comparison of efficacy and safety of milnacipran and fluoxetine in Korean patients with major depression. Current Medical Research & Opinion, 21, 1369-1375.

[49]   Lenox-Smith, A., D’yachkova, Y., Deberdt, W., & Raskin, J. (2010). Meta-Analyses and antidepressant prescribing. Journal of Psychopharmacology, 24, 629-630.

[50]   Lenox-Smith, A., Kelin, K., Brnabic, A. J., & Bradley, A. (2011). efficacy of Duloxetine vs Venlafaxine—An updated non-inferiority analysis in major depressive disorder. In 11th International Forum on Mood and Anxiety Disorders (IFMAD), Budapest, 9-11 November, 2011. International Journal of Psychiatry in Clinical Practice, 15, 30.

[51]   Leuchter, A. F., Husain, M. M., Cook, I. A., Trivedi, M. H., Wisniewski, S. R., Gilmer, W. S., Luthera, J. F., Favaa, M., & Rush, A. J. (2010). Painful physical symptoms and treatment outcome in major depressive disorder: A STAR*D (Sequenced Treatment Alternatives to Relieve Depression) report. Psychological Medicine, 40, 239-251.

[52]   Lobello, K. W., Preskorn, S. H., Guico-Pabia, C. J., Jiang, Q., Paul, J., Nichols, A. I., Patroneva, A., & Ninan, P. T. (2010). Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: A secondary analysis of 4 studies in major depressive disorder. Journal of Clinical Psychiatry, 71, 1482-1487.

[53]   Lobo, E. D., Bergstrom, R. F., Reddy, S., Quinlan, T., Chappell, J., Hong, Q., Ring, B., & Knadler, M. P. (2008). In Vitro and in Vivo evaluations of cytochrome P450 1A2 interactions with duloxetine. Clinical Pharmacokinetics, 47, 191-202.

[54]   Maletic, V., & Raison, C. L. (2009). Neurobiology of depression, fibromyalgia and neuropathic pain. Frontiers in Bioscience, 14, 5291-5338.

[55]   Mallinckrodt, C. H., Goldstein, D. J., Detke, M. J., Lu, Y., Watkin, J. G., & Tran, P. V. (2003). Duloxetine: A new treatment for the emotional and physical symptoms of depression. Primary Care Companion to the Journal of Clinical Psychiatry, 5, 19-28.

[56]   Mease, P. J., Clauw, D. J., Gendreau, R. M., Rao, S. G., Kranzler, J., Chen, W., & Palmer, R. H. (2009). The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial. Journal of Rheumatology, 36, 398-409.

[57]   Nakagawa, A., Watanabe, N., Omori, I. M., Barbui, C., Cipriani, A., McGuire, H., Churchill, R., & Furukawa, T. A. (2008). Efficacy and tolerability of milnacipran in the treatment of major depression in comparison with other antidepressants: A systematic review and meta-analysis. CNS Drugs, 22, 587-602.

[58]   Nelson, J. C., Mazure, C. M., Jatlow, P. I., Bowers Jr., M. B., & Price, L. H. (2004). Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: A double-blind, randomized study. Biological Psychiatry, 55, 296-300.

[59]   Nemeroff, C. B., Entsuah, R., Benattia, I., Demitrack, M., Sloan, D. M., & Thase, M. E. (2008). Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs. Biological Psychiatry, 63, 424-434.

[60]   Nemeroff, C. B., Schatzberg, A. F., Goldstein, D. J., Detke, M. J., Mallinckrodt, C., Lu, Y., & Tran, P. V. (2002). Duloxetine for the treat0 ment of major depressive disorder. Psychopharmacology Bulletin, 36, 106-132.

[61]   Nemeroff, C. B., & Thase, M. E. (2007). A double-blind, placebo-controlled comparison of venlafaxine and fluoxetine treatment in depressed outpatients. Journal of Psychiatric Research, 41, 351-359.

[62]   Nierenberg, A. A., Greist, J. H., Mallinckrodt, C. H., Prakash, A., Sambunaris, A., Tollefson, G. D., & Wohlreich, M. M. (2007). Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: Onset of antidepressant action, a non-inferiority study. Current Medical Research & Opinion, 23, 401-416.

[63]   Papakostas, G. I., Thase, M. E., Fava, M., Nelson, J. C., & Shelton, R. C. (2007). Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? a meta-analysis of studies of newer agents. Biological Psychiatry, 62, 1217-1227.

[64]   Paroxetine: A selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a con0 trolled multicenter study. Danish University Antidepressant Group. (1990). Journal of Affective Disorders, 18, 289-299.

[65]   Perahia, D. G., Gilaberte, I., Wang, F., Wiltse, C. G., Huckins, S. A., Clemens, J. W., Montgomery, S. A., Montejo, A. L., & Detke, M. J. (2006). Duloxetine in the prevention of relapse of major depressive disorder: Double-blind placebo-controlled study. British Journal of Psychiatry, 188, 346-353.

[66]   Perahia, D. G., Kajdasz, D. K., Desaiah, D., & Haddad, P. M. (2005). Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. Journal of Affective Disorders, 89, 207-212.

[67]   Perahia, D. G., Maina, G., Thase, M. E., Spann, M. E., Wang, F., Walker, D. J., & Detke, M. J. (2009). Duloxetine in the prevention of depressive recurrences: A randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry, 70, 706-716.

[68]   Perahia, D. G., Pritchett, Y. L., Kajdasz, D. K., Bauer, M., Jain, R., Russell, J. M., Walker, D. J., Spencer, K. A., Froud, D. M., Raskin, J., & Thase, M. E. (2008a). A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder. Journal of Psychiatric Research, 42, 22-34.

[69]   Perahia, D. G., Quail, D., Desaiah, D., Corruble, E., & Fava, M. (2008b). Switching to duloxetine from selective serotonin reuptake inhibitor antidepressants: A multicenter trial comparing 2 switching techniques. Journal of Clinical Psychiatry, 69, 95-105.

[70]   Plesnicar, B. K. (2010). Efficacy and tolerability of venlafaxine extended release in patients with major depressive disorder. Psychiatria Danubina, 22, 413-417.

[71]   Puech, A., Montgomery, S. A., Prost, J. F., Solles, A., & Briley, M. (1997). Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: An overview of its antidepressant activity and clinical tolerability. International Clinical Psychopharmacology, 12, 99-108.

[72]   Raskin, J., Wiltse, C. G., Siegal, A., Sheikh, J., Xu, J., Dinkel, J. J., Rotz, B. T., & Mohs, R. C. (2007). Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: An 8-week, double-blind, placebo-controlled trial. American Journal of Psychiatry, 164, 900-909.

[73]   Rouillon, F., Berdeaux, G., Bisserbe, J. C., Warner, B., Mesbah, M., Smadja, C., & Chwalow, J. (2000a). Prevention of recurrent depresssive episodes with milnacipran: Consequences on quality of life. Journal of Affective Disorders, 58, 171-180.

[74]   Rouillon, F., Warner, B., Pezous, N., & Bisserbe, J. C. (2000b). Milnacipran efficacy in the prevention of recurrent depression: A 12-month placebo-controlled study. Milnacipran recurrence prevention study group. International Clinical Psychopharmacology, 15, 133-140.

[75]   Rudolph, R. L., & Derivan, A. T. (1996). The safety and tolerability of venlafaxine hydrochloride: Analysis of the clinical trials database. Journal of Clinical Psychopharmacolology, 16, 54S-59S.

[76]   Rudolph, R. L., Fabre, L. F., Feighner, J. P., Rickels, K., Entsuah, R., & Derivan, A. T. (1998). A randomized, placebo-controlled, dose-response trial of venlafaxine hydrochloride in the treatment of major depression. Journal of Clinical Psychiatry, 59, 116-122.

[77]   Savella (package insert) (2012). New York: Forest Laboratories, Inc.

[78]   Schatzberg, A., & Roose, S. (2006). A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression. American Journal of Geriatric Psychiatry, 14, 361-370.

[79]   Schweitzer, I., Maguire, K., & Ng, C. (2009). Sexual side-effects of contemporary antidepressants: Review. Australian and New Zealand Journal of Psychiatry, 43, 795-808.

[80]   Sechter, D., Vandel, P., Weiller, E., Pezous, N., Cabanac, F., & Tournoux, A. (2004). A comparative study of milnacipran and paroxetine in outpatients with major depression. Journal of Affective Disorders, 83, 233-236.

[81]   Shelton, C., Entsuah, R., Padmanabhan, S. K., & Vinall, P. E. (2005). Venlafaxine XR demonstrates higher rates of sustained remission compared to fluoxetine, paroxetine or placebo. International Clinical Psychopharmacology, 20, 233-238.

[82]   Shelton, R. C., Andorn, A. C., Mallinckrodt, C. H., Wohlreich, M. M., Raskin, J., Watkin, J. G., & Detke, M. J. (2007). Evidence for the efficacy of duloxetine in treating mild, moderate, and severe depression. International Clinical Psychopharmacology, 22, 348-355.

[83]   Smith, D., Dempster, C., Glanville, J., Freemantle, N., & Anderson, I. (2002). Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: A meta-analysis. British Journal of Psychiatry, 180, 396-404.

[84]   Stahl, S. M. (2002). Does depression hurt? Journal of Clinical Psychiatry, 63, 273-274.

[85]   Tatsumi, M., Groshan, K., Blakely, R. D., & Richelson, E. (1997). Pharmacological profile of antidepressants and related compounds at human monoamine transporters. European Journal of Pharmacology, 340, 249-258.

[86]   Thase, M. E., Entsuah, A. R., & Rudolph, R. L. (2001). Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. British Journal of Psychiatry, 178, 234-241.

[87]   Thase, M. E., Pritchett, Y. L., Ossanna, M. J., Swindle, R. W., Xu, J., & Detke, M. J. (2007). Efficacy of duloxetine and selective serotonin reuptake inhibitors: Comparisons as assessed by remission rates in patients with major depressive disorder. Journal of Clinical Psychopharmacology, 27, 672-676.

[88]   Thase, M. E., Tran, P. V., Wiltse, C., Pangallo, B. A., Mallinckrodt, C., & Detke, M. J. (2005). Cardiovascular profile of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine. Journal of Clinical Psychopharmacology, 25, 132-140.

[89]   Trivedi, M. H. (2004). The link between depression and physical symptoms. Primary Care Companion to the Journal of Clinical Psychiatry, 6, 12-16.

[90]   Wohlreich, M. M., Martinez, J. M., Mallinckrodt, C. H., Prakash, A., Watkin, J. G., & Fava, M. (2005). An open-label study of duloxetine for the treatment of major depressive disorder: Comparison of switching versus initiating treatment approaches. Journal of Clinical Psychopharmacology, 25, 552-560.

[91]   Wong, D. T., & Bymaster, F. P. (2002). Dual serotonin and noradrenaline uptake inhibitor class of antidepressants potential for greater efficacy or just hype? Progress in Drug Research, 58, 169-222.

[92]   Zanger, U. M., Raimundo, S., & Eichelbaum, M. (2004). Cytochrome P450 2D6: Overview and update on pharmacology, genetics, biochemistry. Naunyn-Schmiedeberg’s Archives of Pharmacology, 369, 23-37.