4. Desvenlafaxine

The O-desmethylvenlafaxine or desvenlafaxine, a RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol derivative, is the synthetic agent of the main active metabolite of venlafaxine. First of all, it was obtained as desvenlafaxine succinate (Pristiq®) and marketed by the company Wyeth Pharmaceuticals, which was subsequently acquired from the American corporation Pfizer [32]. This principal metabolite is 70% produced following the biodegradation of venlafaxine, the two drugs having similar demonstrated pharmacodynamic effects [33].

The development of desvenlafaxine was performed in hoping to improve the pharmacokinetic and clinical profile of the parent substance. It was approved as antidepressant drug by the FDA in February 2008, being available for medical use, in the treatment of MDD in adult patients, in May 2008 [34].

This agent was also experienced for the nonhormonal therapy of menopausal disorders associated by mild-to-serious vasomotor symptoms and in some types of anxiety [35, 36]. At the beginning of 2008, a product containing desvenlafaxine (Ellefore) was withdrawn from the market in the European Union, due to its insufficient documentation and clinical experience; but later in 2012, Pfizer corporation obtained the authorization for the use of Pristiq® in Spain. It also received the market authorization in Canada for the pharmacotherapy of depression in February 2009. A few years later, FDA approved the use of both brand and generic products containing desvenlafaxine fumarate (Desvenlafaxine fumarate, 2013) [37].

### 4.1. Pharmacological properties

During the treatment, the upregulation of the synapses can initially trigger a pseudoserotoninergic syndrome, with psychomotor agitation, akathisia, insomnia, tremor, muscle fasciculation, fever, and vomiting. This syndrome is sensitive to benzodiazepine therapy, and

Pure serotonin syndrome is particularly common for tricyclic antidepressants, more rarely for SSRIs, and most commonly occurs in drug combinations with metabolic inhibitors or with agents that may increase the serotonin level. Serotonin syndrome is manifested by agitation, confusion, excessive sweating, mydriasis, muscle spasms or muscle incoordination, fever, sei-

The therapy with SSRIs is long-lasting, with the shortest treatment indicated being 3–6 months. As expected, a degree of dependence occurs; therefore, avoiding sudden discontinuation of treatment with SSRIs is essential. Otherwise insomnia, agitation, confusion, trembling, anxiety,

• Mixed serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine, desvenlafaxine,

• Dopamine and norepinephrine reuptake inhibitors (bupropion—reserved especially for

Among the antidepressant groups, SSRIs and SNRIs are preferred because not only of their therapeutic efficacy but also of the relatively small number and decreased severity of adverse

The O-desmethylvenlafaxine or desvenlafaxine, a RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol derivative, is the synthetic agent of the main active metabolite of venlafaxine. First of all, it was obtained as desvenlafaxine succinate (Pristiq®) and marketed by the company Wyeth Pharmaceuticals, which was subsequently acquired from the American corporation Pfizer [32]. This principal metabolite is 70% produced following the biodegradation of venlafaxine, the two drugs having similar demonstrated pharmacodynamic effects [33]. The development of desvenlafaxine was performed in hoping to improve the pharmacokinetic and clinical profile of the parent substance. It was approved as antidepressant drug by the FDA in February 2008, being available for medical use, in the treatment of MDD in adult

This agent was also experienced for the nonhormonal therapy of menopausal disorders associated by mild-to-serious vasomotor symptoms and in some types of anxiety [35, 36]. At the

• Serotonin antagonist and reuptake inhibitors (nefazodone, trazodone) [16, 23]

usually the spontaneous resolution appears within a few days [16, 23].

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

and even hallucinatory phenomena may occur during treatment [30]:

• Serotonin disinhibitor and alpha-2 antagonists (mirtazapine)

duloxetine, milnacipran, levomilnacipran)

asthenic and dopamine deficiency cases) • Norepinephrine reuptake inhibitor (reboxetine)

zures, and coma.

effects [28, 30, 31].

4. Desvenlafaxine

patients, in May 2008 [34].

In vitro studies revealed that desvenlafaxine determines the inhibition of serotonin and norepinephrine reuptake (10 times more potent for serotonin than for norepinephrine), thus blocking the removal of the main mediators (serotonin, norepinephrine) that affect mood, increasing their concentration at the synaptic level [32, 38]. No notable influence on muscarine, histamine, or alpha-1 adrenergic receptors and on the activity of monoamino oxidase was proven. Moreover, the lack of the influence on the functionality on sodium, potassium, chloride, or calcium ion channels was also evidenced [34, 39].


Table 2. Pharmacological aspects of desvenlafaxine [32, 34, 38–41].

The drug is available as extended-release tablets for oral administration, which contain desvenlafaxine succinate (Table 2).

Preclinical and clinical investigations argue that venlafaxine and desvenlafaxine are basically equivalent, from the pharmacological point of view, even if there were observed dissimilarities, regarding especially the pharmacokinetic profile, dose regimen, and the

New Antidepressant Medication: Benefits Versus Adverse Effects

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The most important differences between venlafaxine and desvenlafaxine are the following:

• Both antidepressant drugs present the similar mechanism of action, consisting of inhibition of serotonin and norepinephrine reuptake, but the desvenlafaxine's binding affinity at norepinephrine reuptake pumps is higher than venlafaxine's; yet this effect did not prove

• The clinical trials communicated similar tolerability and comparable incidence of adverse effects in patients treated for depression [48, 49]. Different clinical trials, performed during 8 weeks, revealed the superior efficacy of 100 and 400 mg, but not of 200 mg of desvenlafaxine (Pristiq®, Wyeth), on the improvement of depression symptomatology, clinically evidenced and assessed using Hamilton Depression Scale, and also the effectiveness of 400 mg on the remission rates, compared to placebo

• The parent substance, venlafaxine, undergoes primarily biodegradation by the CYP 2D6-mediated oxidative reactions, to be converted into O-desmethylvenlafaxine, while desvenlafaxine is mainly inactivated by glucuronidation and secondarily metabolized by oxidation (through N-demethylation) to N,O-didesmethylvenlafaxine, its biodegradation being not influenced by the enzymatic system of cytochromes P450 (CYP 2D6) [40, 41]. Taking into account these issues, it was suggested that desvenlafaxine may be an advantageous option in patients with genetic polymorphisms of CYP2D6 (such as

• As a result of the fact that desvenlafaxine has no markedly effect on CYP2D6, at therapeutic doses, it has lower risk of drug interactions, compared to venlafaxine, being preferred to prevent possible drug-drug interactions with CYP2D6 substrates (e.g., SSRIs, tricyclic antidepressants, several beta-blockers, quinidine, opioids). However, there are inconsistent evidences that desvenlafaxine would be more effective, better tolerated, or

• On the other hand, the treatment with desvenlafaxine may have a benefit, in terms of simpler dosage regimen compared with venlafaxine (small initial dose and lower minimum therapeutic dose), with more anticipated drug levels [45]. The FDA recommendations mention the indication of using the same 50 mg starting, and maintenance doses, for the treatment with desvenlafaxine, while the administration of extended-release form of venlafaxine needs titration from the starting dose of 37.5 mg per day to the maintenance dose of 150–225 mg per day [51]. The practical aspect is related to the fact that desvenlafaxine dosage choosing is based on the experience gained from several 8 week acute-phase clinical studies, but the real therapeutic response is not generally

drug interactions.

a therapeutic relevance [47].

[36, 45, 50–52].

poor metabolizers) [34].

safer than venlafaxine in clinical use [40, 41, 44, 50].

obtained in this short interval of time [34].

### 4.2. Side effects of desvenlafaxine

Current safety and efficacy information for the treatment of MDD highlights that most patients have well responded and tolerated and did not experience severe side effects to desvenlafaxine [42].

The most often described side effects of desvenlafaxine were nausea, vomiting, dry mouth, constipation, fatigue, headache, dizziness, insomnia, decreased appetite, hyperhidrosis, erectile dysfunction, and delayed ejaculation in men (Table 3) [34, 42].

Of these, the frequent adverse reactions, such as nausea, vomiting, dizziness, and headache, observed in short-term trials of up to 8 weeks in patients treated with desvenlafaxine (Pristiq®, Wyeth), usually lead to discontinuation of the treatment. The other side effects of the desvenlafaxine were related to the drug-drug interactions or to the presence of liver or kidney dysfunctions [38, 43].

### 4.3. Differences between desvenlafaxine and venlafaxine

Literature data highlighted some pharmacological differences between these two antidepressant drugs, but the therapeutic experience did not reveal substantial advantages of desvenlafaxine over venlafaxine use in the treatment of MDD.


Table 3. The most frequent adverse effects of desvenlafaxine [34, 38, 42, 44–46].

Preclinical and clinical investigations argue that venlafaxine and desvenlafaxine are basically equivalent, from the pharmacological point of view, even if there were observed dissimilarities, regarding especially the pharmacokinetic profile, dose regimen, and the drug interactions.

The drug is available as extended-release tablets for oral administration, which contain

Current safety and efficacy information for the treatment of MDD highlights that most patients have well responded and tolerated and did not experience severe side effects to desvenlafaxine [42]. The most often described side effects of desvenlafaxine were nausea, vomiting, dry mouth, constipation, fatigue, headache, dizziness, insomnia, decreased appetite, hyperhidrosis, erec-

Of these, the frequent adverse reactions, such as nausea, vomiting, dizziness, and headache, observed in short-term trials of up to 8 weeks in patients treated with desvenlafaxine (Pristiq®, Wyeth), usually lead to discontinuation of the treatment. The other side effects of the desvenlafaxine were related to the drug-drug interactions or to the presence of liver or kidney

Literature data highlighted some pharmacological differences between these two antidepressant drugs, but the therapeutic experience did not reveal substantial advantages of desvenlafaxine

Cardiovascular Palpitations, hypertension, tachycardia, hot flushes, orthostatic hypotension, peripheral coldness

tremor, paresthesia, dysgeusia, disturbance in attention, tinnitus, vertigo, depersonalization, hypomania, syncope, withdrawal syndrome,

seizures, convulsions, extrapyramidal symptoms, serotonin syndrome

decreased libido, anorgasmia, anorgasmia, abnormal orgasm, erectile dysfunction, delayed

Decreased weight, increased blood cholesterol, decreased appetite, increased blood triglycerides,

Gastrointestinal Nausea, vomiting, dry mouth, constipation, diarrhea, increase in transaminase levels

ejaculation, ejaculation disorders in men, ejaculation failure

tile dysfunction, and delayed ejaculation in men (Table 3) [34, 42].

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

4.3. Differences between desvenlafaxine and venlafaxine

over venlafaxine use in the treatment of MDD.

Nervous system Dizziness, headache, insomnia, somnolence,

Genitourinary Urinary hesitation, proteinuria,

anxiety, abnormal dreams, nervousness,

Respiratory Yawning, epistaxis, interstitial lung disease, eosinophilic pneumonia

increased blood prolactin, hyponatremia

Table 3. The most frequent adverse effects of desvenlafaxine [34, 38, 42, 44–46].

Others Hypersensitivity reactions, fatigue, feeling jittery, blurred visions, mydriasis

System and organ Manifestations

Hematologic Abnormal bleeding

Skin Hyperhidrosis, rash Musculoskeletal Musculoskeletal stiffness

Metabolic and endocrine

desvenlafaxine succinate (Table 2).

4.2. Side effects of desvenlafaxine

dysfunctions [38, 43].

The most important differences between venlafaxine and desvenlafaxine are the following:

