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Antidepressants

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Attention for Chapter 167: Other Antidepressants
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Chapter title
Other Antidepressants
Chapter number 167
Book title
Antidepressants
Published in
Handbook of experimental pharmacology, September 2018
DOI 10.1007/164_2018_167
Pubmed ID
Book ISBNs
978-3-03-010948-6, 978-3-03-010949-3
Authors

T. E. Schwasinger-Schmidt, M. Macaluso, Schwasinger-Schmidt, T. E., Macaluso, M.

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.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 177 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 177 100%

Demographic breakdown

Readers by professional status Count As %
Student > Master 29 16%
Student > Bachelor 24 14%
Researcher 19 11%
Student > Ph. D. Student 16 9%
Student > Postgraduate 10 6%
Other 28 16%
Unknown 51 29%
Readers by discipline Count As %
Medicine and Dentistry 39 22%
Psychology 22 12%
Pharmacology, Toxicology and Pharmaceutical Science 19 11%
Nursing and Health Professions 9 5%
Neuroscience 8 5%
Other 23 13%
Unknown 57 32%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 5. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 18 October 2022.
All research outputs
#6,111,084
of 23,548,905 outputs
Outputs from Handbook of experimental pharmacology
#180
of 653 outputs
Outputs of similar age
#105,673
of 337,451 outputs
Outputs of similar age from Handbook of experimental pharmacology
#5
of 9 outputs
Altmetric has tracked 23,548,905 research outputs across all sources so far. This one has received more attention than most of these and is in the 73rd percentile.
So far Altmetric has tracked 653 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.0. This one has gotten more attention than average, scoring higher than 72% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 337,451 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 68% of its contemporaries.
We're also able to compare this research output to 9 others from the same source and published within six weeks on either side of this one. This one has scored higher than 4 of them.