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.