5.2. Side effects of levomilnacipran

5. Levomilnacipran

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

Australia.

Levomilnacipran, a (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide derivative, is the levo-enantiomer (1S, 2R-milnacipran) of racemate milnacipran, approved in 2009 for the treatment of fibromyalgia [53, 54]. It was discovered by Pierre Fabre Laboratories, France, and coproduced by Forest Laboratories, Inc. (Fetzima™), being approved by the FDA to be used for the treatment of MDD in adult patients in the United States and Japan in July 2013 and in Canada in May 2015 [55, 56]. It is not available on the market in the European Union and

The researches performed in laboratory animals showed that levomilnacipran is the pharmacologically more active enantiomer of the racemic mixture milnacipran, having 50, respectively, and 13 times more intense inhibitory activity on the norepinephrine and serotonin reuptake pumps, a higher peak blood concentration and a prolonged elimination half-life

Currently, it is under clinical research as a therapy of anxiety, bipolar disorders, post-traumatic stress diseases, vasomotor symptoms associated with menopause, peripheral neuropathy (especially associated with diabetes mellitus), and chronic musculoskeletal pain. Levomilnacipran has also been investigated for the treatment of fibromyalgia and phantom limb syndrome but was

In vitro studies revealed that levomilnacipran determines the strong and selective inhibition of serotonin and norepinephrine reuptake transporters (two times more potent and selective for norepinephrine than for serotonin), with a consequent increasing of these mediator concentration in the central nervous system [60]. It proved to have a more balanced reuptake of both serotonin and norepinephrine compared to other known SNRIs [56, 61]. Due to this difference in the selectivity action on these neurotransmitters, it was postulated that levomilnacipran may be beneficial in MDD related to the norepinephrine deficiency, with the demonstrated improvement of core symptoms and, consequently, the patient social and occupational activities [62–64]. It may also be useful in refractory depression or in the cases susceptible to potential increase of weight gain during chronic therapy with other antidepressant drugs [61]. Levomilnacipran provides a "two and a half" action, the inhibition of the norepinephrine transporter facilitating the action of dopamine, as long as this mediator diffuses through the synapses, without requiring the presence of a transporter. No important activity on dopamine, serotonin (5-HT1–5-HT7), muscarine, histamine, and alpha- or beta-adrenergic and opioid receptors and no inhibitory effects on the monoamino oxidase were evidenced. The lack of affinity on the sodium, potassium, chloride, or calcium ion channels was also observed [56].

Recent researches highlighted the inhibitory action of levomilnacipran on the beta-site amyloid precursor protein cleaving enzyme-1, known to be responsible for the formation of β-amyloid plaque, thus arguing its possible use in the treatment of Alzheimer's

compared with the other enantiomer 1S,2R-milnacipran (coded F2696) [56–59].

not approved to be used for these purposes [56].

5.1. Pharmacological properties

disease [64].

Short-term safety clinical trials revealed that most patients with MDD have well responded and tolerated and did not experience important side effects to levomilnacipran [62, 65]. The most common side effects of levomilnacipran were nausea, vomiting, hyperhidrosis, heart rate increase, tachycardia, palpitations, urinary hesitation, erectile dysfunction, and ejaculate disorders in men (Table 5) [56].

Long-term clinical studies documented that levomilnacipran manifested acceptable tolerability compared to placebo. Severe adverse reactions, such as nausea, vomiting, headache, tachycardia, hypertension, extrasystoles, and convulsion, observed in long-term trials of 48 weeks in patients treated with levomilnacipran, generally lead to discontinuation of the treatment. The other side effects of the levomilnacipran were related to the drug-drug interactions (inhibitors of CYP3A4 such as clarithromycin, ketoconazole, or itraconazole will increase its blood level) or to a concomitant hepatic, renal, and cardiac pathology. On the contrary, the association of levomilnacipran with the inducers of CYP3A4, such as rifampicin or carbamazepine, may determine a diminution of its plasma concentration [66, 67].


Table 4. Pharmacological aspects of levomilnacipran [55, 56].


pharmacokinetic profile (with less complex correlation between blood concentration and the

New Antidepressant Medication: Benefits Versus Adverse Effects

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The most important levomilnacipran's advantage is its once-daily administration of a sustainedrelease capsule compared with the twice-daily administration tablets of milnacipran, thus

Vilazodone, 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1) [78], is a new multimodal antidepressant drug indicated in the United States for the treatment of MDD in adult patients [79]. Its discovery program began in the mid-1990s, and FDA approved it in January 2011. It also received market authorization in Mexico and Canada for MDD pharmacotherapy. Moreover, it was found that vilazodone

Vilazodone is an indolalkylamine with a dual mechanism of action which consists of 5-HT1A receptor partial agonist and SSRI activity. It does not bind to the norepinephrine or dopamine

The most prevalent out of the 14 different structurally distinct types of 5-HT receptors in the brain is 5-HT1A, which is localized especially in the raphe nuclei (presynaptic), the hippocampus, the frontal cortex, the dorsal horn of the spinal cord, the lateral septum, and the amygdala (postsynaptic). Presynaptic 5-HT1A receptors exhibit a key role in the pathophysiology and treatment of depression and anxiety disorders. According to Sahli et al., vilazodone is 60 times more selective for the 5-HT1A receptor than buspirone (the only 5-HT1A receptor partial agonist approved as an antidepressant) and has a SSRI activity 30 times more potent than

The drug is available as tablets for oral administration which contain vilazodone hydrochlo-

Due to its unique mechanism of action, vilazodone has the potential benefits of faster onset of action, greater efficacy, and lower adverse event risks compared with currently used antidepressants, especially lower sexual side effects [84, 85]. Preclinical studies and clinical trials showed that vilazodone exhibits a diminished incidence of sexual adverse effects and minimal weight gain, similar for vilazodone and placebo, important aspects given that patients find sexual dysfunction, weight gain, and drowsiness to be the most frequently unpleasant adverse

Sexual dysfunction was reported in 40–70% of SSRI-treated patients [87], and SSRIs therapy can determine sexual dysfunction in all three phases of the human sexual response cycle

improves psychic and somatic symptoms in generalized anxiety disorder [80–82].

pharmacodynamic effect), and a reduced potential for drug interactions [76, 77].

improving the patient's compliance especially to chronic therapy.

6. Vilazodone

ride (Table 6).

6.1. Pharmacological properties

6.2. Benefits versus adverse effects

effects induced by antidepressants [86].

reuptake sites with the same high affinity [81, 83].

fluoxetine (the first SSRI approved by FDA for MDD therapy) [83].

Table 5. The most frequent adverse effects of levomilnacipran [68–71].

Various preclinical researches showed the most intense antidepressant effect of levomilnacipran without substantially influencing the animal spontaneous locomotor activity, compared to other antidepressant drugs (venlafaxine, duloxetine) in different experimental animal models of depression, anxiety, and stress (such as forced swim test, tail suspension test, shock-induced ultrasonic vocalization) [70].

Short-term clinical trials highlighted the superior efficacy of levomilnacipran on depressive and disability symptoms (especially motivation and energy), and functional improvement of the patient status, compared to placebo, was quantified using the Montgomery-Asberg Depression Rating Scale, respectively, and the Sheehan Disability Scale. Significant superiority to placebo was also demonstrated by improvement of the patient's social activity, work, and family life [71–74]. On the other hand, there were insufficient and irrelevant data, regarding the efficacy for the relapse prevention in the long-term use of levomilnacipran [75].

### 5.3. Differences between levomilnacipran and milnacipran

Literature data indicated some pharmacological differences between these two antidepressant drugs, but the performed clinical studies did not prove considerable advantages of levomilnacipran over milnacipran use in the treatment of MDD.

There are few clinically relevant differences between levomilnacipran and milnacipran consisting of the simplicity of dose regimen, a more selective pharmacodynamic activity, an improved pharmacokinetic profile (with less complex correlation between blood concentration and the pharmacodynamic effect), and a reduced potential for drug interactions [76, 77].

The most important levomilnacipran's advantage is its once-daily administration of a sustainedrelease capsule compared with the twice-daily administration tablets of milnacipran, thus improving the patient's compliance especially to chronic therapy.
