Abstract
This chapter addresses the following FDA-approved medications for the treatment of major depressive disorder available for use in the United States including bupropion, mirtazapine, trazodone, vortioxetine, and vilazodone. These medications do not belong to one of the previously featured classes of antidepressants discussed in the preceding chapters. Each medication featured in this chapter has a unique structure and properties that target diverse receptors in the central nervous system. These diverse targets are distinct from other classes of medications used to treat major depressive disorder. This chapter will provide an overview of each medication’s indication for use, history of development, pharmacology, metabolism, dosing recommendations, onset of action, use in special populations, safety and tolerability, adverse effects, potential interactions with additional medications, and data regarding possible overdose with available treatments.
Bupropion was initially developed for its combined effects on the norepinephrine and dopamine neurotransmitters. Currently, bupropion is the only antidepressant on the market in the United States with no appreciable activity on serotonin concentrations in the central nervous system. Bupropion is extensively metabolized in humans into three active metabolites including hydroxybupropion, threohydrobupropion, and erythrohydrobuproprion each with substantial antidepressant activity. The most serious side effect of bupropion is the development of seizures, so the dose must be gradually titrated to a maximum dose of 450 mg per day of the immediate-release formulation and 400 mg per day of the sustained-release formulation. Additional adverse effects include agitation, dry mouth, insomnia, headaches, migraines, nausea, vomiting, constipation, and tremor. The onset of action of bupropion is 2 weeks with full efficacy attained at 4 weeks of treatment. Bupropion produced similar depression remission rates when compared to SSRIs with a median time to relapse of 44 weeks. Bupropion has additionally been approved for smoking cessation and may have a combined role in treating nicotine cravings and depression.
Mirtazapine has a unique method of action by enhancing norepinephrine and serotonin neurotransmission by blocking the alpha-2 presynaptic adrenoceptors resulting in increased release of serotonin at the nerve terminals. Mirtazapine additionally binds to the 5-HT2, 5-HT3, and H1 receptors resulting in increased sedation, which is the most common side effect. Additional side effects include increased appetite and weight gain, dizziness, and transient elevations in cholesterol levels and liver function tests. Mirtazapine is unlike any other antidepressant in that it also has a hormonal effect that reduces cortisol levels within the body. Patients on mirtazapine showed significant improvement in symptoms of major depressive disorder within the first 1–2 weeks of treatment with long-term studies at 40 weeks showing continued improvements in response rates in addition to lower relapse rates. Mirtazapine has an antagonistic effect at the central presynaptic 5-HT2 receptors and alpha-2 adrenergic inhibitory autoreceptors and heteroreceptors resulting in increased norepinephrine release with an indirect release of serotonin due to increased noradrenergic input to the raphe nucleus. Mirtazapine has an effective dose range from 15 to 45 mg once daily with a long half-life preventing dose adjustments more often than every 1–2 weeks.
Trazadone is a 5-HT2A and 5-HT2C receptor antagonist and selective serotonin reuptake inhibitor. While trazodone has only been FDA approved for use in the treatment of major depressive disorder, it has been used off label for numerous conditions including insomnia, anxiety, dementia, Alzheimer’s disease, substance abuse, schizophrenia, bulimia, and fibromyalgia. The most common adverse reaction is drowsiness, followed by dizziness, dry mouth, and nervousness. In the United States, trazadone is the second most commonly prescribed agent used to treat insomnia. The hypnotic action of this medication at lower doses is attributed primarily to the antagonism of the 5-HT2A receptors, H1 receptors, and alpha-1 adrenergic receptors. The most active metabolite is m-chlorophenylpiperazine produced by the CYP3A4 enzyme, which is a more profound inhibitor of serotonin reuptake as compared to the parent molecule of trazadone. The maximum outpatient dose should not exceed 400 mg per day in divided doses, but in hospitalized patients, the dose may be increased to a maximum dose of 600 mg daily in divided doses while the patient is being actively monitored for side effects. One third of inpatients and one half of outpatients had a significant therapeutic response to trazadone by the end of the first week with the remainder of patients responding in 2–4 weeks of therapy.
Vortioxetine is a novel antidepressant classified by the World Health Organization as a N06AX antidepressant that was derived from studies targeting the combination of direct serotonin transporter inhibition and 5-HT1A receptor modulation leading to rapid desensitization of the somatodendritic 5-HT1A autoreceptors and activation of the postsynaptic 5-HT1A receptors. This medication is an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, an agonist at 5-HT1A receptors, and a partial agonist at 5-HT1B receptors. Blockade of the 5-HT3 receptor was noted to produce increased levels of serotonin, dopamine, norepinephrine, acetylcholine, and histamine in the prefrontal cortex and hippocampus, which are known to be associated with the development of depression. The most common adverse effect is nausea followed by sexual dysfunction, constipation, and vomiting. The maximum dose of vortioxetine is 20 mg daily with improvement in symptoms of depression noted at 2 weeks with a full therapeutic effect observed at 4–6 weeks.
Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. This medication works by enhancing serotonergic activity in the central nervous system through selective inhibition of serotonin reuptake with no significant effects noted on norepinephrine or dopamine uptake. Vilazodone additionally binds with high affinity to the 5-HT1A receptors as a partial agonist resulting in faster onset of action, greater efficacy, and better tolerability with reduced sexual side effects when compared to other SSRIs. The most common adverse effects were diarrhea, nausea, vomiting, and insomnia. Additional reported adverse effects included dizziness, dry mouth, fatigue, abnormal dreams, decreased libido, arthralgias, and palpitations which were self-limited with resolution in 4–5 days after starting the medication. The recommended therapeutic dose of vilazodone is 40 mg daily with improvement noted in depressive symptoms within 1 week of initiating therapy with increased remission rates noted at 6 weeks of therapy.
The medications featured in this chapter do not fall within the major categories of antidepressant classes but add additional unique mechanisms for the treatment of major depressive disorder. Each medication targets different receptors in the central nervous system involved in the development of depression. Resolution of depressive symptoms and response rates of these medications are similar to SSRIs with reduced side effects that can often lead to discontinuation of therapy. Use of these unique medications allows clinicians to target specific symptoms and comorbidities often associated with depression resulting in improved symptom resolution and long-term maintenance of remission.
Portions of this chapter are adapted with permission from Preskorn et al. (2004).
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References
Alam A, Voronovich Z, Carley JA (2013) A review of therapeutic uses of mirtazapine in psychiatric and medical conditions. Prim Care Companion CNS Disord 15(5). pii: PCC.13r01525. doi: https://doi.org/10.4088/PCC.13r01525
Brogden RN, Heel RC, Speight TM et al (1981) Drugs 21:401 https://doi.org/10.2165/00003495-198121060-00001
Cooper BR, Hester TJ, Maxwell RA (1980) Behavioral and biochemical effects of the antidepressant bupropion (Wellbutrin): evidence for selective blockade of dopamine uptake in vivo. J Pharmacol Exp Ther 215:127–134
Cruz M (2012) Vilazodone HCL: a serotonin partial agonist and reuptake inhibitor for the treatment of major depressive disorder. P T 37(1):28–31
D’Agostino A, English C, Rey J (2015) Vortioxetine (Brintellix): a new serotonergic antidepressant. P T 40(1):36–40
De Boer T, Ruigt GSF (1995) The selective alpha2-adrenoceptor antagonist mirtazapine (Org 3770) enhances noradrenergic and 5HT1A mediated serotonergic neurotransmission. CNS Drugs 4(S1):29–38
Fagiolini A, Comandini A, Dell’Osso MC, Kasper S (2012) Rediscovering trazodone for the treatment of major depressive disorder. CNS Drugs 26(12):1033–1049. https://doi.org/10.1007/s40263-012-0010-5
Fava M, Rush AJ, Thase ME et al (2005) 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry 7(3):106–113.v
Feighner JP, Boyer WF (1988) Overview of USA controlled trials of trazodone in clinical depression. Psychopharmacology (Berl) 95 Suppl:S50–S53
Georgotas A, Forsell T, Mann J, Kim M, Gershon S (1982) Trazodone hydrochloride: a wide spectrum antidepressant with a unique pharmacological profile. A review of tis neurochemical effects, pharmacology, clinical efficacy, and toxicology. Pharmacotherapy 2(5):255–263
GlaxoSmithKline (2009) FDA prescribing information for bupropion hydrochloride. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018644s039s040.pdf
GlaxoSmithKline (2017) Medication guide for bupropion. FDA approved. https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Wellbutrin_Tablets/pdf/WELLBUTRIN-TABLETS-PI-MG.PDF
Haddjeri N, Blier P, de Montigny C (1995) Noradrenergic modulation of central serotonergic neurotransmission: acute and long-term actions of mirtazapine. Int Clin Psychopharmacol 10(Suppl 4):11–17
Hellerstein DJ, Flaxer J (2015) Vilazodone for the treatment of major depressive disorder: an evidence based review of its place in therapy. Core Evid 10:49–62
Laakmann G, Schüle C, Baghai T, Waldvogel E, Bidlingmaier M, Strasburger C (2000) Mirtazapine: an inhibitor of cortisol secretion that does not influence growth hormone and prolactin secretion. J Clin Psychopharmacol 20(1):101–103
Lavergne F, Berlin I, Gamma A, Stassen H, Angst J (2005) Onset of improvement and response to mirtazapine in depression: a multicenter naturalistic study of 4771 patients. Neuropsychiatr Dis Treat 1(1):59–68
Mead Johnson (2017) Trazadone hydrochloride package insert. http://www.mentalmeds.org/prescription_meds/Desyrel.pdf
Merck (2012) Mirtazapine tablet insert 76621. FDA approved. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020415s019,021208s010lbl.pdf
Merck (2017) Medication guide for mirtazapine. FDA approved. http://www.merck.com/product/usa/pi_circulars/r/remeron/remeron_tablets_pi.pdf
Pierz KA, Thase ME (2014) A review of vilazodone, serotonin, and major depressive disorder. Prim Care Companion CND Discord 16(1). pii: PCC.13r01554
Pragma Pharmaceuticals (2017) Prescribing information for trazodone hydrochloride. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf
Preskorn S, Ross R (2004) Antidepressants: past, present and future. Other antidepressants, vol 157. Springer, Berlin, pp 263–324
Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR (2009) Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double blind, placebo controlled trial. J Clin Psychiatry 70(3):326–333
Sahli Z, Banerjee P, Tarazi F (2016) The preclinical and clinical effects of vilazodone for the treatment of major depressive disorder. Expert Opin Drug Discov 11(5):515–523
Sanchez C, Asin K, Artigas F (2015) Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther 145:43–57
Schüle C, Baghai T, Goy J, Bidlingmaier M, Strasburger C, Laakmann G (2002) The influence of mirtazapine on anterior pituitary hormone secretion in healthy male subjects. Psychopharmacology (Berl) 163(1):95–101
Stahl SM (2009) Mechanism of action of trazodone: a multifunctional drug. CNS Spectr 14(10):536–546
Takeda Pharmaceuticals (2018) Vortioxetine package insert. https://general.takedapharm.com/TRINTELLIXPI
Thase ME, Haight BR, Richard N et al (2005) Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry 66(8):974–981
Trovis (2011) Vilazodone hydrochloride prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022567s000lbl.pdf
Wang S, Han C, Lee S, Patkar A, Masand P, Pae C (2016) Vilazodone for the treatment of depression: an update. Chonnam Med J 52:91–100
Weihs KL, Houser TL, Batey SR, Ascher JA, Bolden-Watson C, Donahue RM, Metz A (2002) Continuation phase treatment with bupropion SR effectively decreases the risk for relapse of depression. Biol Psychiatry 51(9):753–761
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Schwasinger-Schmidt, T.E., Macaluso, M. (2018). Other Antidepressants. In: Macaluso, M., Preskorn, S. (eds) Antidepressants. Handbook of Experimental Pharmacology, vol 250. Springer, Cham. https://doi.org/10.1007/164_2018_167
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DOI: https://doi.org/10.1007/164_2018_167
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