Venlafaxine (Effexor) and Desvenlafaxine (Pristiq) – Mechanism of Action | Differences | Psychopharmacology | Clinical Application

MECHANISMS OF ACTION OF VENLAFAXINE AND DESVENLAFAXINE

Venlafaxine and its major active metabolite, desvenlafaxine, have been demonstrated to block the neuronal reuptake of noradrenaline, serotonin, and to a lesser extent, dopamine by blocking serotonin and noradrenaline transporters (SERT & NAT). [Montgomery 2008]

Venlafaxine, however, has a 30-fold higher affinity for the reuptake of serotonin over noradrenaline, whilst desvenlafaxine has a 10-fold affinity. [Liebowitz and Tourian 2010]

• Venlafaxine sequentially inhibits serotonin and norepinephrine reuptake, such that serotonin reuptake is initially inhibited, followed by norepinephrine reuptake inhibition.
• Venlafaxine thus, at its minimal effective dose in depression (75 mg/d), venlafaxine acts as a selective 5-HT reuptake inhibitor. In contrast, when administered at higher doses (225 and 375 mg/d), it acts as a dual 5-HT and NE reuptake inhibitor exhibiting dose-dependent pharmacology in relation to efficacy and tolerability. [Debonnel et al., 2007]
• Another study indicated that venlafaxine, even at a dose that is four times higher than its minimal effective dose in depression (i.e. 75 mg/d), did not appear to inhibit the NE reuptake process in the present study in healthy volunteers. [Blier et al., 2007]
• The specific dose at which venlafaxine begins to engage NAT was found to be 225 mg OD. [Aldosary et al., 2022]
• These results can explain why responders to low doses but not high doses of venlafaxine experienced a transient recurrence of depressive symptoms when exposed experimentally to tryptophan depletion. Patients requiring higher doses of venlafaxine had an antidepressant response, which may be partly or wholly independent of 5-HT. [Harvey et al., 2000]
• The sequential inhibition of serotonin and NA is reflected in its side effect profile—that initial side effects are predominantly related to serotonin (e.g., headaches, nausea, fatigue, sexual dysfunction). In contrast, subsequent side effects with higher dosing are related to serotonin and norepinephrine (e.g., activation effects, dry mouth, night sweats).
• Desvenlafaxine, on the other hand, blocks the serotonin and norepinephrine reuptake at starting doses. [Lieberman & Massey, 2010] 
• Both venlafaxine and desvenlafaxine demonstrate a weak inhibitory effect on dopamine reuptake, with venlafaxine increasing DA at higher doses only. [Sansone & Sansone, 2014]

In vitro, venlafaxine and desvenlafaxine have been shown to have no significant affinity for muscarinic cholinergic, histaminergic, or α-1 adrenergic receptors. Furthermore, both compounds do not have any monoamine oxidase inhibitory activity.

There is some evidence of the role of opioid receptors contributing to venlafaxine’s antinociceptive effect (mu, kappa1, kappa3, and delta-opioid receptor subtypes). [Schreiber et al, 2002]

Comparison of affinities to other SNRIs:

• Venlafaxine (SERT:NAT): 30:1
• Desvenlafaxine (SERT:NAT): 10:1
• Duloxetine (SERT:NAT): 10:1
• Milnacipran (SERT:NAT): 1:1
• Levomilnacipran (SERT:NAT): 1:2

PHARMACOKINETICS OF VENLAFAXINE AND DESVENLAFAXINE

Venlafaxine has one major active metabolite (O-desmethylvenlafaxine; ODV) and two lower activity secondary metabolites (N-desmethylvenlafaxine and N, O-desmethylvenlafaxine).

Venlafaxine and desvenlafaxine are racemic mixtures of two enantiomers (S-(+)- and R-(-)-): the S-(+)-enantiomer acts primarily on serotonin reuptake, whereas the R-(-)- enantiomer acts on both serotonin and noradrenaline reuptake. [Magalhães et al. 2014]

Venlafaxine is well absorbed (≥92%) and extensively metabolised in the liver, which reduces its bioavailability to 40–45%; however, the metabolite ODV (i.e., desvenlafaxine) has equivalent pharmacological activity. [Wellington and Perry 2001]

Venlafaxine has two formulations, an immediate release (IR) and an extended-release (XR), which affect drug exposure:

• Venlafaxine-IR: Dosed twice per day and reaches peak plasma concentration at 2 hours post-dose (ODV reaches peak plasma concentration at 3 hours).
• Venlafaxine-XR: Dosed once per day and reaches peak plasma concentration at 5.5 hours post-dose (ODV reaches peak plasma concentration at 9 hours).
• Desvenlafaxine-XR: Dosed once per day and reaches peak plasma concentration at 7.5 hours.

Venlafaxine and its metabolites are primarily eliminated via the kidneys (92.1%) as either unchanged (4.7%), unconjugated-ODV (9.8%), or conjugated ODV (26.4%), with conjugated and unconjugated forms of venlafaxine’s other metabolites making up the rest of the metabolic disposition in urine. [Howell et al. 1993]

Research initially showed that age and gender did not significantly affect the pharmacokinetic profile of venlafaxine and ODV and that dose adjustments were not required. [Klamerus et al. 1996] However, it is essential to note that Klamerus et al. did observe that steady-state conditions were affected in the elderly (16% increase in exposure) but that this was deemed non-significant.

Since 1996 however, therapeutic drug monitoring research has suggested that in patients aged >60 years, there was a 46% increase in exposure, whilst there was a 30% increase in women. [Unterecker et al. 2012] As such, age and gender should be considered when recommending therapy.

Desvenlafaxine: 

Desvenlafaxine is primarily metabolised by conjugation (shown to be mediated by UGT isoforms UGT1A1, UGT1A3, UGT2B4, UGT2B15, and UGT2B17 in vitro) and to a minor extent through oxidative metabolism. CYP3A4 is the predominant cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. (small proportion).

DOSING OF VENLAFAXINE AND DESVENLAFAXINE

SAFETY PROFILE OF VENLAFAXINE AND DESVENLAFAXINE- SIDE EFFECTS | DRUG INTERACTIONS | CONTRAINDICATIONS

The most common adverse reactions reported are headache, somnolence, dry mouth, dizziness, insomnia, asthenia, sweating, and nervousness. Clinical trials have reported that treatment-emergent anxiety, nervousness, and insomnia resulted in discontinuation in 2%, 2% and 3%, respectively.

The adverse effect profile of venlafaxine at a dose of 75 mg/day is comparable to that of an SSRI, which is consistent with the fact that its highest binding affinity is for the serotonin uptake pump.

At higher doses, the side effect profile includes noradrenergic side effects such as activation, dry mouth, night sweats etc.

Venlafaxine and desvenlafaxine have also been reported to cause elevated serum aminotransferase levels. This drug-induced hepatotoxicity occurs in <1% of patients and is usually classified as mild, and thus dose modification or discontinuation is unnecessary. Other notable precautions include:

• A loss of ≥5% of body weight occurred in 6% of patients treated with venlafaxine compared with placebo; furthermore, desvenlafaxine has also been shown to be associated with a small but statistically significant decrease of -0.82 kg after 12 weeks. [Tourian et al. 2010]
• A loss of appetite was also more commonly reported with venlafaxine compared with placebo.

Hyponatraemia: 

Hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) may occur with venlafaxine and desvenlafaxine, usually in volume-depleted or dehydrated patients.

Risk factors include:

• Elderly patients
• Patients on diuretics
• Volume-depleted patients

Cardiac effects: 

Post-marketing research has reported that venlafaxine may prolong the QTc interval, causing cardiac arrhythmias and torsade de Pointes (TdP), the latter of which can be fatal. This effect has been suggested to account for the reported higher rates of fatal overdose with venlafaxine than SSRIs. [Martinez C et al. 2010]

• For instance, a case report in 2006 [Letsas et al. 2006] and another in 2015 [Bavle 2015] have reported clinically significant QTc prolongation, whilst a fatal overdose case (19,000 mg) with TdP was also reported. [Isbister 2015]

Over the years, these cardiac repolarisation events have stimulated drug safety studies on the potential cardiovascular changes associated with venlafaxine. [Iribarren et al 2013]; [van Haelst et al 2014]

However, a randomised crossover study in January 2022 showed that a 450 mg dose of venlafaxine-XR did not significantly prolong the QTc interval. [Abbas et al,2022].

There are no published data regarding QTc prolongation outside of premarketing studies in the package insert for desvenlafaxine.

A recent review on QTc interval prolongation risk with venlafaxine and desvenlafaxine put both on the lower end than other antidepressants. Read this for a more detailed review of QTC interval and psychotropics. 

Bleeding: 

• Both venlafaxine and desvenlafaxine may lead to platelet aggregation abnormalities through inhibition of serotonin reuptake. Bleeding abnormalities range from skin and mucous membrane bleeding and gastrointestinal haemorrhage to life-threatening haemorrhages.
• Concomitant aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may increase this risk.

Sexual dysfunction: 

• Both antidepressants are associated with sexual dysfunction, with desvenlafaxine having a lower propensity for this side effect. A study looking at sexual dysfunction with desvenlafaxine showed that sexual dysfunction improved significantly in depressed patients who initiated treatment with desvenlafaxine and those who switched from another AD to desvenlafaxine.
• However, while improvement was noted, desvenlafaxine was not devoid of sexual side effects. [Montejo et al., 2019]

Glaucoma:

• Patients with raised intraocular pressure or at risk for acute narrow-angle glaucoma (angle-closure glaucoma) should be closely monitored.

Discontinuation symptoms:

• Due to both medications associated with discontinuation symptoms, gradual tapering is recommended during discontinuation. Read more on tapering antidepressants and discontinuation symptoms. 

Raised BP: 

• With venlafaxine, the risk of increased blood pressure is a dose-dependent effect. At doses under 100 mg/day, the incidence of sustained elevation of supine diastolic blood pressure in patients on venlafaxine is comparable to that found in patients on placebo. However, the incidence is three-fold greater than on placebo in patients taking more than 200 mg/day of venlafaxine. [Thase, 1998]
• Desvenlafaxine has been associated with cases of elevated blood pressure requiring immediate treatment. In such cases, either dose reduction or discontinuation should be considered.

Children and Adolescents: 

• Venlafaxine or desvenlafaxine are not recommended in children and adolescents and can be associated with treatment-emergent suicidal ideation.

Mania/Hypomania

• Both agents can be associated with manic or hypomanic switches.

Pregnancy and Lactation: 

• Both Venlafaxine and Desvenlafaxine cross the placental barrier and into breast milk.
• Safety for both agents has not been established.
• Infants exposed can present with neonatal withdrawal syndrome.

Read for more details and guidance about antidepressants in pregnancy and breastfeeding.  

Drug Interactions: 

Venlafaxine: 

Venlafaxine undergoes extensive metabolism in the liver by several cytochrome (CYP) P450 isoenzymes, including CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. CYP2D6 is responsible for 56% of venlafaxine’s metabolism to ODV. [Veefkind et al 2000]; [Reis et al 2002]

As such, genetic polymorphisms in CYP2D6 can significantly affect its pharmacodynamic profile.

• Patients classified as poor metabolisers have increased levels of venlafaxine and decreased levels of ODV, causing toxicity and a reduced response to therapy, respectively. [D’Empaire et al. 2011]
• In addition, hepatic dysfunction (i.e., cirrhosis) significantly affects the plasma clearance of venlafaxine and ODV (50% and 30%, respectively). [Wellington and Perry 2001]
• Renal dysfunction can also dramatically affect venlafaxine pharmacokinetics, with its plasma clearance and elimination half-life prolonged by 24% and 50%, respectively.

Relevant drug interactions associated with inhibiting CYP2D6 and increasing venlafaxine’s plasma concentration include bupropion and fluoxetine (CYP2D6 and CYP2C19 inhibition). Fluoxetine has a long half-life (up to 15 days), and as such, the process of antidepressant switching comes with a high risk of serotonin syndrome. [Hiemke et al. 2018]. 

Concomitant use of CYP2D6 inhibitors and venlafaxine may reduce the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of ODV. However, as venlafaxine and ODV are pharmacologically active, no dosage adjustment is required when venlafaxine is co-administered with a CYP2D6 inhibitor.

CYP3A4 Inhibitors Concomitant use of CYP3A4 inhibitors (erythromycin, fluconazole, ketoconazole and grapefruit juice) may increase levels of venlafaxine and ODV. Therefore caution is advised when combining venlafaxine with a CYP3A4 inhibitor.

Desvenlafaxine:

• Desvenlafaxine is minimally metabolised by CYP3A4. It also does not induce or inhibit CYP2D6 or CYP3A4.
• Potent inhibitors of CYP3A4 may result in higher levels of desvenlafaxine.
• Concomitant use of desvenlafaxine with a drug metabolised by CYP2D6 may result in higher concentrations of that drug.
• Concomitant use of desvenlafaxine with a drug metabolised by CYP3A4 may result in lower exposures to that drug.

Contraindications: 

• Concurrent use of MAOIs with Venlafaxine or desvenlafaxine is contraindicated. Venlafaxine or desvenlafaxine should not be used within at least 14 days of discontinuing MAOI treatment.
• Before starting a MAOI, venlafaxine and desvenlafaxine should be stopped for at least 7 days. [Read more on MAOIs]
• Serotonin syndrome may occur with venlafaxine or desvenlafaxine treatment when combined with triptans, SSRIs, other SNRIs, amphetamines, lithium, sibutramine, opioids (e.g. fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone, and pentazocine), or St John’s wort.

CLINICAL EVIDENCE FOR VENLAFAXINE AND DESVENLAFAXINE

Venlafaxine is FDA approved to treat and manage Major Depressive Disorder (MDD), Generalised Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder (PD) and symptoms of cataplexy.

Off-label, venlafaxine can be used for:

1. Attention deficit disorder [Amiri et al., 2012]

2. Fibromyalgia [VanderWeide et al., 2015]

3. Diabetic neuropathy [Rowbotham et al., 2004],  [Aiyer et al., 2017]

4. Hot flashes: 

• Venlafaxine is effective in reducing both the frequency and severity of hot flashes. [Johnson & Carroll, 2011]
• The starting dose for venlafaxine for menopausal hot flashes should be 37.5 mg, which can be increased to 75 mg after one week of therapy

5. Migraine prevention:

• Venlafaxine, when compared to amitriptyline, can decrease the number of migraine attacks per month and decrease the duration and severity of attacks with no significant difference found in effectiveness between venlafaxine and amitriptyline. [Bulut et al., 2004]. [Burch,2019].
• Venlafaxine thus may be beneficial for patients with comorbid depression and migraine.

6. Post-traumatic stress disorder: [Hoskins et al., 2021].

7. Obsessive-compulsive disorder:

• Venlafaxine may be a valuable therapy for obsessive-compulsive disorder but is not superior to SSRIs. [Denys et al., 2003]
• However, venlafaxine has shown to be effective in treatment-resistant OCD ( patients who had failed SSRI trials) at mean doses of  232.2 mg/day. [Hollander et al., 2003].

8. Premenstrual dysphoric disorder.

• Venlafaxine reduces psychological and physical symptoms beginning from the first cycle with relatively low doses. (mean doses 50 mg/day in the first cycle to 130 mg /day mean in the fourth cycle). [Rege, 2020]

Desvenlafaxine: 

• Desvenlafaxine can be a first-line consideration for treating cases of MDD uncomplicated by medical comorbidities. [Norman & Olver, 2021].
• Desvenlafaxine 50 or 100 mg was associated with significant improvement from baseline compared to placebo for all symptom clusters in MDD except a sleep cluster for desvenlafaxine 100 mg. [Katzman et al.,2021].
• Higher doses may be required for more severe depression associated with higher response and remission rates. (See dosing section earlier)

Anxiety Disorders: 

• Desvenlafaxine is evidence-based in generalised anxiety disorder and can also improve anxiety symptoms when comorbid with depression. [Tourian et al.,2010]. 

Pain:

Peri and Postmenopausal Depression:

• Desvenlafaxine was the only antidepressant studied in well designed longitudinal trials in peri and postmenopausal depression. Short-term treatment with 50 mg and 100–200 mg doses of desvenlafaxine led to significant improvement in depressive symptoms compared with placebo. [Maki et al., 2018]

Read more about the treatment of perimenopausal depression. 

Venlafaxine vs Desvenlafaxine: 

• Comparing venlafaxine vs desvenlafaxine, limited evidence from three systematic reviews suggested there was no significant difference in the clinical effectiveness of desvenlafaxine versus venlafaxine for the treatment of adult patients with Major Depressive Disorder.
• However, only two trials were identified that conducted head-to-head comparisons of the clinical effectiveness of desvenlafaxine and venlafaxine. Moreover, there was substantial variability in the antidepressant dosages in the included trials. Poitras & Visintini, 2017]

SUMMARY

Venlafaxine and desvenlafaxine are SNRIs that potentiate serotonin and noradrenaline neurotransmitter activity within the CNS.

However, there are pharmacodynamic and pharmacokinetic differences between the two that are clinically relevant.

Both Venlafaxine and desvenlafaxine have applications in a range of disorders beyond depression and anxiety.