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242 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
TABLE 15–1. Pharmacodynamics and pharmacokinetics of selected
antidepressants
a
Drug Ki
(SERT) Kia (NET) Ki(SERT) binding Half-life
Citalopram 8.9 30,285 3,403 80% 20 hours
Desvenlafaxine 40
Duloxetine
0.8
3
558
7.5
Ki(NET)/ Protein
2
3
14 30% 11 hou rs
9 95%
12.5 hours
1
4
Escitalopram 0.8 7,800 9,750 56% 27–32 hours
Fluoxetine 20 2,186 109 95% 4–6 days
Fluvoxamine 14 4,743 339 80%
5
Levomilnacipran 11.2
Nefazodone 549 713 1.3
91
8 22% 12 hours
99%
15 hours
6 7
4–8 hours
5
Paroxetine 0.83 328 395 95% 21 hours
Sertraline
Venlafaxine
Vilazodone 0.1
Vo r t io x e t i ne
Note. NET =norepinephrine transporter; SERT=serotonin transporter.
a
Uptake binding site binding affinity is expressed as the inhibition constant (Ki), which is an inverse scale
(i.e., lower values are more potent).
b
The half-life of the principal metabolite desmethylsertraline is 66 hours.
c
O-desmethylvenlafaxine’s half-life is 11 hours.
Sources. Adapted from Owens et al. 1997 and manufacturer prescribing information except as noted:
b
c
1
Fredricson Overø 1982.
2
Bridge et al. 2008.
3
Bymaster et al. 2001.
3.3 1,716 520 98% 26 hours
102 1,644 16 27% 5–7 hours
8
1.6
9
4
Sharma et al. 2000.
5
Bruno et al. 2016.
6
van Harten 1995.
56
113 71 98% 7–11 hours
560 98% 20–22 hours
7
DeVane et al. 2002.
8
Sahli et al. 2016.
9
Bang-Andersen et al. 2011.
A question arises as to whether therapeutic response maps to any of these dimensions of mood. Enhancement of serotonin transmission appears to improve elements
of somatic anxiety (e.g., panic, social phobia) and general distress (e.g., generalized
anxiety disorder), which seem to be class effects and are not specific to a limited set
of compounds (Shelton and Tomarken 2001). This would distinguish the difference
between therapeutic effect, based on some underlying neurochemical mechanism of
action, and therapeutic indication, based on submission of research data to the FDA or
other regulatory agencies. By contrast, SERT inhibitors seem to produce a more mixed
effect with regard to positive affect. Although some patients clearly experience a
broad effect on mood symptoms with SSRIs, only about one-third experience remis
sion in a typical 8- to 12-week therapeutic trial. Moreover, some patients describe a
mood “flattening” effect with SSRIs. In fact, persisting symptoms in depression are
often in the “positive” rather than in the “negative” affective domains.
-
TABLE 15–2. Antidepressants and related compounds approved for the
https://t.me/med1917
treatment of depressive, anxiety, or pain disorders by the FDA
(excluding tricyclics)
Dosage
range
Drug U.S. trade name (mg/day) FDA-approved indications
Bupropion Wellbutrin Major depressive disorder
Wellbutrin SR 150–400 Smoking cessation (Zyban)
Wellbutrin XL 150–450
Zyban
Citalopram Celexa 20–60 Major depressive disorder
Duloxetine Cymbalta 60–120 Major depressive disorder
Generalized anxiety disorder
Fibromyalgia
Diabetic peripheral neuropathic pain
Chronic musculoskeletal pain
Escitalopram Lexapro 10–20 Major depressive disorder
Generalized anxiety disorder
Fluoxetine Prozac 20–80 Depression
Prozac Weekly 90–180 Bulimia nervosa
Serafem Obsessive-compulsive disorder
Panic disorder
Premenstrual dysphoric disorder
(Serafem)
Fluvoxamine Luvox 50–300
Obsessive-compulsive disorder
(adults, children)
b
Levomilnacipran Fetzima 40–120 Major depressive disorder
Milnacipran Savella 12.5–200
Fibromyalgia
b
Mirtazapine Remeron 15–45 Major depressive disorder
Remeron SolTab
Nefazodone Serzone 200–600 Major depressive disorder
Paroxetine Paxil 20–50 Major depressive disorder
Paroxetine Paxil CR 25–62.5 Generalized anxiety disorder
a
release PTSD
Sertraline Zoloft 50–200 Major depressive disorder
Venlafaxine Effexor 75–375 Depression
Premenstrual dysphoric disorder
Social anxiety disorder)
Obsessive-compulsive disorder
Panic disorder
PTSD
Premenstrual dysphoric disorder
Social anxiety disorder
Effexor XR 75–225 Generalized anxiety disorder
Social anxiety disorder
Panic disorder
244 The APA Publishing Textbook of Mood Disorders, Second Edition
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TABLE 15–2. Antidepressants and related compounds approved for the
treatment of depressive, anxiety, or pain disorders by the FDA
(excluding tricyclics) (continued)
Dosage
range
Drug U.S. trade name
(mg/day)
FDA-approved indications
Vilazodone
Vortioxetine
Note. CR=controlled release; SR=sustained release; XL=extended release; XR=extended release.
a
Social anxiety disorder, obsessive-compulsive disorder, panic disorder outside the United States.
b
Major depressive disorder outside the United States.
Viibr yd
Trintellix
10–40
10–20
Major depressive disorder
Major depressive disorder
By contrast, the effects of norepinephrine (including the indirect effects on dopaminergic mechanisms) appear to be significant mediators of arousal and activation. Antidepressants that act on catecholamines have been shown to have a beneficial effect in
the positive affect domain. Bupropion, a drug acting predominantly via a catechol
aminergic mechanism, has been shown to have a more robust effect in the positive
affective than the general distress domain (Tomarken et al. 2004). Although the thera
peutic specificity of antidepressant mechanisms of action remains somewhat controversial, at least some evidence indicates that serotonergic agents shade toward antianxiety
effects, whereas catecholaminergic drugs shade toward reduction of anhedonia.
Selective Serotonin Reuptake Inhibitors
As a class of drugs, SSRIs share many characteristics. In addition to their specificity
for SERT and relatively low affinity for other neurotransmitter receptors, they have a
lower side-effect burden relative to TCAs and MAOIs, are relatively safe in overdose,
and are readily absorbed from the gastrointestinal tract. Most circulate in a form that
is highly bound to protein and is in equilibrium with the unbound, biologically active
form. Metabolized in the liver, these antidepressants are broken down by hepatic microsomal enzymes and conjugated, usually with glucuronic acid, allowing clearance
in the urine. Thus, hepatic or renal dysfunction reduces clearance of the drug. Despite
these similarities, these drugs are unique in terms of their receptor affinity and pharmacokinetic properties.
Today, five SSRIs are approved by the FDA for treatment of depression (fluoxetine,
sertraline, paroxetine, citalopram, and escitalopram), and another, fluvoxamine, is
marketed for obsessive-compulsive disorder (OCD) but has been approved for depression in Europe and elsewhere. Table 15–2 lists the available SSRIs, their typical
dosing ranges, and their FDA-approved indications.
-
-
Clinical Use
Newer antidepressants are safer and better tolerated than older medications; therefore,
clinicians are more likely to prescribe them, and patients are more willing to take them.
The popularity of the SSRIs has stemmed largely from their increased tolerability and
not from an increase in drug effi cacy (i.e., “response” or “remission”). Although overall
245 Selective Serotonin Reuptake Inhibitors and Related Antidepressants
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outcomes of treatment may not have improved, SSRIs and later drugs appear to have
increased the proportion of patients treated with antidepressant drugs, which is likely
to have a favorable effect independent of the benefits of any single agent.
Increases in antidepressant tolerability have resulted in a substantial shift among
the physicians treating depression. Whereas depression was once treated mainly by
mental health professionals, nearly three-quarters of all patients seeking treatment
for depression now visit a primary care physician (Montano 1994). Between 1987 and
1997, the rate of people seeking treatment increased from 0.73 to 2.33 per 100 people
per year (Olfson et al. 2002), a roughly threefold increase. The percentage of individ
uals in treatment for depression who are given antidepressants has doubled, from
37.3% in 1987 to 74.5% in 1997. Use is increasing in children as well: between 1988 and
1994, use of antidepressants in children increased three- to fivefold (Zito 2002). Anti
depressants have become among the most prescribed medications worldwide. In the
United States, sertraline ranks at number 14, escitalopram at 22, fluoxetine at 23, and
bupropion at 23 (Kane 2021).
Specific Medications
Fluoxetine
In late 1987, fluoxetine (Prozac) became the first SSRI approved for use in the United
States. Once ingested, it is converted to its active metabolite, norfluoxetine. Both the
parent compound and the metabolite are relatively selective for SERT: the Ki values
for fluoxetine and norfluoxetine are 0.90 and 2.3 nMol, respectively, versus [
pram in human transfected cells (SERT affinity), as opposed to 777 and 3,947 nMol
versus [
dosing starts at 20 mg, taken once daily, and dosage can be increased in increments of
10–20 mg in a dosing range of up to 80 mg/day. Due to the relatively long half-lives
of fluoxetine and norfluoxetine (4–6 days for fluoxetine, 7–15 days for norfluoxetine),
a weekly dosing schedule and formulation (Prozac Weekly) have been approved,
with a dosage of 90 mg taken once or twice per week. Fluoxetine’s long half-life also
makes it less likely than other SSRIs to produce a discontinuation syndrome in pa
tients who stop treatment (Haddad 2001). Fluoxetine is very highly protein bound
(98%) and is a potent inhibitor of cytochrome P450 (CYP) 2D6 and 2C19, and some
what less so for 2B6 and 2C9 (Table 15–3).
in the United States for depression, bulimia nervosa, OCD, panic disorder, and premenstrual dysphoric disorder (see Table 15–2). It remains the most commonly prescribed antidepressant in the United States (Kane 2021).
3
H]nisoxetine binding (NET affinity) (Owens et al. 1997). Typical fluoxetine
Fluoxetine has been studied for a variety of conditions and is currently approved
3
H]citalo-
-
-
-
-
Sertraline
Sertraline (Zoloft), which was approved in 1992, has been among the most widely
used antidepressants. Like fluoxetine, sertraline has been studied for a wide group of
disorders and has been approved by the FDA for depression, OCD, panic disorder,
PTSD, premenstrual dysphoric disorder, and social anxiety disorder (see Table 15–2).
It is highly protein bound (see Table 15–1) and inhibits metabolism of other drugs via
CYP2D6, CYP2B6, CYP2C, and CYP3A4 (see Table 15–3). The primary metabolic
pathway for sertraline is CYP2B6.
246 The APA Publishing Textbook of Mood Disorders, Second Edition
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TABLE 15–3. Metabolic pathways and relative inhibition of selected cytochrome
P450 (CYP) enzymes by newer antidepressants
Primary
metabolic
Drug
pathway(s)
Bupropion CYP2B6 CYP1A2, CYP2A6,
Secondary
metabolic
pathway(s)
CYP enzyme
inhibited
inhibition
CYP2D6 +
CYP2C9, CYP3A4,
CYP2E1, CYP2C19
Citalopram/
Escitalopram
Duloxetine CYP1A2, — CYP2D6
CYP2C19 CYP2D6, CYP3A4 CYP1A2
CYP2C
+
+
b
++
CYP2D6
c
Desvenlafaxine
Fluoxetine CYP2D6 CYP2C19, CYP2D6,
CYP3A4 — None –
CYP2B6
CYP2C9
CYP2C19
+++
CYP3A4/5
d
+
+
CYP2D6 +++
Fluvoxamine
e
Unknown Unknown CYP1A2 +++
CYP2B6 +
CYP2D6 +
CYP2C9 ++
CYP2C19 +++
CYP2D6 +
CYP3A4 ++
Levomilnacipran /
CYP3A4 — None –
milnacipran
Mirtazapine CYP1A2,
— CYP2D6 +
CYP2D6,
CYP3A4
Nefazodone CYP3A4 CYP2D6
f
CYP3A4 +++
Paroxetine CYP2D6 — CYP2B6 +++
CYP2C9 +
CYP2C19 +
CYP2D6 +++
CYP3A4 +
Sertraline CYP2B6 — CYP2D6 ++
CYP2B6 ++
CYP2C ++
CYP3A4 ++
Venlafaxine CYP2D6 — None –
Vilazodone CYP3A4 — None –
Vo r t io x e t i ne CYP2D6 — None –
Note. —=no data available.
a
Relative inhibition: –=minimal or zero; +=mild; ++=moderate; +++=strong.
b
Skinner et al. 2003.
c
Primary metabolism is via glucuronidation by UGT1A1, 1A3, 2B4, and 2B15.
d
Secondary pathways contribute little to fluoxetine’s metabolism unless CYP2D6 metabolism is reduced.
e
van Harten 1995.
f
Forms the psychoactive
Source. Data from Nemeroff et al. 1996; Greenblatt et al. 1998; manufacturers’ prescribing information.
drug meta-chlorophenylpiperazine.
a
247 Selective Serotonin Reuptake Inhibitors and Related Antidepressants
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A typical starting dosage is 50 mg/day (although lower dosages are sometimes
used in anxiety disorders such as panic), and sertraline can be prescribed at dosages
up to 200 mg/day. It is a very potent SERT inhibitor: sertraline and its primary me
tabolite desmethylsertraline potently block SERT, as measured by displacement of
3
[
H]citalopram (Ki=0.15 and 3.7 nMol, respectively) or [3H]serotonin (Ki= 3.3 and 187
nMol) (Owens et al. 1997). Both are weak norepinephrine reuptake inhibitors (Ki vs.
3
[
H]citalopram or [3H]serotonin in the range of 85–328 nMol for sertraline and 811–
2,365 nMol for desmethylsertraline).
Sertraline is sometimes touted as a dopamine reuptake inhibitor, although the binding affinity for the dopamine transporter is modest. Tatsumi et al. (1997) found the affinity for sertraline and desmethylsertraline to be K
=25 and 129 nMol, respectively.
D
However, this is much more potent than other antidepressant drugs (e.g., citalopram’s
K
=28,100 nMol). To our knowledge, sertraline has not been tested via putative dopa-
D
minergic markers in humans (e.g., PET scanning), and its effect at the dopamine transporter in humans is unknown.
Paroxetine
Paroxetine (Paxil) was released soon after sertraline and was initially touted as a
highly selective SERT inhibitor as a result of its high potency of SERT binding and its
high ratio of serotonin-to-NET binding affinity (Boyer and Feighner 1992). Like other
SSRIs, paroxetine has been widely studied, and it is approved for the treatment of depression, generalized anxiety disorder, panic disorder, PTSD, premenstrual dysphoric
disorder, and social phobia (see Table 15–2). The usual dosage is 20 mg taken once
daily, and this can be increased to 60 mg/day. It has a mild affinity to muscarinic receptors, leading some patients to experience anticholinergic side effects such as dry
mouth and constipation (Owens et al. 1997). An enteric-coated controlled-release form
of paroxetine (Paxil CR) is available and appears to be associated with somewhat
lower rates of initial gastrointestinal side effects than the immediate-release version.
Paroxetine truly is a potent blocker of SERT: Ki=0.65 nMol ([
placement) or 0.83 nMol ([
3
H]serotonin displacement) (Owens et al. 1997). However,
although the ratio of SERT/NET inhibition is high, binding at the NET is not inconse
quential: in vitro Ki=85 and 328 nMol versus [
3
H]nisoxetine and [3H]norepinephrine,
respectively (Owens et al. 1997), which is mirrored by in vivo effects in rats (Owens
et al. 2000). An important question, then, is whether this is reflected in human phar
macology.
Prior tests of NET blockade by paroxetine in humans, such as the tyramine pressor
test, have been negative, although the dosage of paroxetine was low in those studies
(20 mg/day). However, Gilmor et al. (2002) found that paroxetine inhibited norepinephrine uptake by 27% at an average serum concentration of 100 ng/mL and by 43%
at 200 ng/mL, suggesting that paroxetine could be a meaningful norepinephrine reuptake inhibitor in humans, at least at higher dosages. However, the relationship between the in vitro effects measured in this study and in vivo effects in the brains of
humans is unclear.
Paroxetine is highly protein bound (see Table 15–1) and inhibits a wide range of
CYP enzymes, including potent inhibition of CYP2B6 and 2D6 and mild inhibition of
CYP2C9, 2C19, and 3A4. It is therefore prone to significant drug-drug interactions. It
is predominantly metabolized by CYP2D6.
3
H]citalopram dis-
-
-
-
248 The APA Publishing Textbook of Mood Disorders, Second Edition
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Citalopram and Escitalopram
Citalopram (Celexa) and its s-enantiomer, s-citalopram (escitalopram, Lexapro), have
been approved for depression in the United States. These drugs are potent and selec
tive SERT inhibitors (Ki ~1–10 nMol) with negligible effects on the norepinephrine or
dopamine transporters (Ki>3,000 nMol) (Owens et al. 1997). They also have very low
binding affinity at other receptor sites (e.g., receptors for norepinephrine, serotonin,
dopamine, histamine, or acetylcholine) (Baumann 1996). Citalopram is prescribed at
a dosage of 20 mg/day, which can be increased to 60 mg/day or more. Escitalopram
typically is dosed in a range of 10–30 mg/day. Only the s-enantiomer is the active
form of the compound (Burke 2002); when citalopram is administered, only about
35% of the circulating plasma level in humans is in the escitalopram form (Rochat et
al. 1995). Comparative clinical trials usually have calculated absolute doses of esci
talopram at one-half the dose of citalopram (e.g., 10 mg vs. 20 mg) (Montgomery et
al. 2001), which, therefore, may not be therapeutically equivalent.
Citalopram and escitalopram are substrates for CYP3A4, 2C19, and 2D6, although
2C19 predominates (Olesen and Linnet 1999; von Moltke et al. 1999). Neither citalo
pram nor the s-enantiomer substantially inhibits CYP metabolism, although modest
inhibition of 1A2 and 2C have been reported (Greenblatt et al. 1998; Nemeroff et al.
1996). Escitalopram appears to have a somewhat lower plasma protein binding affinity (56%) in contrast to racemic citalopram (~80%) (DeVane 1998). This suggests that
protein binding of the r-enantiomer is higher still, a potential therapeutic advantage
for escitalopram when plasma protein displacement is of concern.
-
-
-
Fluvoxamine
Fluvoxamine (Luvox) is an SSRI approved in the United States only for the treatment
of OCD, although it has been used as an antidepressant in Europe since 1984 (Rapa
port et al. 1996). Placebo-controlled depression registration trials were conducted in
the United States, but the findings were not sufficient to gain FDA approval (Ware
1997). Trials in OCD in both adults and children have suggested a robust effect (Goodman et al. 1997; Grados and Riddle 2001; Riddle et al. 2001).
The effects of fluvoxamine in depression, OCD, and other anxiety disorders are
predictable based on the primary mechanism of action: the drug is a highly potent
SERT inhibitor (Ki=1.6 nMol vs. [
minimal effects on NET (Ki=4,743 nMol) (Owens et al. 1997). Like other SSRIs, flu
voxamine inhibits various CYP enzymes, including 1A2, 2B6, 2D6, 2C19, 2C9, and
3A4 (see
tein binding is relatively high at 80%, although this is lower than other SSRIs (see Table 15–1). It is metabolized into various relatively inactive compounds, primarily via
oxidative deamination and demethylation. The half-life of the drug is about 15 hours
initially, although this is increased with continued exposure as a result of autoinhibition of metabolism (van Harten 1995). Although the starting dosage usually is 50 mg/
day, fluvoxamine tends to be effective in a dosage range of 150–200 mg/day.
whether it should be used for this indication if other SSRIs (e.g., sertraline) have
failed. Fluvoxamine is a moderately potent agonist at sigma-1 (σ
nM) (Hashimoto 2009). Sigma-1 receptors are orphan receptors, meaning that their
natural endogenous ligands are unknown, although many amines and hormones
Table 15–3). It therefore is prone to many drug interactions (Table 15–4). Pro-
Fluvoxamine is approved only for OCD in the United States, and a question is
3
H]citalopram and 14 nMol vs. [3H]serotonin) with
) receptors (Ki=39
1
-
-
249 Selective Serotonin Reuptake Inhibitors and Related Antidepressants
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bind to them (Fontanilla et al. 2009; Maurice and Su 2009). σ
antidepressant and anxiolytic effects (Hindmarch and Hashimoto 2010). Whether
these σ
receptor agonist effects contribute to benefits in OCD is unknown.
1
Receptor agonists show
1
Comparative Effectiveness
Drug responsiveness generally refers to a significant decrease in symptomatology, for
example, as measured by a decrease of 50% or greater in score on a scale for depression,
such as the Hamilton Rating Scale for Depression (HAM-D). In contrast, a patient is
considered to be “in remission” if his or her level of symptoms is brought within the
normal range, typically defined as a 17-item HAM-D score of 7 or less. Although re
sponse rather than remission has long been the primary measure of efficacy, many investigators are advocating the use of remission rates with the suggestion that remission
is a better indicator for long-term outcome (Thase 2003). Generally speaking, rates of
response do not vary significantly between antidepressant drugs (Kroenke et al.
2001). Most effective antidepressants produce rates of response in a typical 8- to 12
week clinical trial of 60%–75%. By contrast, remission rates in those same trials can be
quite low, ranging from 30% to 50%. It is important not to consider these rates as
somehow representing what would happen in clinical practice; trials are artificially
truncated, and data usually are reported as last observation carried forward. Therefore, reports of remission may be valid for comparing effectiveness but may not reflect the realities of treatment.
However, some data indicate that SSRIs may induce remission at a rate that is less
than that of alternative treatments, at least among certain subpopulations. Specifically,
evidence suggests that TCA compounds may be more effective than SSRIs at treating
individuals with the melancholic subtype of depression (Perry 1996). It has been speculated that the reason for this more favorable response characteristic is that TCAs
generally block the reuptake of both norepinephrine and serotonin. The Danish Uni
versity Antidepressant Group (1986, 1990) found that clomipramine, a potent norepinephrine and SERT inhibitor, produced a higher proportion of remission compared
with either citalopram or paroxetine. In addition, a meta-analysis of registration trials
with venlafaxine, a putative serotonin-norepinephrine reuptake inhibitor, suggested
that a slightly higher (but statistically significant) proportion of patients achieve therapeutic remission with this drug in comparison with the SSRIs (Thase et al. 2001). Alternatively, some recent data suggest that the overall therapeutic effect of venlafaxine
may not be greater than that of comparably dosed SSRIs (Montgomery et al. 2004).
Therefore, whether SNRIs exert a greater effect than SSRIs or a heightened effect in a
subgroup of depressed patients remains an open question.
The concept of “subgroup specificity” of response was initially supported by findings in the atypical subtype of depression, suggesting that individuals with this subtype preferentially responded to SSRIs. Atypical depression is characterized by socalled reverse vegetative features, including increased appetite and sleep along with
heightened mood reactivity (see Chapter 35, “Atypical Depression, Dysthymia, and
Cyclothymia”
to differential responsiveness to treatment, specifically a tendency to preferentially respond to MAOIs relative to TCAs. Earlier open and small-scale controlled treatment
research suggested that individuals with this subtype might be more likely to respond
). The boundaries of this condition were
described in the past in regard
-
-
-
250 The APA Publishing Textbook of Mood Disorders, Second Edition
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TABLE 15–4. Representative medications metabolized by specific cytochrome
P450 (CYP) enzymes
1A2
Acetaminophen
Amitriptyline
Caffeine
Clomipramine
Clozapine
Cyclobenzaprine
Duloxetine
Artemisinin
Bupropion
Cyclophosphamide
Efavirenz
Amitriptyline
Celecoxib
Diclofenac
Fluoxetine
Fluvastatin
Glibenclamide
Glimepiride
Estradiol
Fluvoxamine
Haloperidol
Imipramine
Mexiletine
Nabumetone
Naproxen
Ifosphamide
Ketamine
Meperidine
Glipizide
Glyburide
Ibuprofen
Irbesartan
Lornoxicam
Losartan
Meloxicam
Olanzapine
Ondansetron
Phenacetin
Propranolol
Riluzole
Ropivacaine
Tacrin
2B6
Methadone
Nevirapine
Propofol
2C9
Nateglinide
Piroxicam
Rosiglitazone
S-naproxen
S-warfarin
Suprofen
Theophylline
Tizanidine
Triamterene
Verapamil
S-warfarin
Zileuton
Zolmitriptan
Selegiline
Sertraline
Sorafenib
Tamoxifen
Tolbutamide
Torsemide
Valproic acid
Verapamil
Zakirlukast
Amitriptyline
Carisoprodol
Chloramphenicol
Citalopram
Clomipramine
Clopidogrel
Cyclophosphamide
Diazepam
Escitalopram
Esomeprazole
Hexobarbital
Imipramine
Indomethacin
Labetalol
Lansoprazole
Moclobemide
2C19
Nelfinavir
Nilutamide
Omeprazole
Pantoprazole
Phenobarbitone
Phenytoin
Primidone
Progesterone
Proguanil
Propranolol
R-mephobarbital
R-warfarin
S-mephenytoin
Teniposide
Voriconazole
251 Selective Serotonin Reuptake Inhibitors and Related Antidepressants
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TABLE 15–4. Representative medications metabolized by specific cytochrome
P450 (CYP) enzymes (continued)
2D6
Alprenolol
Amitriptyline
Amphetamine
Aripiprazole
Atomoxetine
Bufuralol
Carvedilol
Chlorpheniramine
Chlorpromazine
Clomipramine
Clonidine
Codeine
Debrisoquine
Alfentanil
Alprazolam
Amlodipine
Aprepitant
Aripiprazole
Astemizole
Atorvastatin
Boceprevir
Buspirone
Cafergot
Carbamazepine
Cerivastatin
Chlorpheniramine
Cilostazol
Cisapride
Clarithromycin
Cocaine
Codeine
Cycl
osporine
Dapsone
a
HIV antivirals: indinavir, ritonavir, saquinavir, nelfinavir, nevirapine.
Source. Adapted from Indiana University Department of Medicine: “Drug Interactions Flockhart
TM
.” Available at: https://drug-interactions.medicine.iu.edu/MainTable.aspx. Accessed June 30,
Ta bl e
2021.
Desipramine
Dexfenfluramine
Metoclopramide
Mexiletine
Dextromethorphan Minaprine
Donepezil
Duloxetine
Encainide
Flecainide
Fluoxetine
Fluvoxamine
Haloperidol
Imipramine
Lidocaine
Nebivolol
Nortriptyline
Ondansetron
Oxycodone
Paroxetine
Perhexiline
Perphenazine
Phenacetin
Phenformin
3A4,5,7
Dexamethasone
Lovastatin
Dextromethorphan Methadone
Diazepam
Diltiazem
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a
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