This chapter will review each of the eight mechanistically defined classes of antidepressants and summarize their safety, tolerability, efficacy, payment and simplicity (STEPS) characteristics specifying which are an advantage and disadvantages for that class. When there are clinically meaningful differences between members of a class, those differences will be highlighted. The goal is to present a synopsis of the clinically relevant pharmacology of these drugs to aid the practitioner in making the best choice for a specific clinically depressed patient, including the usual patient and also particular subtypes of patients.

This approach and information should aid the busy primary-care practitioner in medication selection, particularly considering only 7 minutes are often allocated for a patient visit. Current prescribing data indicates that the serotonin selective reuptake inhibitors (SSRIs) as a class are the antidepressants of first choice for most practitioners, with over 50% of all antidepressant prescriptions being for one of the five SSRIs (Table 8.1). While a review of STEPS is consistent with that general prescribing pattern, a review of the available data does not support the share of the market commanded by fluoxetine and paroxetine. Their numbers suggest that many prescribers do not understand the significant problems posed by the fact that these SSRIs are prone to cause clinically significant drug-drug interactions as a result of their inhibition of specific cytochrome P450 (CYP) enzymes and have no offsetting advantage when compared to SSRIs (ie, citalopram and sertraline) which do not have this disadvantage. Another interesting fact that emerges from the prescribing data is that tertiary amine tricyclic antidepressants (TATCAs) are the second most commonly prescribed class of antidepressants, representing 20% of antidepressant prescriptions. However, a number of the prescriptions for TATCAs may be for indications other than clinical depression (eg, chronic pain, migraine headache).

Nevertheless, the prescribing data indicates that SSRIs and TATCAs account for seven out of ten prescriptions for antidepressants in the United States. Thus, the other six classes account for only 30% of antidepressant prescriptions, suggesting that some clinicians may not be taking full advantage of all the antidepressant options available. The goal of this chapter is to summarize the clinically relevant pharmacology of each class (and individual members within each class as appropriate) to aid the busy practitioner in selecting the best option for a patient whether the patient:

• Has classic clinical depression or a special subtype of clinical depression (eg, atypical or bipolar depression)
• Is a first-time patient or whose depression has proven to be refractory to the first antidepressant selected
• Is medically healthy
• Is on multiple other medications due to intercurrent medical illness.

Mixed Reuptake Inhibitors and Neuroreceptor Blockers

• Tertiary Amine Tricyclic Antidepressants

The chance discovery of the antidepressant properties of TATCAs and the monoamine oxidase inhibitors (MAOIs) began the modern era of antidepressant pharmacology almost 50 years ago.

Advantages

• Efficacy: No single class of antidepressants works in more patients than TATCAs.¹⁰³ Several studies have reported higher response rates in hospitalized, depressed patients treated with the TATCA, clomipramine, than with the SSRIs, citalopram or paroxetine.^55,56 Clinical trials have also shown that TATCAs are effective in patients who have not benefited from a trial of an SSRI.²⁴⁵
• TATCAs are also useful in a variety of conditions other than clinical depression including:
  - Chronic pain
  - Migraine headaches
  - Insomnia.
  For these indications, practitioners often prescribe considerably lower doses which minimize both the adverse effects of these drugs and their overdose risk.
• Payment: Cost can be an advantage of these antidepressants when the choice is between being able to treat or not. That can occur when the patient's insurance does not cover the cost of medication and the patient has limited personal financial resources (Table 7.10).
• Simplicity of dosing: All of the TATCAs can be taken once a day.¹⁰³ Since therapeutic ranges have been established for these antidepressants, therapeutic drug monitoring (TDM) can be used to rationally guide dose adjustments to ensure the attainment of levels which produce the greatest likelihood of antidepressant response with minimal risk of adverse effect.¹⁹¹

Disadvantages

• Safety: TATCAs have a narrow therapeutic index. Even a moderate overdose (ie, taking a 1-to-2-week supply at once) can cause life-threatening cardiotoxicity.¹⁹⁴ This toxicity risk alone is sufficient reason to rule out members of this class as the preferred agent for most patients.
• The multiple actions of TATCAs also mean that these antidepressants can interact pharmacodynamically with a number of other types of drugs including:
  - Sedative hypnotics and alcohol
  - Antihypertensives
  - Antiarrhythmics
  - Anticholinergics.
• Tolerability: By virtue of their effects on various sites of action, these agents cause many different types of adverse effects. Also, the percentage of patients who report adverse effects on these antidepressants is considerably higher than on any other type of antidepressant (Table 6.7). Adverse effects can affect the patient's functioning at work and home. The sedation and orthostatic hypotension have been linked to the increased incidence of falls resulting in hip fractures and automobile accidents in patients taking TATCAs.^132,239 They can also cause or aggravate other medical conditions. For example, patients on chronic treatment with TATCAs also have an increased likelihood of developing periodontal disease as a result of the loss of the bacteriostatic effects of saliva.⁴
• Simplicity of dosing: Their multiple mechanisms of action also mean that most patients cannot be started on the usually effective antidepressant dose of these drugs. Instead, the dose must be gradually titrated up as the patient develops tolerance to the acute adverse effects of the TATCAs. This approach builds in a delay in terms of relief of the patient's depressive episode. Even with a gradual titration, adverse effects generally persist to some degree and can include a trio of adverse effects including:
  - Sedation due to histamine-1 blockade
  - Dry mouth, constipation, urinary retention, and memory impairment due to cholinergic receptor blockade
  - Orthostatic hypotension or dizziness due to alpha-1-adrenergic receptor blockade (Table 6.7).

Summary

Tertiary amine TCAs are not recommended as the antidepressant of first choice for the general patient. However, they can be quite helpful for specific patients but require careful dose adjustment. TDM is a standard of care issue when prescribing these antidepressants due to their narrow therapeutic index and the wide interindividual variability in patients' metabolism.¹⁹¹ However, TDM generally is needed only once early in treatment to determine whether the patient is a usual, slow or rapid TCA metabolizer. The dose can then be adjusted to ensure the attainment of safe and effective drug concentrations. After that, TDM is only done for cause such as a significant change in the patient's health status, the addition or discontinuation of a drug (eg, fluoxetine) that could affect drug metabolism, or to confirm that the patient is being compliant with the prescription.

The principal reasons to use a TATCA are:

• Low acquisition cost (Table 7.10)
• Treatment refractory clinical depression
• Presence of a comorbid medical condition (eg, chronic pain) which is responsive to these medications.

In such instances, imipramine is the generally preferred TATCA for several reasons. First, it is one of the least expensive antidepressants in terms of acquisition cost (Table 7.10). Second, imipramine is converted in the body to the secondary amine TCA (SATCA), desipramine.¹⁸⁸ In the usual patient on imipramine, 50% of the total circulating TCA level will be desipramine. That percentage can be as high as 90% in rapid demethylators. This conversion is an advantage because desipramine has the best tolerability profile of all of the SATCAs due to its selective action on the norepinephrine uptake pump (Figure 6.1). The tolerability profile of desipramine is generally comparable to most newer antidepressants.

Nevertheless, 50% of patients will have over half of their circulating TCA level be imipramine rather than desipramine.¹⁸⁸ These patients will have the adverse effect profile associated with imipramine rather than desipramine (Tables 6.5 and 6.7). The practitioner can use TDM to establish whether the patient achieves predominantly high levels of desipramine or imipramine. In the case of slow demethylators who accumulate high levels of imipramine relative to desipramine, the clinician may decide to switch to desipramine if there are significant tolerability problems with imipramine. Unfortunately, the cost of desipramine is not appreciably less than many of the newer antidepressants (Table 7.10).

Norepinephrine Selective Reuptake Inhibitors

• Secondary Amine Tricyclic Antidepressants

The SATCAs are structural analogues of the TATCAs. While they were not rationally developed in the same way as the SSRIs, they were developed because they had less antihistaminergic and less anticholinergic effects in animal models than did their TATCA forerunners (Figure 6.1). They also do not potently block alpha-1-adrenergic receptors. At usual therapeutic concentrations, these antidepressants only block the norepinephrine uptake pump which is the presumed mechanism mediating their antidepressant efficacy (Table 6.2). Their clinical advantages and disadvantages stem directly from their pharmacology.

Advantages

• Safety: In comparison to TATCAs, these antidepressants have less potential for causing pharmacodynamic drug-drug interactions being limited to those mediated by norepinephrine uptake inhibition (eg, hypertensive crisis when combined with other norepinephrine agonists, particularly MAOIs).
• Tolerability: The discontinuation rate because of adverse effects on SATCAs is comparable to that of newer antidepressants, including SSRIs. Given their different mechanism of action, the adverse effects produced by these antidepressants are different from SSRIs. For that reason, they are an option for the patient who does not tolerate the adverse effects produced by SSRIs (Tables 6.4 and 6.6). The most common adverse effects on SATCAs are those expected for drugs that are indirect noradrenergic agonists, including:
  - Mild increase in blood pressure
  - Increased diaphoresis
  - Tachycardia
  - Tremors
  - Anxiety.⁸⁸
• Efficacy: They are as effective as any other class of antidepressants, and double-blind, crossover studies have shown them to be effective in 50% of patients who do not benefit from treatment with an SSRI.²⁴⁵ They can also be added to SSRIs to augment partial response or to speed response when clinically necessary (ie, hospitalized patient). This strategy produces dual serotonin and norepinephrine uptake inhibition as occurs with high-dose venlafaxine.¹⁷⁷ The difference is that the use of an SSRI and a norepinephrine selective reuptake inhibitor (NSRI) together allows the dose (and hence the degree of uptake inhibition) of either one to be adjusted independently of the other. In contrast, a dual reuptake inhibitor like venlafaxine is analogous to a fixed combination of an SSRI and an NSRI and, thus, the relative ratio of the uptake inhibition of serotonin and norepineprhine is also fixed.
• Simplicity of dosing: All of the SATCAs can be taken once a day. Since therapeutic ranges have been established for these antidepressants, TDM can be used to rationally guide dose adjustment to ensure the attainment of plasma drug levels associated with the greatest likelihood of antidepressant response and the smallest risk of adverse effects.¹⁹¹ TDM should be repeated when these drugs are being used to augment the effect of fluoxetine and paroxetine because of the substantial inhibition of CYP 2D6 caused by these two SSRIs (Table 6.11). When a TCA is added to a patient on fluoxetine, TDM of the TCA should be repeated every 1 to 2 weeks for at least 6 to 8 weeks. The reason for this recommendation is the long half-life of fluoxetine and its active metabolite, norfluoxetine. As their levels build, the functional activity of CYP 2D6 declines resulting in a gradual increase in the levels of the SATCAs.¹⁸⁶ The long half-life of norfluoxetine must also be considered when switching from fluoxetine to an SATCA or other drugs which are substrates of CYP enzymes moderately to substantially inhibited by norfluoxetine (Table 6.10). For a further discussion of this topic, refer to Chapter 10.

Disadvantages

Safety: While SATCAs avoid many of the actions which plague the use of TATCAs, they do inhibit Na+ fast channels at only 10 times their usually effective concentrations.¹⁹⁴ For this reason, these antidepressants can be as lethal as the TATCAs following even a modest overdose.

Payment: Unlike the TATCAs, the cost of the generic versions of the SATCAs are not appreciably less than the newer antidepressants which do not have the same overdose lethality risk (Table 7.10).

Summary

The recommendation is to reserve SATCAs for refractory cases as either monodrug therapy or as a copharmacy strategy (Chapter 11).

When selecting an SATCA, some clinicians prefer nortriptyline because its optimal therapeutic plasma level range has been arguably better established. Others prefer desipramine because its adverse effect profile is arguably somewhat better.

Serotonin Selective Reuptake Inhibitors

This class of antidepressants has become the first choice for most prescribers (Table 8.1). SSRIs were the first class of antidepressant to be successfully developed using the approach of molecular targeting.170 The goal was to produce antidepressants which both potently and selectively inhibited the serotonin uptake pump (Figure 6.1). That goal of selectivity was achieved for all members of this class in terms of neural mechanisms of action (Figure 6.3) but not in terms of CYP enzymes (Figure 6.2). Figure 6.3 explains why members of this class are so similar in terms of their efficacy and adverse effect profile. Figure 6.2 explains why they are so different in terms of their risk of causing pharmacokinetic drug-drug interactions. The advantages and disadvantages of this class in general and specific members in particular are summarized below.

• Advantages

• Good safety in the event of overdose due to a wide therapeutic index.
• Good safety in terms of pharmacodynamically mediated drug-drug interactions which are limited to those mediated by serotonin reuptake inhibition (eg, serotonin syndrome when combined with other serotonin agonists like MAOIs).^{20,25,32,51,66,74,87,104,138,143,144,154,158,200,204,228,232,233}
• Good tolerability profile with virtually all of the adverse effects being consistent with excessive serotonin agonism:
  - Nausea
  - Loose stools
  - Sexual dysfunction (Table 6.6).
• Efficacy in outpatients with clinical depression which is comparable to any other type of antidepressant.¹⁰³
• Efficacy in several anxiety disorders as well as clinical depression (Table 8.2).¹⁰³
• Simplicity in terms of optimal dosing because of their flat dose-antidepressant response curve (ie, in fixed-dose clinical trials, there is not an average increase in response rate at doses above the usually effective, minimum dose). In the case of fluoxetine, paroxetine, and sertraline, the patient can be started at an effective dose without the need for titration. In the case of citalopram and fluvoxamine, the recommended starting dose in their package insert was not found to be an effective dose in their clinical trials and thus an upward titration is recommended (Table 7.11). Also, all of the SSRIs (with the exception of fluvoxamine) are recommended to be taken once a day.

• Disadvantages

Disadvantages of SSRIs can be broken down into two types:

• Those shared by the SSRIs as a group
• Those which are limited to only certain SSRIs.

Although SSRIs have a good tolerability profile, their adverse effects can be rate-limiting for some patients. That is particularly true for the sexual dysfunction caused by these drugs.^145,147 Some patients will discontinue SSRIs during the maintenance phase because of this adverse effect, putting themselves at risk for a recurrent episode. Approaches that have been tried to minimize this adverse effect are further discussed in Chapter 11.

Like any antidepressant class, SSRIs do not treat all patients with clinical depression. They produce a full remission in approximately 50% of patients. Although it is a popular strategy to try a second SSRI in a patient who has not benefited from a trial of a first SSRI, there is no compelling scientific data to support this practice (Chapter 11). Moreover, the pharmacology of these drugs suggest that this strategy should only work in those patients who do not develop adequate plasma levels of the first SSRI.170 Since the SSRIs do not share the same pharmacokinetics (ie, metabolic pathways) (Table 6.9), there is a percentage of the population who will respond to a second SSRI, but the percentage is likely to be small. A switch to a different mechanism of action or an augmentation strategy would seem the more prudent course of action in such cases (Chapter 11).

As discussed in Chapter 6, a serotonin withdrawal syndrome (Table 6.13) can occur following the discontinuation of any SSRI. However, the likelihood and the severity is inversely related to the half-life of the SSRI, being most common on fluvoxamine and paroxetine, less on citalopram and sertraline, and the least on fluoxetine. Generally, this problem can be avoided or minimized by slowly tapering fluvoxamine or paroxetine. When this tactic does not work, the patient can be switched to fluoxetine, which can then be stopped in this manner. This strategy is analogous to using clonazepam to taper patients off of alprazolam (ie, using a long-lived drug to taper patients of a short-lived drug with the same pharmacodynamics).

While the above disadvantages are shared by all SSRIs, there are others which are not. The most important of these non-shared disadvantages is the fact that three SSRIs inhibit one or more drug-metabolizing CYP enzyme(s) to a substantial degree and thus have the potential for causing clinically important pharmacokinetic drug-drug interactions (Figure 6.2 and Table 6.10). These three SSRIs are:

• Fluoxetine
• Fluvoxamine
• Paroxetine.

Substantial inhibition means coadministration of these SSRIs causes a several-fold increase in the levels of the coprescribed "victim" drugs which are dependent on the inhibited CYP enzyme for their clearance. The increased accumulation of the "victim" drug can result in dose-dependent adverse effects that present in a myriad of ways. Given the importance of this topic for medicine in general, it is further discussed in Chapter 10 with case examples of how such drug-drug interactions can present clinically. Briefly, this issue is important for multiple reasons:

• The majority of patients taking an antidepressant are likely to be also on at least one other systemically taken, prescription medication in addition to their antidepressant. Such patients are at risk for a drug-drug interaction.
• Cytochrome P450 enzyme-mediated drug-drug interactions are the most common types of clinically important pharmacokinetic drug-drug interactions.
• The consequence of such interactions may be erroneously attributed to either a sensitivity problem on the part of the patient or even to a worsening of the patient's underlying health problems.
• The inhibition of CYP enzymes conveys no known therapeutic advantage to outweigh the problems posed.

This difference among SSRIs stems from the fact that when they were developed, drug-development scientists were not able to screen for effects on CYP enzymes which mediate the bulk of oxidative drug metabolism.²²³ That is unfortunate because these effects on CYP enzymes unnecessarily complicate the use of fluoxetine, fluvoxamine, and paroxetine in the patient on other medications.

Given these facts, it is somewhat surprising that fluoxetine and paroxetine are still prescribed as frequently as they are (Table 8.1). That is particularly true for fluoxetine since it inhibits multiple CYP enzymes and this inhibition can persist for weeks after it has been discontinued due to the long half-life of the parent drug and its active metabolite, norfluoxetine.¹⁸⁶ Clinicians need to be mindful of this issue when prescribing another drug to a patient who has been on fluoxetine, even weeks after it has been stopped.

Fortunately, the practitioner has two SSRI options which do not carry substantial liability in terms of CYP enzyme inhibition:

• Citalopram
• Sertraline.

These two SSRIs have all the advantages of this class without the disadvantage of CYP enzyme inhibition (Figure 6.2 and Table 6.10).

Summary

The SSRIs for many clinicians have become the treatment of first choice for the majoritiy of their patients with clinical depression due to their safety, tolerability and simplicity when used alone (Table 8.1). All of the members of this class share these advantages.

Members of this class differ substantially with regard to their safety, tolerability and simplicity when used in a patient on other medications (Chapter 10). Three of the SSRIs (fluoxetine, fluvoxamine and paroxetine) produce substantial inhibition of drug metabolizing CYP enzymes.

While citalopram and sertraline share many of the same advantages over the other SSRIs, sertraline:

• Has been much more extensively studied in terms of drug-drug interactions^172,223
• Has Food and Drug Administration (FDA)- approval as indicated for the treatment of several types of anxiety disorders as well as clinical depression (Table 8.2)
• Has a recommended starting dose which is usually effective (Table 7.11).

Serotonin and Norepinephrine Reuptake Inhibitors

Venlafaxine is the only member of this class available in the United States (Table 6.2). Several other drugs in this class are or have been in clinical trials in the United States and other countries. Venlafaxine has dose-dependent, sequential effects on the uptake pumps for serotonin and then norepinephrine (Figure 6.4). At 75 mg/day, venlafaxine is predominantly a serotonin reuptake inhibitor (SRI) like the SSRIs. At 375 mg/day, it produces comparable norepinephrine uptake inhibition to an NSRI such as desipramine. This pharmacology is consistent with the advantages and disadvantages of this antidepressant.

• Advantages

• Good safety in the event of overdose due to a wide therapeutic index.^73,103
• Good safety in terms of pharmacodynamically mediated drug-drug interactions. At lower doses, these are limited to those mediated by serotonin reuptake inhibition (eg, serotonin syndrome when combined with other serotonin agonists like MAOIs). At higher doses, it is also susceptible to the same potential interactions as an NSRI (eg, hypertensive crisis when combined with other norepinephrine agonists, particularly MAOIs).^73,151
• Good safety in terms of pharmacokinetically mediated drug-drug interactions. Like citalopram and sertraline-but in contrast to fluoxetine, fluvoxamine, nefazodone, and paroxetine-venlafaxine does not produce substantial inhibition of any drug metabolizing CYP enzyme at its usually effective, minimum antidepressant dose (Table 6.10).
• Good tolerability profile. At low doses, its adverse effects profile is similar to that of an SSRI:
  - Nausea
  - Loose stools
  - Sexual dysfunction (Tables 6.5 and 6.7).
• At higher doses, it can also produce the same adverse effects as an NSRI:
  - Mild increase in blood pressure
  - Increased diaphoresis
  - Tachycardia
  - Tremors
  - Anxiety (Tables 6.5 and 6.7).^151,171
• Efficacy at 75 mg/day is comparable to any other type of antidepressant in outpatients with clinical depression.¹⁶⁹
• Better efficacy at higher doses. Venlafaxine has an ascending dose-response curve in terms of antidepressant efficacy in contrast to the SSRIs. That is consistent with its sequential effects on serotonin and norepinephrine uptake inhibition (Figure 6.4 and Table 6.2). In essence, a dose increase with venlafaxine is pharmacologically and clinically a built-in augmentation strategy comparable to adding an NSRI such as desipramine to an SSRI such as sertraline.¹⁷⁷ At doses of 225 mg/day, venlafaxine was superior to 40 mg/day of fluoxetine in treating hospitalized patients with clinical depression.⁴⁸ In another study, a dose increase of venlafaxine converted more nonresponders to responders than did a comparable dose increase of fluoxetine.⁵²
• Simplicity in terms of optimal dosing because of the ability to prescribe a usually effective dose (ie, 75 mg/day) from the beginning without the need for dose titration. As a result of the development of the extended release version, venlafaxine can be taken once a day.
  
  
• Disadvantages
  
  
• A somewhat higher incidence of gastrointestinal adverse effects compared to SSRIs (Table 6.7 versus Table 6.5). In particular, nausea appears to be more common when taking venlafaxine than most of the SSRIs.
• Has the same liability for causing sexual dysfunction as the SSRIs.¹⁰³
• Has adrenergically mediated adverse effects at higher doses.^151,171
• Due to its relatively short half-life, venlafaxine has a risk of causing the serotonin withdrawal syndrome (Table 6.13) comparable to that of fluvoxamine and paroxetine.²¹⁹ The incidence and the severity of the serotonin withdrawal syndrome is in part a function of the half-life of the SRI. The half-life of venlafaxine, including that of its active metabolite O-desmethylvenlafaxine, is approximately 12 hours.¹¹⁹ The extended-release formulation of venlafaxine does not change the half-life of venlafaxine and thus does not change the risk of the serotonin withdrawal syndrome following abrupt venlafaxine discontinuation. While this withdrawal state is not as medically serious as the sedative-hypnotic withdrawal syndrome, it is not innocuous and can be quite unpleasant. Some patients may mistake the withdrawal symptoms for a relapse of their depressive illness and can become so dysphoric or agitated that they can experience suicidal ideations.^209,210 It can also mimic mania which may lead to a misdiagnosis and inappropriate treatment.¹²⁵
• Ironically, dosing with venlafaxine can be viewed as either an advantage or a disadvantage. It is an advantage in that the patient can be started on an effective dose (as with SSRIs) at the beginning of treatment. Moreover, there is more compelling evidence to try a higher dose of venlafaxine in a patient who has not benefited from the usual starting dose than is the case with the SSRIs. Nevertheless, the ability to titrate the dose of venlafaxine means that the practitioner may feel less certain about what constitutes an optimal trial of this antidepressant.

• Summary

Venlafaxine is a dual action drug that predominantly acts like an SSRI at low doses and adds the effect of an NSRI at high doses (Table 6.2 and Figure 6.1). Like citalopram and sertraline and in contrast to fluoxetine, fluvoxamine, nefazodone, and paroxetine, it has minimal effects on CYP enzymes (Table 6.10).

Serotonin 2A Receptor Blockade and Weak Serotonin Reuptake Inhibition

This class includes both nefazodone and its precursor, trazodone. More prescriptions are written for trazodone than nefazodone (Table 8.1), most likely reflecting the extensive use of trazodone as a nonhabit-forming sleep aid rather than as an antidepressant. Nefazodone is a structural analogue of trazodone and was designed with the goal of producing a better antidepressant than trazodone.²⁷¹ Specifically, nefazodone is a less potent antihistamine than trazodone. The antihistaminergic properties of trazodone are in part responsible for its popularity as a sleep aid, but cause significant problems with daytime sedation when it is used as an antidepressant. Nefazodone is also a more potent SRI than trazodone. Nevertheless, nefazodone is a much weaker SRI than the SSRIs and venlafaxine.^31,77 Nefazodone likely only produces serotonin (5-HT)-2A inhibition at doses £ 300 mg/day and even at doses of 500 mg/day does not appear to produce the same degree of the serotonin reuptake inhibition as occurs with the SSRIs and venlafaxine at their starting doses.¹⁵⁰ This pharmacology is consistent with the clinical advantages and disadvantages of nefazodone.

• Advantages

• Good safety in overdose due to a wide therapeutic index.²⁰⁸
• It does not disturb sleep physiology and improves the subjective quality of sleep.^10,82
• It appears to cause minimal sexual dysfunction.¹⁰³
• Efficacy in patients with clinical depression and prominent anxiety.⁷¹

• Disadvantages

• Risk of pharmacokinetically mediated drug-drug interactions. Due to the inhibition of the drug metabolizing CYP 3A3/4 enzyme, nefazodone has the potential to cause CYP enzyme-mediated drug-drug interactions like fluoxetine, fluvoxamine, and paroxetine (Table 6.10). Nefazodone-induced inhibition of CYP 3A3/4 can elevate levels of coprescribed drugs dependent on this CYP enzyme for their oxidative metabolism (Table 6.9) and that, in turn, can cause untoward consequences.²²³
• Tolerability problems limit the starting dose of nefazodone.¹⁷¹ The incidence and severity of the following adverse effects increase as a function of the starting dose of nefazodone:
  - Dizziness/lightheadedness
  - Confusion
  - Sedation
  - Gastrointestinal adverse effects (Table 6.7).
  Stepwise dose titration allows the patient to develop some tolerance for these effects. The package insert advises starting nefazodone at 100 mg twice a day for 1 week before increasing in increments of 100 to 200 mg/day at intervals no less than 1 week (Table 7.11). Using this strategy, the dose of nefazodone can be increased as needed to a maximum of 600 mg/day in equally divided doses administered 2 or 3 times per day. Such a titration schedule means more clinician time, more patient education, and more chances that the patient will call back with issues or questions.
• Antidepressant efficacy at its initial starting dose is less robust than with other antidepressants.¹⁰³,¹⁷⁷ There is no compelling evidence that nefazodone has antidepressant efficacy at a dose of 200 mg/day. In fact, doses of 400 to 500 mg/day are required to produce the same degree of antidepressant efficacy as the SSRIs and venlafaxine at their starting doses as measured by the drop in the Hamilton Depression Rating Scale scores in clinical trials.¹⁰³,¹⁷⁷ That suggests that blockade of the 5-HT2A alone is not a robust mechanism for antidepressant efficacy (Table 6.2). As the dose of nefazodone increases, serotonin reuptake inhibition is added to its overall effect. Thus, dose titration is needed when prescribing nefazodone both to improve its tolerability and increase its antidepressant efficacy.
• Simplicity of dosing and difficulty establishing the optimal dose. While the tolerability and efficacy issues described above account for much of the problem in dosing nefazodone, its pharmacokinetics, including its effects on the drug metabolizing CYP 3A, are also important as follows:
  - Nefazodone has nonlinear pharmacokinetics (ie, its plasma levels increase disproportionately to dose increases).¹⁰⁹ A four-fold increase in dose can produce a 14-fold increase in the plasma concentrations of the parent drug.
  - Nefazodone at low doses has low bioavailability (ie, approximately 20% of the dose reaches the systemic circulation) due to high first pass metabolism via the CYP 3A enzyme.¹⁰³
  - Since nefazodone inhibits CYP 3A, it inhibits its own first pass metabolism. For that reason, its bioavailability (ie, the fraction of the dose reaching the systemic circulation) increases as its dose increases. Since the acute adverse effects of nefazodone (as with many drugs) are dose dependent, its nonlinear pharmacokinetics contribute to the higher frequency and severity of adverse effects at higher starting doses.
• The metabolism of nefazodone is also complicated in that the parent drug has a relatively short half-life of approximately 4 hours and is converted into three pharmacologically active metabolites:
  - Hydroxynefazodone
  - Triazoledione
  - Meta-chlorophenylpiperazine (mCPP).¹³⁹
  Hydroxynefazodone has the same in vitro pharmacology as the parent drug and, thus, is believed to have the same clinical pharmacology.²³⁷ The in vitro pharmacology of the other two metabolites differs substantially from that of the parent drug. The triazoledione metabolite is a relatively pure 5-HT2A antagonist and hence its contribution to the antidepressant activity of nefazodone is uncertain.²³⁷ The mCPP metabolite is a 5-HT2C agonist and, when given alone, causes anxiety and restlessness.⁴²,¹⁰⁷ Unusually high accumulation of this metabolite occurs in approximately 7% of Caucasians because its clearance is dependent on the genetically polymorphic CYP 2D6 enzyme.
• The role of CYP 2D6 in the clearance of mCPP takes on additional significance if the patient is being switched from fluoxetine or paroxetine to nefazodone because these two SSRIs substantially inhibit this drug metabolizing CYP enzyme at their usually effective antidepressant dose (Table 6.11). In fact, fluoxetine at a dose of 20 mg/day has been shown to produce approximately an 800% increase in mCPP levels (Table 6.11). Although not formally studied, paroxetine at 20 mg/day would be expected to produce comparable increases in mCPP levels based on studies with other CYP 2D6 substrates (Table 6.11). This action on CYP 2D6-mediated metabolism of mCPP likely accounts for the paradoxical reactions that can occur when switching patients from either fluoxetine or paroxetine to nefazodone.
• Nefazodone typically improves sleep and decreases anxiety; yet, mCPP given alone does the opposite.^42,107 In most patients, mCPP levels are not sufficiently high to offset the effects of the parent drug, but these levels can be high enough in patients who are either genetically deficient in CYP 2D6 or who have been made functionally deficient in CYP 2D6 as a result of treatment with either fluoxetine or paroxetine (Table 6.11). The greater accumulation of this metabolite leads to greater 5-HT2C agonism which can in turn interact pharmacodynamically with persistent serotonin reuptake inhibition produced by fluoxetine's long-lived active metabolite, norfluoxetine.¹⁹⁷

• Summary

All of the above factors cause an apparently greater degree of interpatient variability in terms of response to nefazodone than is true for many of the other new antidepressants. Nevertheless, nefazodone can be a useful antidepressant option for the primary-care practitioner for selected patients such as those who do not tolerate the adverse effects caused by serotonin reuptake inhibition.

Specific Serotonin and Adrenergic Receptor Blockers

Mirtazapine is the only member of this class available in the United States, although its predecessor, mianserin, is available in other countries. The mechanism of action of mirtazapine is unique.^58,59,77 It does not block the uptake pump for any of the biogenic amine neurotransmitters (ie, serotonin, norepinephrine, and dopamine). Instead, mirtazapine blocks histamine-1 receptors (its most potent action) and specific serotonin and adrenergic receptors: the 5-HT2A, 5-HT2C, 5-HT3 and alpha-2-adrenergic receptors (Figure 6.4).^58,59,77 These actions are believed to mediate its antidepressant activity by increasing the release of serotonin and norepinephrine and hence their availability to their respective synaptic receptors. The blockade of the 5-HT2A, 5-HT2C, and 5-HT3 receptors is postulated to result in a selective increase in serotonin availability to the 5-HT1A receptor which has been implicated in the pathophysiology of clinical depression. Regardless of whether this postulated mechanism is correct, mirtazapine has been shown in clinical trials to have antidepressant activity. The pharmacology of mirtazapine is consistent with its beneficial and adverse effects.

• Advantages

• Good safety in overdose.^33,151
• Probably good safety in terms of pharmacokinetically mediated drug-drug interactions based on in vitro studies which show minimal potency for inhibiting any of the major drug-metabolizing CYP enzymes.¹⁷⁸ However, this in vitro prediction should be tested by appropriate in vivo studies.
• Mirtazapine does not cause many of the adverse effects seen with SRIs (Tables 6.5 and 6.7). Specifically, it does not:
  - Cause nausea or loose stools
  - Disturb sleep physiology (actually, it increases sleep efficiency, most likely as a result of its blockade of both histamine-1 and 5-HT2A receptors)77
  - Cause sexual dysfunction.
• Efficacy in patients with prominent anxiety consistent with the fact that mirtazapine blocks the 5-HT2A and 5-HT2C receptors.²⁶⁷
• Efficacy in severely depressed patients. Mirtazapine was found to be superior to fluoxetine in the treatment of hospitalized patients with clinical depression in one double-blind random assignment clinical trial.²⁶⁷
• Simplicity of dosing. Mirtazapine can be started on a dose which is effective in treating clinical depression and is taken once a day.

• Disadvantages

• Safety: There were three cases of agranulocytosis out of 3000 patients in its clinical trial program.^151,178 That incidence was too low to draw a cause and effect conclusion. Postmarketing experience with the drug has not inidicated an unusual number of cases of agranulocytosis in patients on this antidepressant. Nevertheless, the package insert contains a warning that a white blood cell count should be done if a patient on mirtazapine develops signs of fever or infection.
• Tolerability: Consistent with its histamine-1 receptor blockade, mirtazapine is sedating, which can be helpful for the patient with prominent insomnia, but can persist well into the next day consistent with its half-life. Sedation was listed as the reason for early termination in 10% of patients in its double-blind registration studies.²⁰³ Although it may initially seem paradoxical, higher doses of mirtazapine theoretically could decrease its sedative effects. The postulated explanation is that mirtazapine's most potent action is histamine-1 receptor blockade, but at higher levels, mirtazapine also blocks the alpha-2-adrenergic receptor (Figure 6.4). That latter action causes an alerting effect which could counteract the sedation produced by the more potent effect, central histamine blockade (Figure 6.4).
• Consistent with its 5-HT2C blockade, mirtazapine can cause an increase in appetite and weight gain (Table 6.7). These effects can be desirable in specific patients (eg, patients with clinical depression and a concomitant medical problem such as cancer which causes failure to thrive). However, these effects were also listed as the reason for early termination in 8% of patients in the mirtazapine registration studies.²⁰³
• Difficulty establishing the optimal dose. Appropriate double-blind, fixed-dose studies have not been published with mirtazapine. Therefore, the optimal dose has not been established. There is also no rigorous information on what is the appropriate course of action if the patient does not respond to the initial dose.

• Summary

Mirtazapine may never achieve the level of use of some of the other newer antidepressants (Table 8.1). Nevertheless, its unique pharmacology make it a useful antidepressant option for selected patients.

Dopamine and Norepinephrine Reuptake Inhibitors

Bupropion is the only drug in this class labeled for the treatment of clinical depression. However, psychostimulants (eg, methylphenidate) share its pharmacological actions on the dopamine and norepinephrine uptake pumps.

• Advantages

• Better safety in overdose than tricyclic antidepressants, but can cause seizures.⁵⁷
• Risk of pharmacodynamically mediated drug-drug interactions comparable to that of the NSRIs.
• Tolerability profile comparable to an NSRI and distinct from that of an SSRI (Table 6.7 versus Table 6.5). Specifically, bupropion does not disturb sleep physiology. It causes minimal, if any, sexual dysfunction.²¹³ In fact, some practitioners have reported success in using bupropion as an add-on to treat SSRI-induced sexual dysfunction (Chapter 11).
• Efficacy: Consistent with its dopamine and norepinephrine uptake inhibition, bupropion is an activating antidepressant and could be particularly useful in patients with prominent psychomotor retardation (Tables 6.5 and 6.7). Given its dopamine agonistic properties, it could also be uniquely helpful in the patient with Parkinson's disease as well as in patients with attention deficit/hyperactivity disorder.²⁶⁵ Theoretically, bupropion may work in patients who have not benefited from a trial of an SRI since bupropion inhibits norepinephrine as well as dopamine uptake (Table 6.2 and Figure 6.4).³⁰ Recall that NSRIs such as desipramine have been found to work in 50% of patients who do not benefit from SSRIs.²⁴⁵ Nevertheless, no formal studies have been done with bupropion to test this possibility.
• Efficacy: Bupropion has also gained FDA approval as an aid in smoking cessation.²⁷⁴ That is relevant to its use as an antidepressant because smokers have an increased incidence of clinical depression in comparison to nonsmokers and clinical depression impairs the ability to stop smoking. Thus, bupropion could serve a dual role-both to treat the clinical depression and as an aid to stop smoking.

• Disadvantages

• Safety: This antidepressant has a narrow therapeutic index in terms of the dose needed for antidepressant efficacy versus the dose that causes seizures.⁵⁷ The minimum recommended dose for antidepressant response is 300 mg/day and a number of patients will need the maximum recommended dose of 450 mg/day. At doses of 450 mg/day or less, the seizure risk is 0.4%. Doubling the dose to 900 mg/day causes a five-fold increase in the seizure risk.⁵⁷ Given the dose-dependent nature of the seizures, patients who seize on lower doses are probably slow metabolizers who accumulate unusually high levels of bupropion or its three active metabolites.¹⁸⁰ For that reason, TDM is a potential way to further minimize this risk, but TDM with bupropion has not been adequately studied.¹⁸⁰ Particular care should be taken when switching from an antidepressant, which substantially inhibits specific drug-metabolizing CYP enzymes (ie, fluoxetine, fluvoxamine, nefazodone, or paroxetine), to bupropion, or when adding bupropion to the treatment regimen of patients on these antidepressants or on other drugs which substantially inhibit CYP enzymes (eg, macrolides, fluoroquinoles, antifungals, protease inhibitors).
• Uncertainty about its potential to cause pharmacokinetically mediated drug-drug interactions. Bupropion is one of the oldest of the new antidepressants.¹⁹⁶ The clinical trials that originally led to its registration were conducted in the middle to the late 1970s. For that reason, little has been done to formally test the potential effects of bupropion on CYP enzymes. Following case reports,²²⁵ a formal study was done demonstrating that coadministration of bupropion produces a 500% increase in plasma levels of the CYP 2D6 substrate, desipramine. Thus, bupropion produces substantial inhibition of this CYP enzyme comparable to that of fluoxetine and paroxetine. Its potential in vivo effects on other CYP enzymes have not yet been tested. Conversely, case reports suggest that coadministration of fluoxetine can substantially increase the plasma levels of two of the metabolites of bupropion.¹⁸⁰ Again, the CYP enzyme mediating this effect has not been established, but raises the possibility that bupropion could be the target as well as the cause of CYP enzyme-mediated pharmacokinetic drug-drug interactions. That is potentially important due to the dose and hence concentration-dependent nature of the risk of seizures in patients on bupropion.⁵⁷
• Simplicity of dosing: The recommended dosing guidelines with the immediate-release version of bupropion is for 3 times a day administration. Doses should not be administered closer than 4 hours apart.⁵⁷ This schedule was based on the half-life of bupropion and the concern about its seizure risk being related to peak levels of bupropion and/or its metabolites. A sustained-release version of bupropion has been marketed. Unfortunately, this formulation did not achieve the goal of once-a-day dosing. Instead, the recommendation is to give the sustained-release formulation twice a day. Even with this sustained-release version, there is still the recommendation that the dose should not be taken closer than 4 hours apart.
• Difficulty establishing the optimal dose. The optimal dose of bupropion has not been established using fixed-dose trials. When prescribing this antidepressant, the goal is to keep the dose as low as possible to minimize the risk of seizures without compromising therapeutic efficacy.

• Summary

The seizure risk with bupropion, while not as serious as the cardiotoxicity of the TCAs, initially limited its use. Its clinical acceptance has been helped by its labeling as an aid in smoking cessation and by the development of a sustained-release formulation (Table 8.1). Bupropion is a useful option for patients who do not benefit from or tolerate SRIs. It may be the best choice for the patient with comorbid Parkinson's disease since its mechanism of action could potentiate the beneficial effects of L-dopa.¹⁹⁵ Certainly, bupropion should not aggravate Parkinson's disease as can happen with SRIs because the serotonin is an inhibitory afferent into the dopamine neurons in the substantia nigra.^111,174 Given its pharmacological similarities to methylphenidate, bupropion might also be uniquely effective in patients with both residual attention deficit symptoms and clinical depression.

Monoamine Oxidase Inhibitors

These antidepressants are rarely used by psychiatrists, and even less by other clinicians. Nevertheless, they deserve some comments for the sake of completeness.

• Advantages

These antidepressants can be used effectively and safely assuming the prescriber is knowledgeable with regard to proper patient selection and education, and is conscientious with regard to monitoring the course of treatment. They can work in patients whose depressive illness is refractory to other forms of antidepressant pharmacology. For these reasons, they remain valuable antidepressant options.²⁴³

• Disadvantages

Potentially fatal pharmacodynamic drug-drug interactions can occur with MAOIs when combined with a variety of drugs which are serotonin agonists (ie, the serotonin syndrome), norepinephrine agonists, or with foods rich in tyramine (ie, hypertensive crisis).¹⁰³ The major adverse effect that occurs on MAOIs alone is hypotension which can present as fatigue and may mimic worsening of the underlying depressive syndrome. For this reason, the blood pressure should be monitored when using these antidepressants.¹⁰³

• Summary

For patients who need them, the benefits of the MAOIs can outweigh their liabilities.

Summary

This chapter provides a framework for understanding the clinical pharmacology of the various antidepressants and presents the available clinical data in a way that should aid in optimally selecting an antidepressant for a specific patient. The relative advantages and disadvantages are given for the various classes of antidepressants and within classes for individual members when appropriate. Given the pharmacological differences between the various classes of antidepressant, the choice of a specific medication for a specific patient will often be dependent on the symptom cluster.

Another basis for choosing a specific antidepressant is when a patient has not benefited from an earlier trial with an antidepressant (Chapter 11). Faced with this situation, many practitioners chose to try another antidepressant from the same class, particularly in terms of trying a second or even a third SSRI. Given the unfortunate lack of data, the wisdom of this approach is debatable. Based on pharmacology, it would seem more prudent to switch to a class with a different mechanism of action than to stay within the same class (Table 6.2 and Chapter 11).

Finally, there are sufficient differences among the antidepressants that the final decision may come down to personal preference. For example, does the clinician prefer the advantages of a single-mechanism-of-action antidepressant or a dual-mechanism-of-action drug? The former simplifies dosing and the adverse effect profile, but has potential limitations in terms of antidepressant response. Should the patient not benefit from treatment with an antidepressant having a single mechanism of action, dose escalation is less likely to be a useful way of increasing efficacy. In such instances, the practitioner could either switch to an antidepressant with a different mechanism of action or use an augmentation strategy by adding a drug with another mechanism of action (Chapter 11).

In the case of the antidepressant with dual mechanisms of action, the augmentation strategy may be built-in and the approach would be to escalate the dose. However, that means the determination of the optimal dose is more of an issue than is true for an antidepressant with a single mechanism of action. Moreover, multiple mechanisms can contribute to more adverse effects and increase the potential for pharmacodynamic drug-drug interactions. For all of these reasons, the issue of choosing between a single versus a dual mechanism of action antidepressant becomes a matter of personal preference and clinical experience.