7. Vortioxetine

(desire, arousal, and orgasm). SSRI-induced sexual side effects cannot only reduce patients' quality of life but also cause treatment noncompliance and discontinuation, therefore augmenting

coadministered with strong CYP3A4 inducers for more than 14 days

The effects of vilazodone (20 or 40 mg/day) on sexual functioning were also evaluated in healthy, sexually active adults assessed using the Changes in Sexual Functioning Questionnaire (CSFQ a self-report questionnaire with 14 items used in antidepressant trials); vilazodone proved no

In a rat sexual behavior model, acute, sub-chronic, and chronic vilazodone treatment did not cause sexual dysfunction; moreover, 1 week vilazodone administration normalized sexual

Another benefit of this drug is related to its effect on anxiety disorder, and studies are being conducted to assess its efficacy in generalized anxiety disorder, post-traumatic stress syndrome, and social anxiety illness [80]. As Khan et al. reported, 8-week vilazodone therapy has led to improvements in four psychic anxiety items (anxious mood, depressed mood, tension, intellectual) and five somatic anxiety items (somatic muscular, somatic sensory, respiratory,

function in animals which registered paroxetine-induced sexual dysfunction [88].

the risk of MDD relapse and recurrence [88].

Table 6. Pharmacological aspects of vilazodone [19, 78, 83].

Dosage forms 10 mg pink, film-coated, oval tablet

140 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

augment to 20 mg,

Administration Orally, once daily, with food Dosage Initial dosage of 10 mg for 7 days,

Half-life Approximately 25 hours

Metabolism CYP pathways CYP3A4 (primarily), CYP2C19, CYP2D6

Carboxylesterase

Elimination Unchanged drug (1% in the urine and 2% in the feces)

Diarrhea, nausea, vomiting, and insomnia

Vilazodone dose should be ≤ 20 mg once daily

Absolute bioavailability 72% (with food)

Absorption Tmax 4–5 hours Peak plasma concentration 156 ng/ml

Percentage of protein binding 96–99%

Non-CYP pathways

CYP3A4 inhibitors

CYP3A4 inducers

Common adverse reactions

(>5%)

Drug interactions 20 mg orange, film-coated, oval tablet 40 mg blue, film-coated, oval tablet

the dose may be raised up to 40 mg after at least 7 days between dosage increases

Augment vilazodone dosage by twofold, over 1 to 2 weeks (up to 80 mg once daily) when

cardiovascular, and autonomic symptoms) [82].

significant effect on sexual functioning in healthy adults [87].

Vortioxetine, 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide [91], is another new multimodal antidepressant drug that has been approved for MDD therapy in adult patients, in September 2013 in the United States, in December 2013 in European Union, and later in Canada, South Africa, Australia, Mexico, and South Korea [80].

Besides its antidepressant properties proven in several short-and long-term studies [93], vortioxetine demonstrated pro-cognitive effects in preclinical studies, affecting learning and memory processes (enhancing hippocampal synaptic plasticity and augmenting the output of pyramidal cells) [80, 94]. Positive results on cognitive function (memory and executive functioning) were also highlighted in clinical trials [92].

7.2. Benefits versus adverse effects

[93, 97, 101].

the elderly [95, 97].

from placebo [95, 97].

not recommended (Table 9) [91].

MDD therapy [97].

Studies evaluating the drug have shown the following benefits:

drugs (regarding its effects on cognitive function) [100].

symptoms after rapid cessation of the administration [95, 97].

Sanchez et al. reviewed preclinical studies and clinical trials and concluded that vortioxetine is different from SSRI and SNRI antidepressants on the strength of its multimodal mechanism of action, both inhibition of the potent serotonin transporter and direct modulation of 5-HT receptors [95].

New Antidepressant Medication: Benefits Versus Adverse Effects

http://dx.doi.org/10.5772/intechopen.72003

143

• There are no necessary dose adjustments in patients with mild to moderate renal or hepatic impairment or on the basis of patient age, sex, and race. Yet its efficacy and safety have not been sufficiently studied in children or adolescents, and it is not approved for pediatric patients; nevertheless, some recent results in acute therapy are promising [91, 96–98]. • Cognitive dysfunction is often present in MDD, and a pro-cognitive effect of an antidepressant is an important issue. Rosenblat et al. reported in a systematic review and meta-analysis that of the antidepressants evaluated (vortioxetine, duloxetine, paroxetine, citalopram, phenelzine, nortriptyline, and sertraline), vortioxetine appeared to have the largest effect size on psychomotor speed, executive control, and cognitive control [99]. Pehrson et al. reviewed the preclinical data for vortioxetine's effects, at clinically relevant doses, on cognitive function in mechanistic assays and in animal models of depression. The results suggest its neurogenesis and plasticity-promoting effects and that it may have advantages over other antidepressant

• Vortioxetine exhibited improvement in overall functioning for patients with MDD and high anxiety symptoms, which often co-occurs; frequently, these patients are difficult to treat, with a higher risk of side effects and suicidal ideation, and register a slower response

• Due to its relatively long half-life, vortioxetine presents a low risk of discontinuation

• Vortioxetine therapy had a low incidence of worrisome changes in vital signs, electrocardiogram parameters, and advantages when talking about treating symptoms of MDD in

• Unlike most currently antidepressants, drug-associated weight gain and sexual side effects (decreased/loss of libido, delayed ejaculation, erectile dysfunction, anorgasmia, ejaculation disorder, disturbance in sexual arousal, orgasmic sensation decreased/anorgasmia, abnormal orgasm, sexual dysfunction, and ejaculation failure) were not significantly different

Vortioxetine was well tolerated both in short-term and in long-term studies. Mild to moderate nausea was the most commonly registered side effect, and its frequency was dose related [95, 102]. Due to the lack of well-controlled studies, its administration in pregnancy and lactation is

With more than 50 antidepressant drugs available worldwide (most of them approved for more than 10 years), vortioxetine is the newest agent and needs to determine its place in

### 7.1. Pharmacological properties

Vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and an inhibitor of the serotonin transporter. It enhances 5- HT (more than a SSRI), NE, DA, acetylcholine, and HA levels in rat brain regions associated with MDD (like the PFC and the ventral hippocampus). Furthermore, it increases glutamatergic neurotransmission, probably through inhibiting GABA interneurons [80, 92, 94].

Its discovery program origins in the hypothesis were derived from researches of combined serotonin transporter inhibition and 5-HT1A receptor modulation; subsequently, the profile was modified toward a combination of serotonin transporter inhibition, 5-HT1A receptor agonistic activity, and 5-HT3 receptor antagonism [95].

The drug is available as immediate-release tablets for oral administration which contain the beta-polymorph of vortioxetine hydrobromide (Table 8).


Table 8. Pharmacological aspects of vortioxetine [91, 96, 97].
