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Outpatient Management of Depression 6 - The Rational Basis for the Development and Use of Newer Antidepressants

A decade ago, the practitioner had limited options for treating patients with clinical depression. Those options were:

• Tricyclic antidepressants (TCAs)
• Monoamine oxidase inhibitors (MAOIs)
• Trazodone.

  TABLE 6.1 — Classification of Antidepressants By Putative Mechanism(s) of Action Responsible for Antidepressant Efficacy:* Generic/(Trade) Names By Drug Class

  Mixed Reuptake and Neuroreceptor Antagonists† • Amitriptyline (Elavil) • Amoxapine (Ascendin) • Clomipramine (Anafranil) • Doxepin (Sinequan) • Imipramine (Tofranil-PM) • Trimipramine (Surmontil)

  Norepinephrine Selective Reuptake Inhibitors (NSRIs)‡ • Desipramine (Norpramin) • Maprotiline (Ludiomil) • Nortriptyline (Pamelor, Aventyl) • Protriptyline (Vivactil)

  Serotonin Selective Reuptake Inhibitors (SSRIs) • Citalopram (Celexa) • Fluoxetine (Prozac) • Fluvoxamine (Luvox) • Paroxetine (Paxil) • Sertraline (Zoloft)

  Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)§ • Venlafaxine (Effexor)

  Serotonin-2A (5-HT2A) Receptor Blocker and Weak Serotonin Uptake Inhibitor|| • Nefazodone (Serzone) • Trazodone (Desyrel)

  Serotonin (5-HT2A and 2C) and a-2 Norepinephrine Receptor Blocker|| • Mirtazapine (Remeron)

  Dopamine and Norepinephrine Reuptake Inhibitors • Bupropion (Wellbutrin, Wellbutrin SR, Zyban Sustained-Release)

  Monoamine Oxidase Inhibitors (MAOIs)¶ • Phenelzine (Nardil) • Tranylcypromine (Parnate)

  Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin).

  * The presumptive mechanism of action for each drug is based on the preclinical pharmacology of the drug and the fact that it and/or its active metabolites reach sufficient concentration in vivo to affect this site of action, given its in vitro potency. † All of these drugs are tertiary amine tricyclic antidepressants (TCAs) except amoxapine. ‡ All of these drugs are secondary amine TCAs except maprotiline. There are nontricyclic NSRIs available in other parts of the world, such as reboxetine. Those drugs share the ability to inhibit norepinephrine uptake with the secondary amine TCAs and maprotiline but do not carry the risk of serious toxicity even after a substantial overdose. § At present, venlafaxine is the only member of this class available in the United States although several others are in various stages of clinical testing. || Both nefazodone and mirtazapine also have other mechanisms of action that are engaged at concentrations which occur under clinically relevant dosing guidelines (see Table 6.2). ¶ Only irreversible and nonselective monoamine oxidase inhibitors (MAOIs) are available in the United States, but selective and reversible MAOIs are marketed elsewhere in the world.

The practitioner now has 22 different antidepressants from eight different mechanistically defined classes of antidepressants (Table 6.1).

This chapter will explain how this mechanistically based classification system can be used to conceptualize the clinical relevance of the various antidepressants available to treat patients. Thus, this chapter can be used as a reference when reading subsequent chapters. The goal is to summarize the knowledge necessary to:

• Predict the clinical effects of different antidepressants
• Choose a specific antidepressant for a specific patient based on those predicted effects
• Rationally think about sequential treatment options for the patient who has not benefited from a trial of a specific type of antidepressant
• Anticipate potential drug-drug interactions when using a specific antidepressant in combination with other medications.

Rational Drug Development

Drug development in psychiatry has evolved from a process based on chance to one based on molecularly targeting specific sites of action in the central nervous system (CNS) (ie, specific neuroreceptors or neuronal uptake pumps for neurotransmitters). The goal of such development is to affect only mechanisms mediating antidepressant efficacy while simultaneously avoiding affects on other mechanisms which mediate tolerability and/or safety problems.^181,183,236 The intent is to produce antidepressants which are:

• Safer
• Better tolerated
• Less likely to interact with other coprescribed drugs than was the case with the older agents (ie, TCAs, MAOIs and trazodone).

The success of this approach is underscored by the fact that the risk of the clinical depression is now clearly worse than the risk of the treatment such that even a hint of clinical depression may be sufficient to warrant an empirical trial of a newer antidepressant. That explains the substantial expansion in the use of antidepressants that has occurred over the last decade.¹⁶⁴

The eight functional pharmacologic classes of antidepressants based on their presumed mechanism(s) of antidepressant action are listed in Table 6.1. Table 6.2 indicates which mechanisms of action are engaged by these different antidepressants at their usually effective antidepressant dose. In Table 6.3, the clinical consequences that occur as a result of blocking specific sites of action are listed. By using Tables 6.2 and 6.3 in combination, the clinician can determine what specific effects a particular antidepressant will produce in the usual patient on the usual antidepressant dose. Tables 6.4 through 6.7 summarize the usual adverse effects produced by these various drugs based on the results of double-blind, placebo-controlled clinical trials. These tables will serve as reference points throughout the remainder of the book.

Relationship Between Pharmacodynamics, Pharmacokinetics and Interindividual Variability

The nature and magnitude of a drug's effect is determined by its:

• Site of action
• Binding affinity for that site
• Concentration at the site.¹⁷⁰

These factors determine the "usual" effect of the drug in the "usual" patient on the "usual" dose as determined in a clinical trial. However, all patients are not "usual" due to interindividual variability caused by factors such as:

• Age
• Genetics
• Gender
• Intercurrent diseases affecting organ function
• Concomitant drug therapy
• Social habits (eg, smoking).¹³¹

The clinician must take into account how a specific patient may differ from the "usual" patient in a clinical trial when selecting and dosing a drug. The three important variables determining the effect of a drug on a patient are summarized in the following equation:

(Equation 1)

This equation can be restated as follows:

(Equation 2)

The first two terms in this equation explain the relationship between pharmacodynamics and pharmacokinetics. The first term determines the nature of the drug's effect and how much drug is needed at the site of action to engage that site to a clinically meaningful extent in the usual patient. The second term in the equation determines the magnitude of the drug's effect by determining how much drug reaches the site of action. The third term explains how interindividual variability in the patient can shift the dose-response curve (ie, greater or lesser effect than usually expected relative to the dose prescribed).

TABLE 6.2 — Comparison of the Mechanisms of Action of Antidepressants*
Mechanism of Action†	Ami-triptyline	Desi-pramine	Ser-traline	Ven-lafaxine	Nefa-zodone	Mir-tazapine	Bupro-pion	Tranylcy- promine
Histamine-1 receptor blockade	Yes‡	No	No	No	No	Yes‡	No	No
Acetylcholine receptor blockade	Yes	No	No	No	No	No	No	No
NE uptake inhibition	Yes	Yes	No	Yes	No	No	Yes	No
5-HT2A receptor blockade	Yes	No	No	No	Yes‡	Yes	No	No
-1 NE receptor blockade	Yes	No	No	No	Yes	No	No	No
5-HT uptake inhibition	Yes	No	Yes	Yes‡	Yes	No	No	No
-2 NE receptor blockade	No	No	No	No	No	Yes	No	No
5-HT2C receptor blockade	No	No	No	No	No	Yes	No	No
5-HT3 receptor blockade	No	No	No	No	No	Yes	No	No
Fast Na+ channels inhibition	No	No	No	No	No	No	No	No
Dopamine uptake inhibition	No	No	No	No	No	No	Yes	No
Monoamine oxidase inhibition	No	No	No	No	No	No	No	Yes
Abbreviations: NE, norepinephrine; 5-HT, 5-hydroxytryptamine (serotonin); Na+, sodium.
* Amitriptyline represents the mixed reuptake and neuroreceptor blocking class, desipramine—norepinephrine selective reuptake inhibitors, sertraline—serotonin selective reuptake inhibitors, venlafaxine—serotonin and norepinephrine reuptake inhibitors, nefazodone—5-HT2A and weak serotonin uptake inhibitors and mirtazapine—specific serotonin and norepinephrine receptor blockers, bupropion—dopamine and norepinephrine uptake inhibitor. Monoamine oxidase inhibitors (MAOIs) do not directly share any mechanism of action with other classes of antidepressants, although they affect dopamine, norepinephrine, and serotonin neurotransmission via their effects on monoamine oxidase. † The effects of these various antidepressants are listed using a binary (yes/no) approach for simplicity and clinical relevance. The issue for clinician and patient is whether the effect is expected under usual dosing conditions. A “yes” means that the usual patient on the usually effective antidepressant dose of the drug achieves concentrations of parent drug and/or metabolites that should engage that specific target to a physiologically/clinically significant extent given the in vitro affinity of the parent drug and/or metabolites for that target. If the affinity for another target is within an order of magnitude of desired target, then that target is likely also affected to a physiologically relevant degree. For example, under usual dosing conditions, amitriptyline achieves concentrations that engage the norepinephrine uptake pump. At such concentrations, it also substantially blocks histamine-1 and muscarinic acetylcholine receptors since it has even more affinity for those targets than it does for the norepinephrine uptake pump. Since the binding affinity of amitriptyline for the 5-HT2A and a-1 norepinephrine receptors and the serotonin uptake pump are within an order of magnitude of its affinity for the norepinephrine uptake pump, amitriptyline at usual therapeutic concentrations for antidepressant efficacy will also affect those targets. On the other hand, amitriptyline will not typically affect Na+ fast channels at usual therapeutic concentrations because there is more than an order of magnitude (ie, > ten-fold) separation between its effects on this target versus norepinephrine uptake inhibition. Nevertheless, an amitriptyline overdose can result in concentrations which engage this target. That fact accounts for the narrow therapeutic index of the tricyclic antidepressants (TCAs) and is the reason therapeutic drug monitoring to detect unusually slow clearance is a standard of care when using such drugs. ‡ Most potent effect (ie, effect that occurs at lowest concentration). See previous footnote for further explanation.
The binding affinities of all drugs listed in the table (except mirtazapine) are based on the work of Cusack et al and Bolden-Watson and Richelson. Information on the binding affinities of mirtazapine (including affinities for 5-HT2A and 5-HT3 receptors) is based on the work of de Boer et al. Although the publications by the Richelson group did not include values for the 5-HT2A and 5-HT3 receptors or the other antidepressants, Elliot Richelson of the Mayo Clinic in Jacksonville, Florida (personal communication) confirmed that the other antidepressants would be unlikely to affect these receptors under usual dosing conditions.
Adapted from: Bolden-Watson C, Richelson E. Life Sci. 1993;52:1023-1029; Cusack B, et al. Psychopharmacology. 1994;114:559-565; de Boer T, et al. Neuropharmacology. 1988;27:399-408; de Boer T, et al. Hum Psychopharmacol. 1995;10:107S-118S; and Frazer A. J Clin Psychiatry. 1997;58(suppl 6):9-25.

The following equation explains how dose is related to the drug concentration, which is the second term in Equation 2:

(Equation 3)

Concentration = dosing rate (mg/day)/clearance (mL/min)

In other words, the concentration achieved in a specific patient is determined by the dosage of the drug the patient is taking relative to the patient's ability to clear the drug from the body.

Pharmacodynamic Principles Central to Understanding Antidepressant Options

As a general rule, most drugs (including antidepressants) act as antagonists at their site(s) of action. Table 6.3 shows the effects produced by blocking a specific neural mechanism. If a drug were to act as an agonist at a specific site, then it would produce the opposite effect to that shown in Table 6.3.

Antidepressants which block neuronal uptake pumps for serotonin, norepinephrine and dopamine act as indirect agonists by increasing the concentration of these neurotransmitters at their respective receptors. Thus, the clinical effects of uptake inhibitors will be the opposite of those shown in Table 6.3. For example, by increasing the availability of serotonin or 5-hydroxytryptamine (5-HT) receptors, serotonin reuptake inhibitors (SRIs) act as indirect agonists at the following receptors:

• 5-HT2A
• 5-HT2C
• 5-HT3.⁸³

As outlined in Table 6.2, SRIs include all of the serotonin selective reuptake inhibitors (SSRIs) and the serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine.

The above helps to explain why all SRIs can:

• Decrease rapid eye movement (REM) sleep and shift sleep architecture from restorative, deep stage IV sleep to light stage I sleep due to indirect stimulation of the 5-HT2A receptor^{9,159,217,226,230}
• Decrease appetite and cause motor restlessness due to indirect stimulation of the 5-HT2C receptor²³⁸
• Cause nausea by indirect stimulation of the 5-HT3 receptor.⁸³

The indirect stimulation of one of these 5-HT receptors (or perhaps another) likely mediates the sexual dysfunction seen with all SSRIs, including:

• Anorgasmia
• Delayed ejaculation
• Decrease libido.^145,147

TABLE 6.7 — The Most Likely Specific Adverse Effects on Specific Antidepressants Above and Beyond the Parallel Placebo Condition (Percentage on Drug Minus Percentage on Placebo Based on Registration Studies)*†
Antidepressant	> 7.5%	> 10%	> 15%	> 20%	> 25%	> 30%	> 35%	> 40%	> 45%
Bupropion	Dry mouth Constipation Sweating	Tremors Nervousness	—	—	—	—	—	—	—
Imipramine	Fatigue	Tremors Sweating	Constipation	Dizziness	—	—	—	—	Dry mouth
Mirtazapine	—	Weight gain Dry mouth	Appetite	—		—	Drowsiness	—	—
Nefazodone	Confusion Respiratory	Drowsiness Vision disturbance Nausea Dry mouth	—	Dizziness	—	—	—	—	—
Venlafaxine-IR	Insomnia Anorexia Constipation Sweating	Nervousness Dizziness Dry mouth	Drowsiness	—	Nausea	—	—	—	—
Venlafaxine-XR	Nervousness Drowsiness	Sweating Dizziness	—	Nausea		—	—	—	—
Abbreviations: IR, immediate release; XR, extended release.
* This table is based on Table 6.5. † The above adverse effect data come from product labeling as opposed to head-to-head trials. Such data may not necessarily reflect the actual rate of these adverse effects in clinical practice or the actual differences between these various drugs.

The reverse logic explains the effects of other antidepressants. For example, nefazodone and mirtazapine can increase stage IV sleep most likely by blocking the 5-HT2A receptor.²¹⁴ Mirtazapine can also increase appetite and decrease motor restlessness by blocking the 5-HT2C receptor and can treat nausea by blocking the 5-HT3 receptor.⁸³ Trazodone is also a 5-HT2A blocker which is consistent with its widespread use as an antidote for the sleep disturbances that occur in some patients on SRIs.¹⁵⁵ In addition, the effects of mirtazapine and trazodone on sleep are further amplified by their shared ability to block central histamine receptors.^{31,54,58,59,77} The fact that nefazodone and mirtazapine cause minimal, if any, sexual dysfunction is consistent with their minimal inhibition of serotonin uptake perhaps coupled with their blockade of the 5-HT2A receptor.^{31,54,58,59,77} These issues are further discussed in Chapters 8 and 11.

Some antidepressants, like SSRIs, directly affect only one site of action at the usual concentration achieved under therapeutic dosing conditions; other antidepressants affect more than one site. As shown in Table 6.1, venlafaxine and nefazodone affect more than one site; the same is also true for bupropion. Tertiary amine tricyclic antidepressants (TATCAs), such as amitriptyline, affect six different targets at usual therapeutic concentrations.

Drugs which affect more than one site of action often act sequentially (ie, as their concentration increases, they affect additional targets) which explains why these drugs exhibit different effects to different degrees at different doses. Figure 6.1 illustrates this pharmacologic principle: amitriptyline can affect multiple sites of action, in contrast to desipramine and sertraline which are selective for a single (although different) neural site of action. Parenthetically, some SSRIs (eg, fluoxetine) affect cytochrome P450 (CYP) enzymes, which are non-neural sites of action with important pharmacokinetic drug-drug interaction consequences (Figure 6.2). This issue is discussed in greater detail in Chapters 8 and 10.

FIGURE 6.1 — Relative Potency for Different Sites of Action for Three Different Types of Antidepressants: Amitriptyline, Desipramine, and Sertraline

Abbreviations: NE, norepinephrine; SE, serotonin; DA, dopamine; H-1, histamine; ACh, acetylcholine; 5-HT, 5-hydroxytryptamine (serotonin).

Based on data from: Bolden-Watson C, Richelson E. Life Sci. 1993;52:1023-1029 and Cusack B, et al. Psychopharmacology. 1994;114:559-565.

FIGURE 6.2 — In Vivo Profile of SSRIs on SE Uptake Inhibition Versus CYP Enzyme Inhibition

Abbreviations: SSRI, serotonin selective reuptake inhibitor; SE, serotonin; CYP, cytochrome P450 enzyme.

Based on data from: Shad MU, Preskorn SH. In: Levy R, et al, eds. Philadelphia, Pa: Lippincott, Williams &Wilkins. In press.

The multiple actions of the TATCAs (eg, amitriptyline, doxepin, imipramine, trimipramine), like the effects of some newer antidepressants on CYP enzymes, are now generally considered to be a clinical disadvantage.^170,171 To understand the pharmacology of amitriptyline, imagine the number of single mechanism of action drugs the patient would have to take to achieve all the effects that can be obtained with amitriptyline alone (Table 6.8). At low doses (or concentrations), amitriptyline blocks histamine receptors; at higher doses, amitriptyline sequentially blocks the other sites as illustrated in Figure 6.1 and enumerated in Tables 6.2 and 6.3.

The pharmacology of TATCAs such as amitriptyline served as the blueprint for what effects newer antidepressants should and should not have and, thus, amitriptyline also served as the basis for the classification system presented in Table 6.1.^181,236 Table 6.2 lists specific neural mechanisms in the order in which they are affected by amitriptyline; the most potent mechanism (histamine receptor blockade) being listed at the top and the least potent (inhibition of sodium [Na+] fast channels) listed near the bottom. The latter action occurs at drug concentrations approximately 10 times higher than those needed to block neural uptake pumps for norepinephrine and serotonin. While inhibition of neural uptake pumps for these chemical transmitters is believed to be responsible for the antidepressant efficacy of the TATCAs, the inhibition of Na+ fast channels results in slowing of intracardiac conduction and hence can cause fatal arrhythmias. The potency of TATCAs for this site of action explains why only modest overdoses can be lethal in suicide attempts.¹⁹⁴

One goal of rational drug development with regard to newer antidepressants was to widen the therapeutic index by avoiding the inhibition of Na+ fast channels.¹⁷⁰ Another goal was to avoid the adverse effects of TATCAs, which can be troublesome even if not seriously toxic. For example, all of the SSRIs share with TATCAs the ability to block the neural uptake of serotonin, but do not share the ability to block histamine, muscarinic cholinergic and alpha-1-adrenergic receptors. For this reason, SSRIs avoid the adverse effects of sedation, constipation and orthostatic hypotension which plague the users of TATCAs (Figure 6.3). Other newer antidepressants engage other neural targets at concentrations achieved under clinically relevant dosing conditions (Figure 6.4 and Table 6.2).

Pharmacodynamic Drug-Drug Interactions

The clinician can also use Tables 6.2 and 6.3 to anticipate what type of pharmacodynamically mediated drug interactions are likely to occur when a specific type of antidepressant is used in combination with other agents. For example, all SSRIs can interact with MAOIs to cause the serotonin syndrome.^{51,87,144,158,228,233} Similarly, all antidepressants that centrally block the histamine receptor potentiate the adverse cognitive-motor effects of alcohol.^140,151,192 All antidepressants that block the alpha-1-adrenergic receptor have the potential to aggravate the orthostatic hypotension caused by other antihypertensive medications.^103,192

FIGURE 6.3 — Relative Potency for Different Sites of Action for the Various Members of the SSRI Class of Antidepressants

Abbreviations: SSRI, serotonin selective reuptake inhibitor; 5-HT, 5-hydroxytryptamine (serotonin); NE, norepinephrine; DA, dopamine; H-1, histamine; ACh, acetylcholine.

Based on data from: Hyttel J. Nord J Psychiatry. 1993;47(suppl 30)5-12.

FIGURE 6.4 — Relative Potency for Different Sites of Action for Non-SSRI Antidepressants: Bupropion, Imipramine, Mirtazapine, Nefazodone, and Venlafaxine

Abbreviations: SE, serotonin; NE, norepinephrine; DA, dopamine; H-1, histamine; ACh, acetylcholine; 5-HT, 5-hydroxytryptamine (serotonin).

Based on data from: Bolden-Watson C, Richelson E. Life Sci. 1993;52:1023-1029; Cusack B, et al. Psychopharmacology. 1994;114:559-565; de Boer T, et al. Neuropharmacology. 1988;27:399-408; and de Boer T, et al. Hum Psychopharmacol. 1995;10:107S-118S.

A Non-neural Target: Cytochrome P450 Enzymes

As mentioned earlier, CYP enzymes can be a site of action for a drug.^93,94 Although CYP enzymes may be unintended and unnecessary targets for an antidepressant, they are clinically important because inhibition of these enzymes (Figure 6.2) carries with it the liability for causing specific types of pharmacokinetic drug-drug interactions.

While newer antidepressants were designed to selectively affect specific neural targets (eg, a specific intake pump) and avoid others (eg, muscarinic cholinergic receptors), they were not rationally designed to avoid the inhibition of CYP enzymes. The reason is simple: the newer antidepressants were developed before the isolation of the first CYP enzyme in 1988.⁸⁴ In fact, the newer antidepressants were synthesized and screened against targets known in the mid- to late 1970s. Since it is not possible to avoid "hitting" what is not known, some of the new antidepressants have subsequently been found to unintentionally inhibit one or more drug-metabolizing CYP enzyme to a clinically meaningful degree (Figure 6.2 and Table 6.6).

The five major CYP enzymes mediating oxidative drug metabolism (in order of importance) are:

• CYP 3A3/4
• CYP 2D6
• CYP 1A2
• CYP 2C9/10
• CYP 2C19.^93,94,223

Of these, CYP 3A3/4 and CYP 2D6 are responsible for approximately 50% and 30% of known oxidative drug metabolism, respectively.^115,255

Since the isolation of the first CYP enzyme, knowledge in this area has exploded. Drugs such as terfenadine (Seldane) and mibefradil (Posicor) have been withdrawn from the US market as a result of CYP enzyme-mediated drug interactions. Testing for effects on CYP enzymes is now part of rational drug development and is done to avoid developing new agents that inadvertently inhibit these enzymes.¹⁷⁰ Similar testing is also being done on currently available drugs to determine which CYP enzymes are important for their clearance and whether they induce or inhibit specific CYP enzymes.

Such testing is generally done in two steps:

• First, an in vitro approach is used to determine the ability of a CYP enzyme to metabolize a drug (Table 6.9) and conversely to estimate the potential (ie, potency) for a new candidate drug to inhibit a CYP enzyme
• Second, formal drug-drug interaction studies in humans are performed to establish whether clinically meaningful inhibition occurs under usual dosing conditions (Tables 6.10 and 6.11).^93,94,223

This technology thus yields two sets of complementary data that can be used to predict clinically meaningful CYP enzyme-mediated drug interactions, as illustrated in Figure 6.5:

• The first set of data determine whether a drug inhibits a specific CYP enzyme and to what extent under clinically relevant dosing conditions.
• The second set of data establish which drugs are dependent on which CYP enzyme for oxidative metabolism.

Table 6.10 summarizes the effects of newer antidepressants on these five CYP enzymes. Table 6.9 lists the drugs known to be metabolized by these CYP enzymes.

The principal distinguishing characteristic among the various SSRIs is their differential effects on CYP enzymes.^{93,94,170,223} While all five drugs block the neural uptake of serotonin and avoid effects on other neural targets, they differ substantially with regard to their effects on CYP enzymes. Fluoxetine, fluvoxamine and paroxetine all inhibit one or more CYP enzymes to a clinically significant degree at their usually effective antidepressant dose, whereas citalopram and sertraline do not. Since the inhibition of CYP enzymes conveys no clinical benefit to the best of our knowledge, the absence of substantial effects on CYP enzymes conveys a distinct advantage for citalopram and sertraline relative to other SSRIs.

Pharmacodynamic Principles Central to Understanding Antidepressant Options

In general, all antidepressants are similar with regard to a number of pharmacokinetic parameters (ie, absorption and distribution). The clinically important pharmacokinetic differences among these drugs include:

• Which CYP enzymes mediate their metabolism? This information is listed in Table 6.9 and can be used to predict CYP enzyme-mediated drug-drug interactions in which the antidepressant is the target rather than the cause of the interaction.
• Some antidepressants (eg, nefazodone) are converted into metabolites with clinically important effects.^103,139
• Difference in half-lives of the various antidepressants.^103,176 This issue is arguably the single most important pharmacokinetic difference among antidepressants beyond their effect on CYP enzymes.

TABLE 6.9 — Effect of Cytochrome P450 Enzymes on Specific Drugs (ie, Metabolism)
CYP 1A2
Antidepressants	Amitriptyline, clomipramine, imipramine
Antipsychotics	Clozapine,* olanzapine,* thioridazine*
-Blockers	Propanolol
Opiates	Methadone*
Miscellaneous	Caffeine,* paracetamol, tacrine,* theophylline,* R-warfarin*
CYP 2C9/10
Miscellaneous	Phenytoin,* S-warfarin,* tolbutamide*
CYP 2C19
Antidepressants	Citalopram,* clomipramine, imipramine
Barbiturates	Hexobarbital, mephobarbital, S-mephenytoin*
-Blockers	Propranolol
Benzodiazepines	Diazepam
CYP 2D6
Antiarrhythmics	Encainide,* flecainide,* mexiletine, propafenone
Antipsychotics	Haloperidol (minor), molindone, perphenazine,* risperidone,* thioridazine (minor)
-Blockers	Alprenolol, bufuralol, metoprolol,* propranolol, timolol
Miscellaneous	Debrisoquine,* 4-hydroxyamphetamine, perhexiline,* phenformin, sparteine*
Opiates	Codeine,* dextromethorphan,* ethylmorphine
SSRIs	Fluoxetine, N-desmethylcitalopram, paroxetine*
TCAs	Amitriptyline,* clomipramine,* desipramine,* imipramine,* N-desmethylclomipramine
Other antidepressants	Venlafaxine,* mCPP metabolite of nefazodone* and trazodone*
CYP 3A3/4
Analgesics	Acetaminophen, alfentanil
Antiarrhythmics	Amiodarone, disopyramide, lidocaine, propafenone, quinidine
Anticonvulsants	Carbamazepine,* ethosuximide
Antidepressants	Amitriptyline, clomipramine, imipramine, nefazodone,* sertraline,* O-desmethylvenlafaxine*
CYP 3A3/4
Antiestrogens	Docetaxel, paclitaxel, tamoxifen*
Antihistamines	Astemizole,* loratadine,* terfenadine*
Antipsychotics	Quetiapine,* clozapine
Benzodiazepines	Alprazolam,* clonazepam, diazepam, midazolam,* triazolam*
Calcium channel blockers	Diltiazem,* felodipine,* minodipine, nicardipine, nifedipine,* niludipine, nisoldipine, nitrendipine, verapamil*
Immunosuppressants	Cyclosporine,* tacrolimus (FK506-macrolide)
Local anesthetics	Cocaine, lidocaine
Macrolide antibiotics	Clarithromycin, erythromycin, triacetyloleandomycin
Steroids	Androstenedione, cortisol,* dehydro-3-epiandrosterone, dexamethasone, estrogen,* testosterone,* estradiol,* ethinylestradiol, progesterone
Miscellaneous	Benzphetamine, cisapride,* dapsone,* lovastatin, omeprazole (sulfonation)
Abbreviations: CYP, cytochrome P450 enzyme; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants; mCPP, meta-chlorophenylpiperazine.
* Principal CYP enzyme.
NOTE: Such lists are not comprehensive since the CYP enzyme(s) responsible for biotransformation is known for only approximately 20% of marketed drugs. The reason is that many drugs were developed before the necessary knowledge and technology existed. Some drugs are listed under more than one CYP enzyme. That does not necessarily mean that each of these enzymes contributes equally to the elimination of the drug. One enzyme may be principally responsible based on substrate affinity and capacity and abundance of the enzyme.
Adapted from: Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. Caddo, Okla: Professional Communications, Inc; 1996:158-159.

The Clinical Importance of Half-Life

Half-life is the time needed to decrease plasma drug concentration by 50% after drug discontinuation. As a general rule, steady-state is achieved when the drug has been administered at a stable dose for a period equal to 5 times its half-life. The same is true for washout following drug discontinuation. Thus, half-life is an important determinant of how long it will take to achieve maximal drug effect once started, and how long the effect will persist once the drug is stopped.¹⁷⁵

The optimal dosing schedule for antidepressants is virtually never established empirically. Instead, the half-life is almost always used to determine the dosage schedule for a drug in the clinical trials required for its registration. That is done to maximize the chance for showing acceptable efficacy and tolerability. Since the FDA requires that the dosing schedules in the package inserts be based on the schedules used in the clinical trials, that means the half-life of the drug determines the recommended dosing schedule contained in the package insert.

In general, the half-life of most antidepressants is approximately 24 hours. For this reason, most of these drugs were administered once a day during clinical trials.^103,176 For the same reason, steady-state and virtually complete washout are achieved within 5 days of starting or stopping most of the newer antidepressants.

A few antidepressants have half-lives shorter than 24 hours including:

• Bupropion
• Fluvoxamine
• Nefazodone
• Venlafaxine.¹⁰³

For this reason, these drugs were tested using either a twice-a-day or even a three-times-a-day schedule during registration trials.

Since frequent dosing schedules are perceived as a disadvantage, extended-release formulations of bupropion and venlafaxine have been developed. Although the half-life of the drug remains the same, the extended absorption of these formulations produce reasonably stable blood levels of the drug over a more prolonged dosing interval.

The only antidepressant with a half-life substantially in excess of 24 hours is fluoxetine. The parent drug has a half-life of 2 to 4 days and norfluoxetine, its active metabolite, has a half-life of 7 to 15 days.¹⁷⁰ This half-life is even longer at doses above 20 mg/day in physically healthy older patients.¹⁹⁷ These half-lives mean that fluoxetine is essentially an oral depot drug that requires more than a month to:

• Reach steady-state once started
• Clear once stopped.

The practitioner must realize that once fluoxetine has achieved steady state, its effects cannot rapidly be reversed and that there will be an appreciable interval after its discontinuation during which fluoxetine (or norfluoxetine) can affect the response of the patient to other drug treatment, either through blockade of the serotonin uptake pump or through the inhibition of specific CYP enzymes (Chapter 10).

Antidepressant Withdrawal Syndrome

A general rule in clinical psychopharmacology is that the brain adapts to the presence of drugs. For example, uptake inhibitors produce downregulation of the receptors for the specific neurotransmitter whose uptake pump has been inhibited (eg, some serotonin receptors in the case of serotonin uptake inhibitors and beta-adrenergic receptors in the case of norepinephrine uptake inhibitors).¹⁷ In fact, such downregulation has been postulated to mediate the antidepressant efficacy of these drugs.

Such downregulation likely also mediates the withdrawal syndromes that can be seen when some of these antidepressants are abruptly stopped. Anticholinergic withdrawal syndrome can be seen when high-potency muscarinic cholinergic receptor blockers (ie, TATCAs) are abruptly stopped. The symptoms of anticholinergic withdrawal syndromes (sometimes called "cholinergic rebound") are listed in Table 6.12.

The SRI withdrawal syndrome can be seen when serotonin uptake inhibitors are stopped (Table 6.13).^{26, 38, 53, 78, 125, 126, 133, 198, 209, 210, 219, 229, 272} The SRI withdrawal syndrome is more clinically important than is the anticholinergic withdrawal syndrome because it is more common, more severe, and more easily misdiagnosed. It can mimic worsening of the underlying depression or even as the emergence of mania. Such misdiagnosis can lead to inappropriate treatment.^{38,125,126,128,209,210} The diagnosis is confirmed when the symptoms remit (typically within 12 to 24 hours) after restarting the SRI. After that, a more gradual taper can be done to wean the patient off the drug.

Risk factors for antidepressant withdrawal syndromes are:

• Time on drug
• Potency of drug
• Half-life of drug.^53,198,209

As mentioned above, the shorter the half-life, the more likely the drug will wash out before the brain has had an opportunity to re-equilibrate (eg, upregulation of receptors) and, hence, the more likely that withdrawal symptoms will occur after drug discontinuation. Thus, the order of likelihood of the SRI withdrawal syndrome following abrupt discontinuation of an SRI is: fluvoxamine, paroxetine, and venlafaxine > citalopram and sertraline, > fluoxetine.^{53,198,209,219} The SRI withdrawal syndrome rarely occurs after nefazodone discontinuation.

Paroxetine and nefazodone deserve additional comment since the risk of an SRI withdrawal syndrome does not appear to correlate with their half-lives. In the case of paroxetine, the incidence of the SRI withdrawal syndrome is higher than might be expected for a drug with a half-life of 24 hours. However, the half-life of paroxetine is a function of its plasma levels. At low levels, the half-life of paroxetine is only 10 hours (ie, shortest of all the SRIs) due to the fact that it is preferentially metabolized by CYP 2D6 at low levels.^93,94,170 CYP 2D6 is a high-affinity, but low-capacity, enzyme for the metabolism of paroxetine and is inhibited by paroxetine. For this reason, this CYP enzyme becomes saturated at therapeutic levels of paroxetine (ie, autoinhibition), and CYP 3A3/4 becomes the primary mechanism for its elimination. CYP 3A3/4 is a low-affinity, but high-capacity, enzyme and hence produces a paroxetine half-life of 24 hours. When paroxetine is discontinued, its clearance accelerates as its level falls, and that likely accounts for the increased likelihood of an SRI withdrawal syndrome following its discontinuation.

In the case of nefazodone, the incidence of an SRI withdrawal syndrome is less than might be expected given its short half-life of 4 hours. There are several possible explanations that are not mutually exclusive:

• Nefazodone has several active metabolites which may cushion the withdrawal state, particularly the triazoledione metabolite, which has a considerably longer half-life than the parent drug, nefazodone.¹⁰³
• Nefazodone is relatively weak as an SRI. Its most potent action is 5-HT2A blockade, which does not appear to cause a withdrawal liability. In fact, pharmacologically relevant serotonin uptake inhibition requires a daily dose of nefazodone of at least 500 mg/day and possibly more.¹⁵⁰

Either of these reasons may account for why patients treated with nefazodone at doses below 500 mg/day have a minimal risk of experiencing the SRI withdrawal syndrome following its discontinuation.