A number of antidepressants were introduced after SSRIs. Venlafaxine is a nonselective serotonin and norepinephrine reuptake inhibitor. Desvenlafaxine, the primary metabolite of venlafaxine, has a similar profile to its parent compound, but dosing may be easier. Duloxetine is also a nonselective serotonin and norepineph-rine reuptake inhibitor, but has greater potency than venlafaxine (181). Neither compound has significant anticholinergic or antihistaminic effects. Mirtazapine is a noradrenergic a2 antagonist at auto- and heteroreceptors, enhancing serotonin release and a 5-HT2A and 5-HT3 antagonist. Nefazodone and trazodone are phe-nylpiperazine derivatives. Nefazodone is a 5-HT2A antagonist and serotonin reuptake inhibitor. Bupropion is an aminoketone that in vivo may block norepi-nephrine reuptake via its active metabolite hydroxybupropion and also increase dopamine activity by an unknown mechanism. Reboxetine is a selective norepi-nephrine reuptake inhibitor that is currently used to treat mood disorders in Canada and Europe but is not available in the United States. These newer antidepressants offer some advantages in tolerability over the older agents and perhaps more importantly have different mechanisms of action, which may provide alternatives for patients who do not respond to other antidepressants.
Bupropion is an aminoketone compound that was introduced in the United States in 1989 amid concerns about its seizure-inducing potential, a factor that delayed its marketing from the original FDA approval in 1985. A large study in the interim period established that the seizure risk from bupropion at usual therapeutic doses was similar to the cyclic antidepressants. Bupropion has three active metabolites: hydroxybupropion, threobupropion, and erythrobupropion. The relative contributions of the metabolites to clinical or adverse effects are unclear; however, they reach higher plasma levels than the parent compound. Bupropion's plasma half-life after chronic dosing is about 20 h and it is 80% protein bound. The half-life of hydroxy-bupropion is longer, about 22 h, and it is a norepinephrine reuptake inhibitor (182).
Bupropion is believed to exert its antidepressant action by inhibiting norepi-nephrine reuptake and enhancing dopamine activity. It has no serotonergic, anticho-linergic, or antihistaminergic effects, nor does it interact with monoamine oxidase (182). There is still some ambiguity concerning its mechanism of action which arises from differences in bupropion's actions in vivo and in vitro. Bupropion is a potent dopamine reuptake inhibitor as well as a moderate norepinephrine reuptake inhibitor in vitro. In vivo, the drug is twice as potent in its norepinephrine reuptake inhibition compared to its dopamine reuptake inhibition (183). Although bupropion has demonstrated dopamine uptake inhibition using in vitro models, the concentrations required may not have clinical relevance. In addition, even though homovanillic acid is increased during bupropion treatment (an indication of enhanced dopamine activity), these levels are not associated with a positive antidepressant response. Hydroxybupropion is associated with down-regulation of postsynaptic b-adrenergic receptors in animal models.
Bupropion IR (immediate release) carries a relatively higher risk of lowering seizure threshold compared to SSRIs. Bupropion IR has a risk of seizures of 0.4% at doses up to 450 mg/day, which is about 2-4 times higher than the incidence of seizures associated with SSRI treatment (0.1-0.2%) (184). Seizure risk is strongly related to dose and the rate of dosage escalation. Even with modest increases of the dose to 450-600 mg/day seizure risk increases tenfold. An extended release formulation has lowered the risk of seizures to a level comparable to other antidepressant classes. A seizure rate of 0.1% was associated with bupropion SR (sustained release) at doses of 300 mg/day and 0.4% at 400 mg/day (184). Clinicians should be aware that Wellbutrin® and Zyban® are both bupropion, and inadvertent overdoses have occurred when both have been prescribed for the same patient to treat depression and for smoking cessation.
Because of bupropion's dopaminergic and adrenergic actions, it can be activating and may cause overstimulation, agitation, nausea, nervousness, and insomnia as well as tremors and palpitations (182, 184, 185); however, in our experience, it is usually very well tolerated. It has the potential to induce mania in bipolar patients; however, bupropion-induced mania tends to be milder and have a shorter course than either spontaneous mania or mania elicited in patients by tricyclic or SSRI antidepressants (77). Bupropion has a favorable cardiovascular profile and does not cause orthostatic hypotension or conduction delay. Some patients may have elevated blood pressure with bupropion, but in our experience is not as frequent a problem as with venlafaxine.
Since bupropion does not interact with serotonergic receptors, it has an extremely low incidence of sexual side effects which are common with SSRIs and most other antidepressants (97, 184, 185). Bupropion is a reasonable alternative to SSRI when sexual adverse effects limit their use. Bupropion is not associated with weight gain.
Dermatologic adverse effects of bupropion are rare but may also include urticarial and pruritic rashes and very rarely extreme dermatologic reactions (186).
Because of its unique mechanism of action and good tolerability it has become one of the first choices for SSRI augmentation for many clinicians.
Venlafaxine is a bicyclic phenylethylamine derivative marketed as a racemic mixture of its R- and S-enantiomers; the R-enantiomer is more potent of the 2 (187). Venlafaxine is only 27% protein bound and has a half-life of 4-5 h. It undergoes first-pass metabolism to O-demethylvenlafaxine, ODV, which is active and just as potent as its parent compound, and has an elimination half-life 11 h. Clearance of both venlafaxine and ODV is decreased by 55% in patients with severe renal disease and by 33% in patients with cirrhosis (188). Venlafaxine XR (extended release) formulation has become the preferred agent, and the immediate release formulation is rarely used in the US. Pharmacologically, the XR it is quite similar to the original venlafaxine IR (immediate release); the differences are increased time to peak plasma concentration as well as lower plasma concentrations of the XR drug (189).
Venlafaxine acts on both serotonergic and norepinephrine reuptake at higher therapeutic doses (225 mg or higher), but at lower doses, it affects mainly serotonin, making it comparable to SSRI. However, as the dose is increased, it becomes a potent inhibitor of the synaptic reuptake of norepinephrine (182, 187, 188). At low doses, inhibition of serotonin reuptake is about three to fivefold higher than that of norepinephrine reuptake (32, 188). Venlafaxine also possesses weak affinity toward the dopamine receptor (188). It rapidly down-regulates b-adrenergic receptors, a property that some contend supports those studies that have found a more rapid onset of antidepressant effect with venlafaxine compared to other agents. It has minimal or no interaction with muscarinic, histaminic, or a-adrenergic receptors, which accounts for its low incidence of adverse effects (187). It is an effective antidepressant and antianxiety agent.
Most common adverse effects include those associated with SSRI, such as nausea, vomiting, sexual dysfunction, somnolence, and sweating (182, 185, 190). The incidence of sexual dysfunction is thought by some to be lower than SSRI (103, 185, 191).
Of most concern has been elevated blood pressure which occurs at higher doses of venlafaxine (between 101 and 300 mg daily) that returns to normal after drug discontinuation (69, 182). Blood pressure changes are dose related, with an incidence of about 5% at doses under 200 mg daily and 13% at doses greater than 300 mg daily. Pre-existing hypertension does not appear to be a risk factor for this effect. If the dose cannot be reduced, blood pressure should be treated pharmacologically, using standard drug algorithms.
Discontinuation syndromes upon abruptly stopping venlafaxine have been reported (192). The most common symptoms are dizziness or lightheadedness, excessive sweating, irritability, dysphoria, and insomnia, which is similar to the SSRI discontinuation syndrome (192). A slow taper of the medication usually prevents the occurrence of this syndrome. On rare occasions, it may be necessary to reinstitute the medication or switch to a long-acting SSRI, such as fluoxetine.
Venlafaxine is one of the few antidepressants that has been studied in pregnancy. A recent prospective study of 150 pregnant women receiving venlafaxine found no significant differences between women taking venlafaxine during pregnancy and those taking either SSRI antidepressants or known non-teratogenic drugs (193). The rates of major neonatal malformations in all groups were the same as baseline rate for the general population of 1-3%. It should be noted that the sample size is too small to detect rare occurrences of adverse effects, such as teratogenic risk.
Desvenlafaxine is the major active metabolite of the SNRI antidepressant venla-faxine formulated as an extended-release tablet for once-daily, oral administration. It inhibits the neuronal reuptake of both serotonin and norepinephrine and, to a lesser degree, dopamine. It is approximately tenfold more potent at inhibiting serotonin uptake than norepinephrine uptake. Desvenlafaxine lacks monoamine oxidase inhibitory activity and shows no affinity for muscarinic cholinergic, Hj-histaminergic, or aj-adrenergic receptors in vitro.
Desvenlafaxine is well absorbed after oral administration (80% bioavailability) but somewhat slowly, with a T of 7-8 h. It has a mean terminal half-life (M) of
approximately 9-15 h. Metabolism is primarily through phase II glucuronidation and, to a minor extent, through CYP3A4. It has linear pharmacokinetics through supratherapeutic doses, with very small differences between subjects. It does not inhibit CYP2D6 to a clinically significant extent. Desvenlafaxine plasma binding is approximately 30% and independent of drug concentration. There are no active metabolites, and it is excreted by the kidney as unchanged desvenlafaxine and the glucuronide conjugate.
Several studies have established the efficacy of desvenlafaxine in major depression and it is FDA approved for that indication. Despite an active research program in the area, studies do not yet support the efficacy and safety of desvenla-faxine for vasomotor symptoms associated with menopause, such as hot flushes, night sweats, and associated sleep disruptions.
Similar to its parent compound, discontinuation symptoms are observed after cessation of desvenlafaxine treatment in both short-term and long-term MDD studies. The most common symptoms reported by patients after discontinuation of short-term desvenlafaxine treatment were dizziness, nausea, irritability, and diarrhea, which are characteristic of the serotonin reuptake inhibitor discontinuation syndrome. Symptoms associated with treatments of 6-month duration include fatigue, abnormal dreams, anxiety, and hyperhidrosis. About half of patients taking desven-lafaxine have some discontinuation symptoms, but they are relatively few and mild compared to short-acting SSRI withdrawal syndromes. At the recommended dose of 50 mg daily, discontinuation symptoms appear shortly after abrupt discontinuation and resolve within a week.
In summary, desvenlafaxine offers a few advantages over venlafaxine, although among them are ease of dosing—a single dose of 50 mg for initiation and maintenance, lower potential for pharmacokinetic drug interactions, and apparently a less severe discontinuation syndrome.
Duloxetine is an antidepressant that inhibits both serotonin and norepinephrine reuptake. Although similar to venlafaxine, duloxetines's greater potency at nora-drenergic reuptake is thought to contribute to its greater efficacy in pain treatment than venlafaxine. It is approved by the FDA for use in major depression, generalized anxiety disorder, diabetic neuropathic pain, and fibromyalgia. The recommended therapeutic doses range from 40-60 mg daily, but lower doses (20-30 mg daily) should be used for the first week of treatment to avoid adverse effects. Although clinical studies do not support doses higher than 60 mg daily, our experience suggests that higher doses are usually necessary for pain syndromes related to fibromyalgia and other autoimmune diseases. Common adverse effects are nausea, decreased appetite, constipation, headache, dry mouth, insomnia, and somnolence. Men, but not women, treated with duloxetine experience more difficulty achieving orgasm compared to placebo. Increases in both systolic and diastolic blood pressure of approximately 2 mm Hg and an increase in heart rate of 3-4 beats per minute. Some patients experience palpitations but clinically significant changes in electrocardiograms were not different in duloxetine and placebo groups in premarketing studies. The drug is among a class of agents that increase urethral resistance, which may lead to urinary hesitation. Duloxetine has an elimination half-life ranging from 8-17 hours, with hepatic metabolism by P450 isozymes CYP1A2 and CYP2D6. Numerous metabolites are produced, but it is believed that the primary therapeutic effect is from the parent compound.
Nefazodone and trazodone are two closely related antidepressants. Nefazodone is a phenylpiperazine derivative of trazodone with lower aj activity. Trazodone is a triazolopyridine derivative developed in early 1980s as an alternative to TCAs, but its efficacy has always been questioned, and its most common use today is to promote sleep. Its antidepressant properties are believed to be related to its 5-HT2 receptor antagonism and only partially from its weak serotonin reuptake inhibition (32, 187). Aside from its therapeutic actions, trazodone is a weak to moderate histamine Hj receptor antagonist as well as aj-adrenergic antagonist, which makes it similar to TCAs in terms of the undesired side effects (187).
Nefazodone has three pharmacologically active metabolites: hydroxynefazodone (OHN), triazole-dione, and m-chlorophenylpiperazine (mCPP). Both triazole-dione and OHN contribute to the antidepressant effect of nefazodone. Like nefazodone, OHN is a very potent inhibitor of 5-HT2A receptors as well as serotonin reuptake. The triazole-dione metabolite has weak 5-HT2A antagonism. mCPP is an agonist at the 5-HT1A,1B,1C,1D and 5-HT2C receptors but is not considered to have a significant impact on nefazodone's overall actions (182, 189). Nefazodone antagonizes and down-regulates postsynaptic 5-HT2A receptors, which in turn leads to enhanced 5-HT receptor-meditated postsynaptic neurotransmission (194). It is a moderate presynaptic serotonin reuptake inhibitor (194). Nefazodone also inhibits presynap-tic norepinephrine reuptake, but to a much lesser degree, and this probably does not contribute to its therapeutic actions (182). Nefazodone is a weak aj-adrenergic antagonist and has very little if any a2-adrenergic, antihistaminic, or dopamine receptor interactions (187, 195).
As discussed above, trazodone is a histamine H1 receptor antagonist, as well as an a1-adrenergic antagonist, which makes it similar to TCA drugs in terms of the undesired side effects (187). Despite isolated case reports of conduction delay and arrhythmias with trazodone (especially in overdoses), studies have not found this effect even in patients with pre-existing cardiac disease. Anticholinergic and anti-histamine effects are negligible (182, 187). Due to its aj-adenoreceptor blocking properties, trazodone may cause orthostatic hypotension (69). The most serious adverse effect of trazodone therapy in male patients is priapism, a urologic emergency (196). The incidence of trazodone-induced priapism is unknown with estimates ranging from 1 in 1,000 to 1 in 10,000 patients. It tends to occur early in treatment, usually within the first month, but has also been reported after 18 months of treatment. It can occur at doses as low as 50 mg daily. Approximately one-third of patients require surgical intervention. Priapism is believed to be due to a-adren-ergic blockade.
Nefazodone has weak a1 and cholinergic receptor antagonism and virtually no a2-adrenergic, dopamine, or histaminic blockade (182, 190). Nefazodone does not cause sexual dysfunction, and it is a reasonable alternative to SSRI when this effect is of concern (97, 103). It has not been associated with priapism, despite its structural similarity to trazodone (34, 69). The most frequent side effects of nefazodone as compared to placebo in patients in clinical trials are nausea (21 vs. 14%), somnolence (19 vs. 13%), dry mouth (19 vs. 13%), dizziness (12 vs. 6%), constipation (11 vs. 7%), lightheadedness (10 vs. 4%), and blurred vision (6 vs. 3%) (195). It should be noted that occurrence of nausea and gastrointestinal distress in patients taking nefazodone or trazodone is usually less than that produced by either SSRI or venlafaxine treatment (185).
A study of hepatotoxicity of the newer antidepressants using the Spanish Pharmacovigilance System database reported a high incidence of hepatotoxicity with nefazodone, with 28.96 cases per 100,000 patient-years, compared to 1.28 for sertraline and 4.0 for clomipramine (72). The Canadian Adverse Drug Reaction Monitoring Program found 32 cases of hepatotoxicity associated with nefazodone, with 26 classified as severe (197). Patients were between 30 and 69 years old and were taking doses of 100-600 mg daily. Sixty-eight and eight-tenths percent were women; 88% developed toxicity within 6 months of beginning the drug. Toxicity is hepatocellular in such cases, with high serum aminotransferase levels and increased total bilirubin. Withdrawal of nefazodone may lead to improvement in liver function; however, deaths have also been reported (72, 198). It is likely that both pharmacovigilance studies suffer from underreporting (72). If this is so, the incidence of hepatotoxicity associated with nefazodone may be even higher. In the United States, nefazodone now carries a "black box" warning concerning hepatotoxicity, and some countries have removed it from the market. It retains a niche market in the U.S. for anxious and depressed patients, often with substance abuse, who have not responded to several other agents.
Mirtazapine, is a 6-aza-analogue of mianserin but has a different pharmacologic profile (199). Mirtazapine is a less-potent noradrenergic reuptake blocker and 5-HT2 antagonist than mianserin (199). Mirtazapine is an effective antidepressant and antianxiety agent, and some authorities believe it has a more rapid onset than other antidepressants.
Mirtazapine's mechanism of antidepressant action is believed to be related to enhancement of serotonin and norepinephrine neurotransmission through potent and direct blockade of a2-adrenergic autoreceptors and heteroreceptors (199, 200). This action results in increased noradrenergic transmission which stimulates a1-adrenergic receptors on the serotonergic cell body. Blockade of the a2-adrenergic heteroreceptor on the serotonin nerve terminal prevents this receptor from "turning off' the increased serotonin activity (199, 200). Mirtazapine is also a weak agonist of the 5-HT1A serotonin receptor and causes some enhancement of 5-HT1A-mediated serotonergic transmission through this mechanism (200). Another major action of mirtazapine is inhibition of 5-HT2 and 5-HT3 receptors postsynaptically, which may limit the adverse effects that are usually associated with increased serotonin activity and may also contribute to mirtazapine's anxiolytic and hypnotic effects. Because it has a unique pharmacodynamic profile, it is among the first agents used for augmentation and combination therapy with SSRI.
Mirtazapine is marketed as a racemate of R- and S-enantiomers (187). The R-enantiomer is more active, reaches higher plasma concentrations, and has a longer half-life than the S-enantiomer. Mirtazapine is rapidly absorbed from the gastrointestinal tract after oral administration with high bioavailability. It is 85% plasma protein bound and has an elimination half-life of20-40 h (201). Mirtazapine's major metabolite is demethylmirtazapine, which has only weak activity compared to the parent compound. Hepatic and renal impairment may cause a 30 and 50% decrease in oral mirtazapine clearance, respectively, necessitating a dose adjustment in some patients (201).
Mirtazapine is associated with dry mouth, drowsiness, and sedation in about 25% of patients (199, 202). Because of its antihistaminic activity, this drug may also cause weight gain in approximately 10-20% of patients. A similar percentage of patients have elevated cholesterol and somewhat fewer have elevated triglycerides. Mirtazapine has low incidence of sexual side effects among antidepressants (103).
A causal association of mirtazapine with severe neutropenia (absolute neutrophil count less than 500/ml3) has been reported in three cases. Of these, 2 patients developed agranulocytosis. All 3 patients recovered upon discontinuation of the drug. It is therefore recommended that mirtazapine be stopped if any signs of infection with a low white cell count occur (201).
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