The Newer Antidepressants

Herbert Ward, M.D.
Herbert Ward, M.D. is Assistant Professor , Department of Psychiatry,
at the University of Florida College of Medicine, Gainesville.

Reprinted with permission. Ward HE. The Newer Antidepressants. IM Internal Medicine. 1997; 18(7): 65-76.

Depression is a common disorder associated with significant morbidity and mortality. The 1-month prevalence of major depression in the general population is estimated at 5%.¹ In medical patients, the prevalence ranges from 9% in the ambulatory setting to as high as 30% in hospitalized patients.² More specifically, major depression occurs in approximately 20% of patients with coronary artery disease,³ 24% of patients with cancer,⁴ and 34% of patients after stroke.⁵ Prior to the introduction of the first selective serotonin reuptake inhibitor (SSRI) in 1987, medical treatment of depression was limited primarily to the tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs). Although these agents have not been surpassed in their efficacy or onset of antidepressant activity, remarkable advances have been made in safety and side effect profiles with the newer antidepressant agents.

It is now possible to aggressively treat depression in medically fragile patients without affecting cardiac conduction or inducing anticholinergic side effects or orthostatic changes in blood pressure. Additionally, the improved tolerability of the newer agents has resulted in better compliance and quicker escalation in dosing to establish therapeutic levels.

This article reviews four SSRIs: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and fluvoxamine (Luvox) and four other compounds: bupropion (Wellbutrin), nefazodone (Serzone), venlafaxine (Effexor), and mirtazapine (Remeron).

Selective Serotonin Reuptake Inhibitors

Fluoxetine was the first SSRI available in the US. Since its introduction in 1987, sertraline, paroxetine, and fluvoxamine have become available for clinical use.^6-9

The SSRIs are comparable in efficacy to the older antidepressants but differ markedly in their safety and side effect profiles. Notably, SSRIs lack the quinidine-like effect seen with the TCAs, have little or no anticholinergic effects, and do not block peripheral a₁- receptors. Their excellent side effect profile makes SSRIs a good choice for use in cardiac patients and avoids lethality in cases of overdose.

The SSRIs also lack affinity for the histamine₁ receptor and, therefore, avert the weight gain and sedation seen with the TCAs. Additionally, SSRIs do not potentiate the effects of alcohol or other central nervous system (CNS) depressants. Because of their selectivity for neuronal uptake of serotonin, these agents have a greater therapeutic index and do not require monitoring of blood levels to establish therapeutic concentrations or avoid toxicity.

The most common side effects with the SSRIs include initial nervousness or agitation, gastrointestinal symptoms, and sexual dysfunction. The anxiety seen with the SSRIs often abates with time, but some patients may require slower dosage titration. Taking these agents with food can reduce the gastrointestinal symptoms of nausea and diarrhea that some patients experience. With the SSRIs both men and women can experience delayed orgasm. This side effect may resolve spontaneously or persist until the SSRI is discontinued or the dose is reduced.

Three SSRIs, fluoxetine, sertraline, and paroxetine, are highly protein bound (>95%). Fluvoxamine is approximately 77% bound to plasma proteins. All four SSRIs undergo extensive hepatic metabolism, therefore, the dose should be reduced in patients with hepatic impairment or renal insufficiency.

The SSRIs are well-tolerated in the elderly (>65 years); but starting doses should generally be lower, upward titration of doses slower, and final doses lower in this population. With the exception of fluoxetine, the dose of SSRIs should be tapered to avoid a discontinuation syndrome. ¹⁰ Specific prescribing considerations for each of these SSRIs are summarized in Table 1.

Fluoxetine

In the US, there are now more than 10 years of postmarketing experience with fluoxetine,¹¹ which has Food and Drug Administration (FDA) approval for the treatment of depression and obsessive compulsive disorder (OCD). Additionally, fluoxetine is effective in the treatment of panic disorder¹² and social phobia.¹³

The dose of fluoxetine should be lower in patients with renal impairment and at least a 50% reduction is recommended in patients with cirrhosis. Fluoxetine is extensively metabolized in the liver to norfluoxetine which has similar activity as the parent compound. The parent compound has a half-life of 1-3 days after acute administration and 4 to 6 days after chronic administration. Norfluoxetine has a half-life of 4 to16 days. This extended half-life allows for the option of every other day dosing as a strategy for dealing with side effects in patients sensitive to the medication.

Once steady state is reached, significant effects on plasma levels or therapeutic efficacy should not occur in the less compliant patient who misses an occasional dose. Fluoxetine's long half-life makes tapering the medication unnecessary when it is being discontinued. By the same token, a longer washout period is required when starting a second medication where drug-drug interaction is a concern. In particular, there should be at least a 5-week period between discontinuation of fluoxetine and the start of a MAOI.

Sertraline

This agent, which was the second SSRI marketed in the US,¹⁴ has FDA approval for the treatment of major depression, OCD¹⁵, and panic disorder.¹⁶ Sertraline has a half-life of 26 hours. However, a 40% decrease in plasma clearance has been reported in geriatric patients, and dosing should be adjusted accordingly. In the elderly and patients with hepatic impairment, sertraline should be started at a dose of 25 mg.

Paroxetine

The third SSRI marketed in the US, paroxetine¹⁷ has FDA approval for major depression, panic disorder, and OCD. Paroxetine's half-life is 21 hours. Withdrawal symptoms, including nightmares, tremor, dizziness, insomnia, myalgias, and a "flu-like" syndrome have been reported with abrupt discontinuation of paroxetine.¹⁸ Therefore, it is best to taper the medication over several days, particularly in patients receiving more than 20 mg per day.

Fluvoxamine

Although marketed in the US for OCD, fluvoxamine is available in several other countries mainly for the treatment of depression.¹⁹ Controlled clinical trials have confirmed its safety and efficacy in treatment of depression²⁰ and panic disorder.²¹

Fluvoxamine has an elimination half-life of 15 hours in patients with normal hepatic function. In patients with cirrhosis and the elderly, there may be as much as a 40%-50 reduction in clearance and dosing should be adjusted accordingly.

Role Of SSRIs

Because of their tolerability, the SSRIs have become first-line agents in the treatment of depression. This improved tolerability over the older antidepressants allows for their use within a busy medical practice. More specifically, it is not necessary to monitor blood levels, and most outpatients can be started on a therapeutic dose, maintaining their usual interval between visits. For the medically fragile or elderly patient, the general principles of reduced dosing to allow for reduced clearance is usually sufficient to avoid unwanted side effects. There is little data to support one SSRI over the other in a specific medical condition. However, in the medically ill patient who is likely to be on one or more other medications, the potential for drug-drug interactions (discussed below) should always be taken into consideration.

Other Compounds

Several other compounds that are structurally unrelated to the SSRIs are also useful for the treatment of depression in patients with concomitant medical problems. Specific prescribing considerations for each of these compounds are summarized in Table 2.

Bupropion

This aminoketone is structurally related to the sympathomimetic agent dihydropropion.²² The mechanism of bupropion's antidepressant activity is poorly understood but is thought to be mediated through noradrenergic or dopaminergic pathways or both.²³ It does not block central cholinergic, histaminergic or a₁-adrenergic receptors. Because of its sympathomimetic properties and lack of sexual effects, bupropion has been popular in depressed patients who present with anergy, psychomotor slowness, and hypersomnolence.

Bupropion is approximately 85% bound to plasma proteins and undergoes extensive hepatic metabolism. The elimination half-life of the parent compound is approximately 14 hours and that of its active metabolite, hydroxybupropion, is about 22 hours. Dosing is, therefore, recommended on a 2 or 3 times daily schedule.

A slow-release form of bupropion (Wellbutrin SR®) has recently become available, but it still requires a twice daily dosing schedule. The apparent sympathomimetic effects of both the sustained- and immediate-release formulations can cause insominia, restlessness, and agitation, particularly early in treatment that may limit upward titration.

The immediate-release form of bupropion is associated with seizures in approximately 0.4% (4 of 1000) of patients treated in doses up to 450 mg per day, which is higher than that of other marketed antidepressants.²⁴ The incidence of seizures seems to be strongly associated with dose, increasing almost tenfold between 450 mg and 600 mg. Therefore, the maximum dose of 450 mg should not be exceeded, and single doses of the immediate-release preparation should not exceed 150mg.

The sustained-release form of bupropion apparently has a much lower incidence of seizures. In patients treated with the usual daily dose for the sustained-release formulation (300 mg), the incidence of seizures is approximately 0.1% (1 per 1000). The risk of seizures with the sustained-release formulation in doses above 300 mg per day has not been evaluated.

Predisposing factors such as head trauma, prior seizure, CNS tumor, or concomitant medications that lower seizure threshold seem to contribute to an increased incidence of seizures. Bupropion is contraindicated in patients with a diagnosis of anorexia nervosa or bulimia because of a higher incidence of seizures noted in this population.

Bupropion should not cause sexual dysfunction, orthostasis, cardiac conduction problems, weight gain, or anticholinergic side effects. However, there is some concern that bupropion may exacerbate psychotic symptoms in patients with a history of psychosis, and it is one of the few antidepressants that is not effective in treating panic disorder.

Nefazodone

This phenylpiperazine is structurally related to trazodone.²⁵ Presynaptically, nefazodone inhibits neuronal uptake of serotonin and, to a lesser extent, norepinepherine. In addition to its presynaptic effects, nefazodone blocks postsynaptic 5-HT₂ receptors. Nefa-zodone has weak affinity for cholinergic and a₁- adrenergic receptors and, therefore, is associated with less sedation and orthostasis than trazodone.

Nefazodone is >99% bound to plasma proteins. Based on an elimination half-life of the parent compound of 2 to 4 hours and 2 to 18 hours for its three active metabolites, nefazodone must be given on a twice daily schedule. The dose should be reduced in patients with renal and hepatic disease. Geriatric patients should be started at 50 mg twice a day, which is one half the initial dose for adults.

The most common side effects with nefazodone are headache, dry mouth, nausea, dizziness, and sedation. In general, however, nefazodone is well-tolerated in medical patients. It has a favorable cardiac side effect profile and a low incidence of sexual side effects. Because of its short half-life, nefazodone should be tapered when being discontinued.

Venlafaxine

This agent is a phenylethylamine bicyclic compound that is structurally unrelated to other antidepressants.²⁶ Like the TCAs, venlafaxine inhibits the neuronal uptake of both serotonin and norepinepherine. However, it has no significant affinity for central muscarinic, histaminic, or a-adrenergic receptors.

Venlafaxine is only 20 to 30% bound to plasma proteins and undergoes extensive hepatic metabolism to its active metabolite, O-desmethyvenlafaxine. The elimination half-life of the parent compound is 3 to 4 hours and that of its active metabolite is approximately 10 hours. These half-lives necessitate a 2 or 3 times daily dosing schedule. An extended-release form of venlafaxine (XR) is now available that allows for once-daily dosing.

The dose of venlafaxine should be reduced by 25% in patients with mild to moderate renal impairment and by 50% in patients with creatinine clearance values <30 mL/min. In moderate hepatic impairment, the dose should be reduced by 50%. There are no specific dosage adjustment recommendations based on the patient's age alone.²⁷ Side effects with venlafaxine are similar to those associated with SSRIs and include nausea, somnolence, dizziness, and sexual dysfunction. In premarketing studies, a dose-dependent increase in supine diastolic blood pressure (usually between 10 mm Hg to 15 mm Hg) was reported with venlafaxine. The incidence of hypertension was 3% at doses <100 mg per day, 5% for doses of 101 mg to 200 mg per day, 7% at 201 to 300 mg per day, and 13% for patients receiving doses >300 mg per day. Therefore, it is wise to monitor blood pressure, particularly in patients with existing hypertension, during dosage escalation, in patients with hepatic or renal impairment, or when higher doses are being used. To minimize risk of discontinuation symptoms, gradually taper the dose of venlafaxine over a 2-week period.

Mirtazapine

This drug is the most recently released antidepressant and is the first a₂-antagonist marketed as an antidepressant.²⁸ Mirtazapine's unique mechanism of action does not involve enzyme inhibition or blockade of neurotransmitter reuptake. Mirtazapine increases the release of norepinepherine from central noradrenergic neurons by blocking the presynaptic inhibitory alpha-2 autoreceptors. It spares the alpha-1 postsynaptic receptor and therefor results in net increase noradrenergic transmission. As a second presynaptic receptor blocking function, mirtazapine blocks the inhibitory alpha-2 heteroreceptors located on serotonergic neurons, resulting in increase release of serotonin. Postsynaptically, mirtazapine has low affinity for the 5-HT1A receptor, thus allowing serotonin released into the synapse to bind to and stimulate this receptor. However, it blocks postsynaptic 5-HT2 and 5-HT3 receptors. Stimulation of the 5-HT2 receptor is thought to be responsible for the serotonergic side effects of insomnia, agitation, and sexual dysfunction seen with the SSRI's and 5-HT3 receptor stimulation is thought to mediate nausea seen with these agents.^29,30,31 Therefore, mirtazapine's receptor blocking profile prevents the side effects seen with nonselective activation of serotonin receptors which occurs with pure reuptake blockers.

Mirtazapine is a potent antagonist at the histamine₁ receptor but has low affinity for muscurinic cholinergic and dopaminergic receptors. Most common side effects are dry mouth, sedation, increased appetite, and weight gain.

Mirtazapine has an elimination half-life of about 20 to 40 hours. It should be given in a single daily dose at bedtime. The clearance of mirtazapine is reduced in elderly patients and in patients with renal or hepatic impairment. Specific dosing recommendations in this population are not available. However, based on its pharmacokinetic profile, a 30%-50% reduction in dose may be warranted.

Drug-Drug Interactions

None of the newer antidepressants should be combined with an MAOI, and at least 14 days should pass after the discontinuation of a MAOI before starting these drugs. Most of these agents are highly protein bound and, theoretically, can displace other agents similarly bound to plasma proteins.

The hepatic CyP-450 enzyme system is responsible for the oxidative metabolism of several medications, some with narrow therapeutic indices. To the extent that the newer antidepressants serve as a substrate or an inhibitor of one or more of these enzymes, a potential for drug-drug interaction exists. The CyP-450 2D6, CyP-450 3A4, CyP-450 1A2, and CyP-450 2C isoenzymes have received considerable attention in an effort to explain observed drug-drug interactions and to alert clinicians to potential interactions. For a comprehensive review of the in vitro and in vivo data supporting interactions between the newer antidepressants and these four isoenzymes the reader is referred to recent reviews on this subject. ^32,33 However, some of the more clinically significant interactions should be noted.

The CyP-450 2D6 isoenzyme is involved in the metabolism of tricyclic antidepressants, antipsychotics, ß-adrenergic blockers, type 1C antiarrhythmics (encainide, flecainide, mexiletne, propafenone), codeine, and dextromethorphan. Quinidine is the prototype inhibitor of CyP-450 2D6. Although much less potent, all of the SSRIs also inhibit this enzyme. When combining an SSRI and a TCA, lower doses of the TCA must be used and blood levels judiciously monitored to avoid TCA toxicity.

The CyP-450 3A4 isoenzyme metabolizes the triazolo-benzodiazepines (triazolam, alprazolam, midazo-lam), terfenadine, and astemizole. Ketoconazole, erythromycin, and cimetidine are potent inhibitors of CyP-450 3A4. Life-threatening arrhythmias have occurred from terfenadine toxicity when terfenadine was administered with ketoconazole. The SSRIs and nefazodone also inhibit this enzyme. Therefore, use of terfenadine or astemizole combined with either fluvoxamine or nefazodone is contraindicated. A 50% reduction in the dose of alprazolam and a 75% reduction in the dose of triazolam is recommended if these compounds are administered with nefazodone. Nefazodone should not be combined with triazolam in the elderly. Lorazepam, oxazepam, and temazepam are metabolized by glucuronidation rather than CyP-450, and their levels should not be altered by drugs undergoing hepatic metabolism.

CyP-450 1A2 metabolizes theophylline and the tertiary TCAs (imipramine, clomipramine, amytriptyline). Fluvo-xamine is a potent inhibitor of this enzyme, and fluoxetine, sertraline and paroxetine are weak inhibitors. Fluvoxamine has been shown to elevate plasma levels of theophylline and the tertiary TCAs.

CyP-450 2C9 metabolizes phenytoin, tolbutamide, warfarin, and diazepam. Elevations in these compounds have been noted during concomitant therapy with the SSRIs.

There are no data to indicate that bupropion inhibits any of the cytochrome P450 enzymes. However, patients receiving L-dopa and bupropion have reported a high incidence of adverse effects, particularly nausea, vomiting, and restlessness, necessitating smaller dosage titration if this combination is attempted.³⁴

It should be emphasized that most of the concerns regarding drug-drug interactions with the newer antidepressants are theoretical, and clinically significant interactions are unusual. However, it is sound practice to monitor plasma levels of any medication with a narrow therapeutic index (TCAs, antiarrhythmics, theophylline, terfenadine, for example) when combining it with one of the newer antidepressants known or suspected to inhibit hepatic metabolism.

Summary

There have been eight new antidepressants marketed in the United States in the last ten years. Selectivity for neuronal reuptake of serotonin (fluoxetine, sertraline, paroxetine, fluvoxamine) has enabled clinicians to treat depression without inducing anticholinergic, orthostatic, and cardiac side effects seen with the older tricyclic antidepressants. This selectivity however only speaks to neuronal reuptake and not the postsynaptic receptor activation. Increased levels of serotonin in the synapse is equally available to receptors mediating the therapeutic response and receptors mediating typical serotonergic side effects of nausea, sexual dysfunction, and insomnia. Thus the effort to design agents that increase serotonergic neurotransmission without activating subtypes of receptors responsible for typical serotonin side effects. This challenge was partially met with the introduction of nefazodone which blocks 5-HT2 postsynaptic receptors thought to mediate sexual side effects and insomnia. The most recent addition to the antidepressant armamentarium, mirtazapine, offers a unique mechanism of action by increasing serotonergic and noradrenergic neurotransmission via presynaptic alpha-2 antagonism while blocking of both 5-HT2 and 5-HT3 receptors. Bupropion offers a non-serotonergic mechanism of action and venlafaxine gives the clinician an option of mixed serotonin/noradrenergic reuptake blockade with a similar side effect profile as the SSRI's. All of these agents clearly represent major advancements in safety and side effect profiles over the TCA's and MAOI's. Future agents will likely demonstrate even further refinement in synaptic specificity as the clinical relevance of receptor subtypes is better characterized.

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August, 1998/ Jacksonville Medicine

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