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Clinical Pharmacology of SSRI's 6 - What Are the Clinically Relevant Pharmacokinetic Differences Among SSRIs?

While the serotonin selective reuptake inhibitors (SSRIs) were rationally developed to be similar in terms of avoiding effects on several neural sites of action (SOAs), they were not designed to be similar with regard to their pharmacokinetics. Not surprisingly, this area is one where there are clinically meaningful differences among these drugs.

Concentration-dependent Effects of SSRIs

The concentration-dependent effects of SSRIs are summarized in Table 6.1. Chapter 5 reviewed the data on the concentration-dependent nature of the effects of SSRIs in terms of the inhibition of the serotonin uptake pump, their antidepressant efficacy, and the incidence and severity of their serotonin-mediated adverse effects. The concentration-dependent inhibition of specific CYP enzymes by specific SSRIs will be presented in Sections 7 and 8. The concentration-dependent nature of these effects is the basis for the clinical importance of the pharmacokinetic differences among SSRIs (Table 6.2).

The only pharmacokinetic parameters shared by all the SSRIs is that they are relatively slowly, but completely, absorbed from the gut (ie, time to peak plasma concentration is 3 to 8 hours) and have large apparent volumes of distribution.²¹³ They differ with regard to:

• Their protein binding
• Their metabolism including which CYP enzymes are principally responsible for their biotransformation
• Their half-lives
• Whether they have linear or nonlinear pharmacokinetics over their clinically relevant dosing range
• Whether they have active metabolites
• The effect of age and specific organ impairment on their elimination rates

Protein Binding

Fluoxetine, paroxetine and sertraline are highly protein bound (ie, > 95%).²¹³ In contrast, the protein binding of citalopram (50%) and fluvoxamine (77%) is considerably less.^94,199 High protein binding raises the possibility of displacement interaction with other highly protein bound drugs. However, SSRIs are weakly bound primarily to a1-acid glycoprotein. Perhaps for this reason, even the highly protein bound SSRIs have not been found to increase the free fraction of concomitantly administered drugs that are also highly protein bound.

Metabolism

While some SSRIs can competitively inhibit specific CYP enzymes, the interaction between CYP enzymes and SSRIs is a two-way street. All of the SSRIs undergo extensive oxidative metabolism as a necessary step in their eventual elimination; however, different CYP enzymes mediate the metabolism of different SSRIs (Table 6.3). This knowledge is important because it forms the basis for understanding many of the other pharmacokinetic differences among the SSRIs. It is also important in terms of knowing whether concomitantly administered drugs can affect the clearance of specific SSRIs and hence their efficacy and tolerability. After all, SSRIs can be the target of pharmacokinetic drug-drug interactions as well as being the cause of such interactions.

Information about their metabolism varies substantially from one SSRI to another. The metabolism of citalopram and paroxetine have been the best characterized and sertraline is intermediate in terms of our knowledge; whereas there is considerably less information on the metabolism of fluoxetine and fluvoxamine, although for different reasons.

As reviewed in Section 2, citalopram is marketed as a racemic mixture and there are differences in the enantiomers in terms of their rate of metabolism. Racemic citalopram is metabolized by both CYP 2C19 and CYP 2D6 based on a study comparing the steady-state levels of citalopram, desmethylcitalopram, and didesmethylcitalopram in individuals who were extensive metabolizers of sparteine (ie, CYP 2D6) and mephenytoin (ie, CYP 2C19), and individuals who were poor metabolizers of either sparteine or mephenytoin respectively.²⁵⁴ Both the total clearance of citalopram and the clearance of desmethylcitalopram were significantly slower in poor versus extensive metabolizers of mephenytoin (ie, deficient in CYP 2C19) while the demethylation clearance of desmethylcitalopram was significantly lower in poor versus extensive metabolizers of sparteine (ie, deficient in CYP 2D6). Both of these CYP enzymes exhibit considerable genetic polymorphism in specific populations: approximately 5% to 10% of white populations in western Europe and North America are genetically deficient in CYP 2D6^84,265 whereas 20% of Orientals are genetically deficient in CYP 2C19.^104,152 The fact that citalopram is dependent on these 2 enzymes will be expected to increase the interindividual variability in plasma levels of this drug.

Although fluvoxamine was one of the first SSRIs developed, it was developed before the technology existed to readily identify which CYP enzyme(s) was responsible for its biotransformation. Hence, there have been no formal studies examining which CYP enzymes are responsible for its biotransformation. This is unfortunate since the biotransformation of fluvoxamine is extensive and occurs mostly by oxidation.¹⁹⁸ Only negligible amounts of fluvoxamine are excreted unchanged in the urine. Eleven different metabolites have been identified in urine. However, a plot of the areas under curve (AUCs) of fluvoxamine in nearly 100 individuals did not reveal bimodality in distribution as would be expected if CYP 2D6 or CYP 2C19 were the rate-limiting enzyme.⁷³ However, smokers have a 23% reduction in fluvoxamine compared to nonsmokers, suggesting a possible role for CYP 1A2 in fluvoxamine metabolism.²⁷⁵ The fact that fluvoxamine plasma levels are somewhat higher after multiple doses than after a single dose is also partially consistent with the fact that fluvoxamine can be metabolized by CYP 1A2 since fluvoxamine inhibits this enzyme. However, the nonlinearity in its plasma levels are not as great as would be predicted based on its effects on other CYP 1A2 substrates such as theophylline.

Knowledge about fluoxetine metabolism is also limited in part because such investigations are complicated by several factors:

• First, fluoxetine is marketed as a racemic mixture like citalopram.
• Second, it is N-demethylated to norfluoxetine, which is also chiral as discussed in Section 2.
• Third, fluoxetine and particularly norfluoxetine are slowly cleared (ie, extended half-lives).
• Fourth, both inhibit multiple CYP enzymes to varying degrees at clinically relevant concentrations and are known to inhibit their own metabolism presumably by inhibiting the responsible CYP enzymes. This matter is further complicated by the fact that the relative potency for such inhibition can vary between the enantiomers of both fluoxetine and norfluoxetine.

Thus, the knowledge about which CYP enzyme mediates the metabolism of fluoxetine is limited but will be summarized below to the extent possible.

The N-demethylation of both enantiomers of fluoxetine is probably at least in part metabolized by the same CYP enzyme(s) based on the results of an in vitro study showing a reasonable correlation between the rates at which human liver microsomes catalyze this reaction.²⁶⁷ The R-fluoxetine was metabolized about 50% faster, which is consistent with reports of higher levels of S-fluoxetine in individuals on the drug.^18,267

There are probably multiple CYP enzymes involved in the metabolism of fluoxetine at different concentrations, accounting for the nonlinear pharmacokinetics of the drug. As higher affinity enzymes become inhibited, lower affinity enzymes become relevant as the concentration of the drug increases. There is evidence suggesting a role for both CYP 2D6 and CYP 3A3/4. First, the metabolism of fluoxetine cosegregates with the CYP 2D6 polymorphism.^7,24 N-demethylation of fluoxetine positively correlates with CYP 2D6 levels in human microsomes, but is inhibited only 20% by quinidine and 27% by antisera to CYP 2D6 and does occur in human microsomes lacking the CYP 2D6 enzyme.^18,267 The fact that the N-demethylation of fluoxetine is autoinhibited at higher concentration suggests that this step is mediated at least in part by another CYP enzyme which is more weakly inhibited than CYP 2D6, such as CYP 3A3/4, 2C19, 2C9/10 or another CYP enzyme.

Paroxetine is metabolized principally to an intermediate, which is then conjugated and eliminated.¹⁴¹ Two CYP enzymes mediate this reaction. There is ample evidence that at low paroxetine concentrations, this enzyme is CYP 2D6. First, enzyme activity at low concentrations of paroxetine cosegregates with the sparteine polymorphism and in vitro is responsible for approximately 75% of the activity in CYP 2D6 extensive metabolizers.^252,253 Second, this activity is inhibited by quinidine and by paroxetine itself, which are both known inhibitors of CYP 2D6.^32,252 The second CYP enzyme has a much lower affinity for paroxetine. It is responsible for 25% of the in vitro metabolism of paroxetine in CYP 2D6 extensive metabolizers at low concentrations but is the primary enzyme in CYP 2D6 poor metabolizers and in extensive metabolizers at higher concentrations.²⁵³ This low affinity enzyme has not been identified but may be inhibited by cimetidine,^16,111 may decline in efficiency with age,²⁵³ and may be induced by some anticonvulsants.⁸

While paroxetine is principally metabolized by CYP 2D6 at low concentrations, it also inhibits this enzyme in a concentration-dependent manner (see Section 8). Hence, this pathway becomes saturated at higher concentrations and paroxetine elimination becomes dependent on the lower affinity, but higher capacity, enzyme. The relative roles of these two enzymes in the metabolism of paroxetine is the apparent explanation for why paroxetine has nonlinear pharmacokinetics including a half-life of 10 hours after a single 20 mg dose, but a half-life of almost 24 hours after multiple doses of 20 mg/day.¹⁴¹

Sertraline, like the other SSRIs, is mainly eliminated by oxidative metabolism and the dominant metabolite is N-desmethylsertraline.²⁸⁸ Several observations rule out a major role for CYP 2D6 in the metabolism of sertraline. First, there is no evidence of a bimodal distribution of plasma drug levels in populations of northern European extraction. Second, sertraline has linear pharmacokinetics even up to doses of 200 mg/day in terms of:

• No change in half-life from single dose to multiple dose
• No change in half-life over its full dosing range
• Proportional changes in plasma levels of both sertraline and desmethylsertraline with dose increases
• No change in the ratio of sertraline to desmethylsertraline²⁸⁸

These findings are not consistent with the conversion of sertraline to desmethylsertraline and its eventual elimination's being substantially dependent on CYP 2D6 since sertraline at a dosage of 150 mg/day does produce approximately a 50% to 65% increase in the plasma levels of the CYP 2D6 substrate, desipramine.^153,298 Also, an immediate switch from fluoxetine to sertraline exerts only a modest effect on sertraline and desmethylsertraline levels under conditions that produce a 400% increase in the levels of the desipramine. Third, the in vitro conversion of sertraline to desmethylsertraline correlates more with CYP 3A3/4 activity (r = 0.93) than with CYP 2D6 activity.²⁰⁹ Therefore, higher and lower doses, respectively, of sertraline may be necessary when it is used in combination with drugs that induce (eg, carbamazepine and phenytoin) and inhibit (eg, ketoconazole) CYP 3A3/4.

The CYP enzymes responsible for the subsequent biotransformation of desmethylsertraline have not been well characterized. Several observations suggest that there is more than one potential pathway for the further biotransformation of sertraline prior to its elimination and that these pathways may be mediated by more than 1 CYP enzyme. Several different metabolites have been characterized in the plasma and/or urine of individuals receiving sertraline. Additionally, sertraline is excreted approximately equally in the feces and urine, suggesting that there is more than one metabolite.

Metabolites

There has been considerable discussion about whether the different SSRIs have "active" metabolites. One problem is that these discussions often do not begin with a definition of what is meant by the term "active" and how such activity was assessed. The two primary metabolites of fluvoxamine reportedly are not capable of inhibiting the serotonin uptake pump,²⁷⁴ but no studies have been done on the effect of its numerous metabolites on specific CYP activity.

Fluoxetine has a metabolite that is as potent and more selective than the parent drug in terms of the inhibition of the serotonin uptake pump (Table 3.8). Since this metabolite has an unusually extended half-life (ie, 7 to 15 days), its level and hence indirect serotonin agonistic effects take time to fully develop and then persist for an extended interval after the fluoxetine is discontinued. Norfluoxetine is also more active than fluoxetine as an inhibitor of CYP 3A3/4 and equal to fluoxetine as an inhibitor of CYP 2D6 (Table 8.7). Plasma levels of norfluoxetine correlate with the magnitude and duration of the inhibition of both of these enzymes following fluoxetine administration.^112,219

As with fluvoxamine, there are apparently no paroxetine metabolites capable of inhibiting the serotonin uptake pump, but the M2 metabolite is a potent inhibitor of CYP 2D6 (Table 8.7). There is no data on what plasma levels of this metabolite could be expected in the normal population or any of the special populations discussed later in this section.

Desmethylsertraline is 1/10th to 1/25th as potent as sertraline at inhibiting the serotonin uptake pump (Table 3.8). Since its concentrations are only 1.5 times higher than the parent drug under clinically relevant dosing conditions,²¹⁹ it would be predicted to contribute only 6% to 15% (ie, 1.5 times higher levels times 1/10th to 1/25th the potency) to the serotonin uptake inhibitory effects that would occur in patients on sertraline under clinically relevant dosing conditions. The magnitude of this contribution is probably too small to be clinically meaningful in most situations. However, desmethylsertaline like the major metabolites of fluoxetine and paroxetine is virtually equipotent to the parent SSRI as an inhibitor of specific CYP enzymes (Table 8.7). Hence, it would be expected to contribute to the magnitude of such an effect. Since its half-life (62 to 104 hours) is longer than that of the parent drug, it would also be expected to prolong the duration of the effect, but not to the extent that norfluoxetine does.²⁸⁸ The clinical impact of this fact is mitigated by the relatively weak inhibitory effect of sertraline and desmethylsertraline on specific CYP enzymes.

Linear Versus Nonlinear Pharmacokinetics

Citalopram and sertraline show linear pharmacokinetics (ie, changes in drug concentration proportional to the change in dose). In contrast, fluvoxamine, fluoxetine and paroxetine have nonlinear pharmacokinetics (Tables 6.4 and 6.5). The evidence for nonlinearity with fluvoxamine and fluoxetine primarily comes from the observation that their half-lives are substantially longer after multiple dose administration than after single dose administration (Table 6.4). The same observation also holds for paroxetine, but in addition, there is good evidence that under steady-state conditions, the half-life of paroxetine is progressively longer at higher doses.¹⁴¹

TABLE 6.4 — Change in Half-life (t1/2) as a Function of Multiple Dose Administration
SSRI	Single- dose t1/2	Multiple- dose t1/2	% Change
Citalopram1	33 hours	33 hours	—
Fluoxetine2	1.9 days	5.7 days*	300
Fluvoxamine3	15 hours	22 hours	50
Paroxetine4	10 hours†	21 hours	200
Sertraline5	26 hours	26 hours	—
* Only the effect on t1/2 of fluoxetine is published. † Paroxetine has the shortest half-life of any SSRI in terms of single dose which may increase the risk of withdrawal reactions on this drug. Tapering the drug rather than abrupt discontinuation should minimize such a reaction.
References: 1146, 223, 3234, 4141, 5288

The nonlinearity of paroxetine is also apparent based on the fact that paroxetine plasma levels increase disproportionately with the dose increases (Table 6.5). In contrast, there is a linear relationship between dose and plasma drug level increases with both citalopram and sertraline (Table 6.5). Although fluoxetine has been the most extensively-used SSRI and fluvoxamine has been the longest-used SSRI, there are minimal data on what plasma drug levels can be reasonably expected at different doses administered long enough to achieve steady-state. Undoubtedly, the long half-life of fluoxetine has discouraged such studies. It would require almost 1 year to determine the steady-state plasma levels of fluoxetine and norfluoxetine that could be achieved in the same individual on the 4 different doses that comprise its clinically relevant dosing range (ie, 20 to 80 mg/day).

Nonlinearity has the potential to be clinically significant with these SSRIs for several reasons. While fixed-dose studies with these drugs suggest that generally higher doses do not produce a greater antidepressant effect, physicians frequently try higher doses when the response has been suboptimal. Due to nonlinearity, the concentration-dependent effects of fluvoxamine, fluoxetine and paroxetine will be expected to increase disproportionally with higher doses; that will not be expected with citalopram or sertraline. This knowledge can be helpful to the clinician in terms of what to expect with higher than usual doses of these different SSRIs. The dose-dependent (ie, concentration-dependent) effects of the SSRIs are reviewed in Section 5.

TABLE 6.5 — Effects of Dose and Age on the Plasma Levels of SSRIs
SSRI	Age (yrs)	Dose (mg/day)	Dose Effect*	Age Effect†
			Plasma Level (ng/ml)
Citalopram		5 20 25 50 12 47‡ 58 120 NA 109 NA NA
	< 651		NC
	> 652			133%
Fluoxetine		20 40 60 200 NA NA NA NA NA
	< 653		?
	> 653			?
Fluvoxamine		50 100 200 NA 93 250 NA 62 NA
	< 654		­ 25%
	> 655			33%
Paroxetine		20 30 40 49 86 129 79 147 228
	> 656		­ 25%
	> 656			50% to 90%
Sertraline		50 100 200 15§ 29§ 68§ NA NA 90
	< 657,8		NC
	> 658			37%§
NA = Not available; NC = No change
* (Plasma level on dose [x + n] divided by plasma level on dose X) divided by (dose [X + n] divided by dose X) minus 1, or D change in plasma level, D change in dose minus 1 expressed as %. † (Plasma level for the elderly group divided by plasma level for the younger age group) minus 1 expressed as %. ‡ This result was extrapolated from the other values based on the linearity of citalopram plasma levels in this age group over this dose range. § These results are for males only. These results overestimate the effect of age since young males develop lower plasma levels on sertraline than do young females or older males or females. The values for young females at 20 mg/day is 104 ng/ml, which is essentially the same as for older males and females.
References: 131, 295, 3Table 3.7, 473, 590, 6141, 7223, 8243

Half-life

Considerable variability among the SSRIs exists with regard to half-life (Table 6.2). The half-life of fluvoxamine is 15 to 22 hours.⁷³ For this reason, and to reduce the incidence and severity of nausea, it is generally administered in equally divided doses twice a day. The half-lives of citalopram, paroxetine and sertraline allow them to be administered once a day (Table 6.2). Fluoxetine and its active metabolite, norfluoxetine, have unusually extended half-lives for orally administered drugs: 2 to 4 days for fluoxetine and 7 to 15 days for norfluoxetine (Table 6.2). Because of the extended half-lives, this drug can be administered as infrequently as once a week and still reach stable steady-state levels.

Figure 6.1 provides a graphic illustration of the difference in duration of drug administration needed to reach steady-state and the time to 95% washout following drug discontinuation for fluoxetine and norfluoxetine versus the other SSRIs. Due to this extended period, the magnitude of any concentration-dependent effect of fluoxetine will take several weeks to be achieved and will persist for several weeks after it has been discontinued. The clinical consequences may be either desirable or undesirable depending on the specific situation. Such an extended half-life might provide an added measure of safety against possible relapse if the patient were intermittently noncompliant. While this proposal has theoretical appeal, it was not substantiated by the relapse prevention studies reviewed in Section 5 (Table 5.3). Instead, these studies show remarkably similar results for fluoxetine, paroxetine and sertraline versus a parallel placebo control. For the same theoretical reason, a slower onset of antidepressant efficacy may be expected with fluoxetine versus the other SSRIs, but there is no convincing data to support that proposal. While data are lacking on the above points, there are compelling data that the full magnitude of fluoxetine-induced inhibition of CYP 2D6 and 3A3/4 is not achieved until steady-state has been reached, and that full recovery of enzyme activity is not achieved until fluoxetine and norfluoxetine have fully washed out of the body.^112,219 These points are clinically important because the gradual accumulation and washout can affect the concentration of a concomitantly prescribed drug administered to a patient taking fluoxetine or recently discontinued from fluoxetine therapy. The extended half-life also is responsible for the long interval of washout that is recommended before initiating treatment with a monoamine oxidase inhibitor (MAOI) following fluoxetine discontinuation. At present, there is no good explanation for the unusually long half-life of norfluoxetine.

The half-life of paroxetine is a function of its plasma drug level. Following a single 20 mg dose, paroxetine has a half-life of 10 hours (Table 6.4). Paroxetine does not reach a half-life of 20 hours until steady-state has been reached on 20 mg/day (Table 6.4) because paroxetine inhibits CYP 2D6, which is the CYP enzyme responsible for its biotransformation. When paroxetine levels fall after this drug is discontinued, its clearance rate increases as the inhibition of the enzyme is decreased. Thus, paroxetine and fluvoxamine are more quickly cleared from the body than the other SSRIs.

FIGURE 6.1 — Time to Steady-state and Time to 95% Washout

Reference: 217

Rapid clearance may explain the increased incidence of withdrawal reactions seen after these 2 SSRIs are discontinued in comparison to the other SSRIs. Certainly, such withdrawal syndrome would be highly unlikely with fluoxetine due to its extended half-life. If such a reaction were to occur after abrupt SSRI discontinuation, reinstituting the drug and more gradual tapering will commonly handle the problem. This approach may be taken prophylactically with fluvoxamine and paroxetine, particularly if the patient previously had problems with abrupt discontinuation or if the patient has been on higher than the usually effective, minimum dose.

Effect of Age and Gender on Clearance

Although the reasons have not been elucidated, there is considerable difference among the SSRIs with regard to changes in apparent clearance of specific SSRIs in the physically healthy "young old" (ie, in these studies, most of the "old" individuals were between 65 and 75 years of age) versus younger healthy individuals (Table 6.5). Plasma levels of citalopram and paroxetine are approximately 100% higher in the elderly compared with the young.^95,141 Fluvoxamine has no apparent change in its metabolism as a function of age;^73,234,285 however, recent data suggest males develop plasma levels 40% to 50% lower than females with the magnitude of the effect possibly being greater at lower doses.¹¹⁸ The basis for this gender effect has not been established. Fluoxetine has not been adequately studied, but data from clinical trials suggest that plasma levels of fluoxetine plus norfluoxetine can be twice as high in the elderly compared to the young.^86,159 There is an age by gender interaction for sertraline with its plasma levels being 35% to 40% higher in elderly females versus young males; however, sertraline plasma levels do not differ between elderly females and elderly males or young females.²⁸⁸

There are at least two reasons why these age related changes in plasma drug levels can be clinically important:

• First, it will be predicted to increase treatment limiting adverse effects in the elderly since the discontinuation rate for SSRIs due to adverse effects is dose-dependent and, hence, concentration dependent.
• Second, the inhibition of specific CYP enzymes by specific SSRIs is concentration dependent; hence, the elderly will be expected to experience a greater degree of inhibition on average than younger patients given the same dose of the same SSRI. The apparent order of the age effect from most to least appears to be citalopram > paroxetine ³ fluoxetine (probably, although not well studied) > sertraline ³ fluvoxamine (Table 6.5).

The latter issue is important since the elderly are more likely to be on concomitant therapy and more sensitive to any adverse consequences produced by elevation of the levels of such coadministered drugs. This phenomenon is particularly relevant to fluoxetine and fluvoxamine due to the number of CYP enzymes inhibited by these 2 SSRIs, which will be reviewed in Sections 7 and 8.

Effect of Specific Organ Impairment on Clearance

As discussed above, all of the SSRIs are dependent on oxidative metabolism for their elimination, and the resultant polar metabolites are primarily excreted via the urine. Based on these facts, significant impairment in liver, renal and cardiac function will be expected to affect the levels of either the parent drug and/or its metabolites for each of the SSRIs.

Appreciable impairment in liver function and/or size can slow the individual's ability to biotransform drugs and thus result in greater drug accumulation per dose prescribed. Reduced renal function generally leads to the increased accumulation of polar metabolites that may be pharmacologically active, either in a way similar to or different from the parent drug. The accumulation of those metabolites can appreciably alter the patient's response to the medication, including the risk of adverse effects. Significant reduction in left ventricular function will cause a reduction in hepatic and renal arterial blood flow, which is another important determinant of both hepatic- and renal-mediated clearance of drugs. For these reasons, impairment in the function of these organs can significantly alter a patient's response to what is a usually therapeutic dose of a medication. The effect of specific organ impairment on the clearance of specific SSRIs has been studied to varying degrees with the different SSRIs.

Based on single-dose studies, the half-lives of all the SSRIs are approximately doubled in individuals with cirrhosis compared to physically healthy individuals (Table 6.6). Since the clearance of fluoxetine and paroxetine, to a substantial degree, and fluvoxamine, to a more modest degree, is prolonged when going from a single dose to multiple doses (Table 6.4), these single-dose studies in patients with cirrhosis are likely an underestimate of the magnitude of the effect of such impairment on the clearance of these SSRIs. As with the elderly, the elevated levels of specific SSRIs will translate into greater inhibition of specific CYP enzymes in this medically ill population.

The data on the effect of renal disease (Table 6.7) are even more limited than with cirrhosis particularly because the effect should principally be an increase in plasma levels of more polar metabolites, but the studies that have been done have focused only on the parent drug. In a single-dose study of paroxetine (30 mg) in individuals with renal impairment, the plasma AUC and Cmax were significantly increased.²⁸¹ Since the polar paroxetine metabolite, M2, is a potent inhibitor of CYP 2D6, accumulation of this metabolite may be relevant to the increase in paroxetine plasma levels in renally impaired individuals and also in the elderly since renal function decreases with age. The single-dose pharmacokinetics of fluvoxamine,²³⁴ fluoxetine,¹¹¹ and sertraline^281,288 are similar in individuals with renal failure versus in healthy volunteers. As discussed above, single-dose studies with fluoxetine, and to a lesser extent with fluvoxamine, should be cautiously interpreted since the nonlinear pharmacokinetics of these drugs observed in healthy individuals (Tables 6.4 and 6.5) may well be increased in individuals with such organ impairment.

There have been no studies of the effect of significant left ventricular pump impairment on the clearance of any SSRI. In the absence of data, it would be prudent to use conservative dosing in such patients for the same reasons as discussed with hepatic and renal impairment.

The disease-related changes in the clearance rates of the SSRIs have several clinically important implications. Patients with such organ impairment will need lower doses to achieve the same plasma drug levels that occur in healthy individuals on the usually effective, minimum dose. Hence, a dose reduction will be appropriate for such individuals to compensate for the reduction in their clearance; otherwise, they will be at increased risk for having more of the dose-dependent adverse effects of the SSRIs and a poorer antidepressant responses. Additionally, these patients will be at increased risk for pharmacokinetic drug-drug interactions. Since inhibition of specific CYP enzymes produced by specific SSRIs is concentration-dependent (see Section 8), the higher levels that will occur in these patients without an appropriate dose adjustment will result in a greater degree of enzyme inhibition. The hepatic and cardiac impairment may also make these patients more sensitive to the enzymes inhibiting effects of these drugs (ie, a greater degree of enzyme inhibition may occur in these individuals than those with normal organs at the same concentration of the SSRI). There are no data on this matter because the formal pharmacokinetic drug interaction studies with the SSRIs have been done in healthy individuals with normal organ function.

These issues are important because these patients, due to their comorbid medical illnesses, are likely to be on multiple medications and at greater risk for a drug-drug interaction. Moreover, their medical illnesses may make them more susceptible to any adverse effects arising out of such an interaction. Being aware of these considerations can help the physician make a prudent choice with regard to SSRI selection and dose adjustment for a specific patient based on whether and to what degree one or more organ(s) is impaired, what other medications the patient is taking, and the overall health status of the patient.