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252 The APA Publishing Textbook of Mood Disorders, Second Edition
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to SSRIs than to TCAs. However, at least two subsequent controlled trials did not support this contention, and another report suggested that atypical features predicted
earlier relapse in continuation and maintenance treatment after initial response.
In spite of this recent debate over the efficacy of SSRIs, these new antidepressants
have clearly had a positive impact on patient care because they have made pharma
cological treatment much more accessible to many patients with depression. Their
relatively long half-lives (most are around 24 hours) have made once-daily dosing
possible, a factor that promotes drug adherence.
Clinically Relevant Mechanisms of Action
When is an SSRI truly selective? Early in the evolution of SSRIs, serotonin selectivity
was touted as a therapeutic advantage, playing off of the idea that the broader recep
tor binding profiles of TCAs produced considerable side effects; theoretically, then,
selectivity would be expected to reduce the side-effect burden. However, given more
recent data suggesting a modestly improved effect with SNRIs, several studies have
tested the relative selectivity of antidepressant drugs. Most of the newer antidepres
sants are more potent serotonin than norepinephrine reuptake inhibitors, and determining when a drug has a dual versus single mechanism has been the focus of fierce
debate. Much discussion has focused on the relative binding affinities of drugs for the
SERT and NET in vitro (expressed as SERT/NET ratio), which is essentially a meaningless concept. The potency of a given drug at a site of action is the product of both
binding affinity and concentration. Therefore, a drug with very low affinity but a high
concentration in the brain may ultimately produce an equivalent effect to another
drug with the opposite properties.
Paroxetine did not show evidence of a stronger effect on the tyramine pressor test
as compared with amitriptyline (Hassan et al. 1985). Given the very high ratio of
SERT/NET binding affinity, this finding has been taken as evidence of paroxetine’s
relative selectivity for the SERT. However, although paroxetine binds to the SERT
much more potently, its affinity for the NET may not be trivial relative to other antidepressants. The in vitro binding affinity of [
is Ki=328 nMol, while that of venlafaxine is Ki=1,644 nMol. We have used the term
“serotonin-selective dose” to describe dosages of antidepressants in which the serotonergic effects predominate over the noradrenergic effects—for example, paroxetine
20 mg/day, sertraline 50 mg/day, or venlafaxine 75 mg/day. However, based on rel
ative affinity, certain compounds show changes in binding affinity (e.g., for NET) as
the dosage is increased, although exactly where these effects occur can be obscure.
Gilmor et al. (2002), as noted earlier, found that higher plasma levels of paroxetine
produced moderate blockade of the NET; low concentrations of paroxetine produced
relatively modest NET blockade (27%), but this effect increased somewhat at 200 ng/
mL (43%), leading the authors to conclude that paroxetine at higher dosages and
plasma concentrations could have a clinically meaningful noradrenergic effect.
Again, the actual effect within the brain is unclear.
3
H]norepinephrine for the human NET
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Related Side Effects
Certain side effects are common among SSRIs. These include nausea, vomiting, diarrhea, somnolence, fatigue, dizziness, tremor, insomnia, decreased libido, and erectile
253 Selective Serotonin Reuptake Inhibitors and Related Antidepressants
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dysfunction. Most side effects dissipate within 2 weeks of starting the medication, except for sexual dysfunction, which can be more persistent.
Serotonin-Norepinephrine Reuptake Inhibitors
Venlafaxine and Desvenlafaxine
Venlafaxine (Effexor and Effexor XR) was introduced into the United States in 1994,
and its primary metabolite, O-desmethylvenlafaxine (desvenlafaxine) (Pristiq), in
2008. Both are weak inhibitors of serotonin and norepinephrine reuptake (see
15–1) and very weak inhibitors of dopamine reuptake. Nonetheless, as noted earlier,
in human studies venlafaxine shows significant effects in measurements of both SERT
and NET blockade. This is due in part to the relatively high blood and cerebrospinal
fluid levels of the parent compound and the primary metabolite desvenlafaxine and
the very low protein binding of both. The low protein binding, and the fact that the
drugs do not significantly affect CYP enzymes, suggests that drug-drug interactions
would not typically be expected to occur (Ereshefsky and Dugan 2000). The primary
metabolic pathway is CYP2D6 for venlafaxine and CYP3A4 for desvenlafaxine, al
though the latter is primarily eliminated via direct glucuronide conjugation mediated
by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, 1A3, 2B4, and 2B15 en
zymes (Fossom 2008).
Venlafaxine is approved in a dosing range of 75–225 mg/day for the extendedrelease form (Effexor XR) and 375 mg/day for the immediate-release form (Effexor) (see
Table 15–2). Due to venlafaxine’s short half-life, twice-daily dosing is required for the
immediate-release form; however, the extended-release form and desvenlafaxine
(which is available only in an extended-release form) can be dosed once a day. Desvenlafaxine is approved at a dosage range of 50–100 mg/day. Venlafaxine has been approved by the FDA for the treatment of both major depressive disorder (MDD) and
generalized anxiety disorder (Gutierrez et al. 2003), and desvenlafaxine only for MDD.
Montgomery et al. (2002) conducted a survival analysis with data from two longerterm studies of venlafaxine in MDD and found an overall better response and fewer
dropouts at 150 mg/day relative to the 75 and the 37.5 mg/day dosages, indicating
that higher dosages may be more effective (Montgomery et al. 2002).
As discussed, both venlafaxine and desvenlafaxine have short half-lives, and
therefore, discontinuation reactions can be observed even after only brief interrup
tions (Haddad 2001). Like other sustained-release preparations (e.g., Paxil CR), venlafaxine XR and desvenlafaxine extended-release are not less prone to inducing such
reactions. Therefore, patients should be warned about interruptions in dosing. Venlafaxine and desvenlafaxine are also associated with mild elevations in blood pressure;
the immediate-release form of venlafaxine at higher dosages is more liable in this regard. It should be emphasized that these are not severe hypertensive events as seen
with MAOIs, and hypertensive responses are not more common in patients with a history of hypertension. However, monitoring blood pressure is recommended (Feighner 1995). Other common side effects associated with venlafaxine and desvenlafaxine
include nausea, somnolence, dry mouth, constipation, sweating, decreased libido,
and erectile dysfunction.
Table
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Duloxetine
Duloxetine (Cymbalta) is another dual reuptake inhibitor approved for marketing for
MDD in the United States. Dosing in clinical trials has ranged up to 40 mg twice per
day, and the drug has shown good tolerability (Nemeroff et al. 2002; Schatzberg 2003;
Sharma et al. 2000). In contrast to venlafaxine, this drug appears to induce low rates
of spontaneous hypertension (<2%) (Schatzberg 2003).
Because mild hypertensive reactions occur with other norepinephrine reuptake inhibitors (e.g., TCAs, venlafaxine), the question arises of whether duloxetine causes a
clinically meaningful blockade of norepinephrine reuptake. Duloxetine binds to SERT
and NET at Ki=0.8 and 7.5 nMol, respectively, yielding a SERT/NET ratio of 9 (as op
posed to 16 for venlafaxine [Owens et al. 1997]) (see Table 15–1) (Bymaster et al. 2001).
Work by Turcotte et al. (2001) and Chalon et al. (2003) called into question the in
vivo potency of duloxetine in blocking norepinephrine reuptake. Both studies in
volved administering duloxetine to healthy volunteers and performing the tyramine
pressor test as described earlier for venlafaxine. In both instances, duloxetine did not
produce the expected increase in blood pressure induced by the administration of
tyramine, in contrast to TCAs, although in the latter study it did increase whole-body
norepinephrine turnover (an indirect measure of reuptake inhibition). Duloxetine
showed evidence of SERT blockade, which is in contrast to both in vitro studies and
in vivo studies in animals, which indicated potent norepinephrine reuptake inhibi
tion. In addition, meta-analyses of clinical trials suggest that duloxetine was no more
effective than SSRIs for MDD (Cipriani et al. 2009, 2012, 2016).
Additional support for duloxetine’s norepinephrine reuptake inhibition comes
from the considerable number of preclinical (Wang et al. 2015, 2016) and clinical (Cit
rome and Weiss-Citrome 2012; Pergolizzi et al. 2013) studies on its use in pain. Potent
SNRIs such as TCAs and milnacipran improve peripheral pain (Häuser et al. 2012).
These effects on pain are mediated through three mechanisms: serotonin and norepinephrine reuptake inhibition and sodium channel blockade. Serotonin and norepinephrine have inhibitory effects on sensory transmission in nociceptive fibers in the
dorsal horn of the spinal cord (Micó et al. 2006). Duloxetine (Wang et al. 2010) and
TCAs such as amitriptyline (Furgała et al. 2018) also block Na
voltage-gated sodium channels, which produces antinociceptive effects in preclinical
models (Horishita
Duloxetine is approved in the United States for the treatment of fibromyalgia, dia
betic neuropathic pain, and chronic musculoskeletal pain. In addition, duloxetine has
been shown to be effective in reducing urinary stress incontinence in women, which
also supports a meaningful norepinephrine reuptake inhibition effect (Moore 2004).
Common side effects with duloxetine include nausea, dry mouth, somnolence,
constipation, decreased appetite, and sweating. The effects on sexual function were
assessed in four clinical trials using the Arizona Sexual Experience Scale (ASEX) (Eli
Lilly 2020). Overall, patients treated with duloxetine experienced more sexual dysfunction than did patients treated with placebo, as indicated by the ASEX total score. A sexspecific analysis showed that sexual dysfunction occurred only in males, who had more
difficulty achieving orgasm with duloxetine compared with placebo. Females did not
experience more sexual dysfunction on duloxetine than on placebo as measured by
ASEX total score; in fact, women given duloxetine or placebo and men given placebo
et al. 2017) that may mediate some of the beneficial effects on pain.
1.3, Na
v v
1.7, and Na v 1.8
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experienced a slight improvement in ASEX total score. Duloxetine and placebo were
generally neutral on other aspects of sexual function, including sex drive and sexual
arousal in both men and women and the ability to achieve an erection in men.
The primary metabolic pathways of duloxetine are via CYP1A2 and 2D6. It is
highly protein bound and is a moderate inhibitor of CYP2D6. It therefore has a mod
erate potential for drug-drug interactions.
Milnacipran and Levomilnacipran
Milnacipran (Savella) and its levorotary enantiomer levomilnacipran (Fetzima)
(Zadka et al. 2016) are highly potent SERT and NET inhibitors approved both in and
outside of the United States for a range of conditions, including depression and pain.
Milnacipran is approved outside of the United States for MDD, but it has never received FDA approval for this indication and is approved only for fibromyalgia. Levomilnacipran is only approved in the United States for MDD. The effects of SNRIs for
pain syndromes are discussed further in the earlier section on duloxetine.
Milnacipran and levomilnacipran are more “balanced” SNRIs in that NET binding
is higher relative to SERT binding than for other SNRIs. The relative SERT/NET ratios
of SNRIs are as follows: venlafaxine, 30:1; desvenlafaxine, 14:1; duloxetine, 10:1; milnacipran, 1.6:1.0; and levomilnacipran, 1:2 (Sansone and Sansone 2014). In spite of the
relatively high NET binding affinity, levomilnacipran produces only modest in
creases in blood pressure and pulse in the dosing range of 40–120 mg/day (Allergan
2019). Common side effects include nausea, vomiting, dizziness, sweating, insomnia,
constipation, urinary hesitancy, tachycardia, and palpitations. Effects on sexual interest were assessed in at least one clinical trial with levomilnacipran (Gommoll et al.
2014), using the ASEX as described earlier with duloxetine. In this trial, no differences
were found in ASEX total score between levomilnacipran and placebo in the overall
groups for males and females separately. By contrast, erectile dysfunction in men was
reported in clinical trials in 6%, 8%, and 10% of men given levomilnacipran 40, 80, or
120 mg/day, respectively, versus 2% in those given placebo (Allergan 2019). Rates of
other sexual side effects in both women and men participating in clinical trials were
low, but these trials may have underestimated the frequency. Milnacipran and levomilnacipran are metabolized by CYP3A4 and do not inhibit any CYP enzymes.
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Other Antidepressants
Nefazodone
Nefazodone (Serzone) is a phenylpiperazine derivative that is structurally similar to
trazodone but with an improved side-effect profile (Owens et al. 1997). It has low potency for the human SERT and NET (Ki=549 and 713 nMol, respectively) (Owens et
al. 1997). By contrast, binding of nefazodone and its principal metabolite, hydroxy
nefazodone, to the serotonin (5-hydroxytryptamine [5-HT]) type 2A (5-HT
is considerably greater (ketanserin binding Ki=7.1 and 7.2 nMol, respectively) (Owens
et al. 1997). Therefore, blockade of this receptor seems to be the basis of the therapeutic effect of nefazodone, much like trazodone. 5-HT
) receptor
2A
blockade shows antidepres-
2A
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sant- and antianxiety-like effects in animal behavioral models. Nefazodone is a
relatively potent norepinephrine α
receptor antagonist (Ki=5.5 nMol) (Owens et al.
1
1997) and a moderately potent histamine-1 blocker (Ki=30 nMol), which may account
for some of the side effects associated with the drug, including orthostatic hypoten
sion and sedation. The drug has a very short half-life (4–8 hours [DeVane et al. 2002]),
requiring it to be taken at least twice per day. It is usually started at a dosage of 200
mg/day, which is typically advanced to the 300–600 mg/day range, divided into two
doses. Rates of sexual dysfunction are relatively low.
There are some significant concerns associated with this drug. For example, it is a
potent inhibitor of CYP3A4, an enzyme responsible for the metabolism of many
drugs (see
Table 15–3) (Nemeroff et al. 1996). In addition, it has been reported to induce severe hepatotoxicity resulting in liver failure. The rate of serious hepatotoxicity
is low (~1/250,000–300,000 exposures [Sedky et al. 2012]), but the outcome is poten
tially catastrophic. Routine monitoring of hepatic function has not been established
to be effective in preventing toxicity and is not required by the FDA, although early
detection may improve outcome. Alternatively, counseling patients with regard to
this adverse outcome and the symptoms of hepatic dysfunction (e.g., nausea, jaundice, anorexia, malaise) is essential. Furthermore, nefazodone should be avoided in
people with baseline elevated transaminases, not because of an increased risk in these
patients but because of difficulties in prospective monitoring (Sedky et al. 2012).
Nefazodone is metabolized by CYP3A4, with CYP2D6 being a minor secondary
pathway. However, in the case of CYP3A4 inhibition, a higher proportion of metabo
lism is via CYP2D6. This is important because CYP2D6 metabolism forms meta-chloro-
phenylpiperazine, a psychoactive drug with anxiety-producing effects (Preskorn et al.
2012).
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Vilazodone
Vilazodone (Viibryd) is a very potent SERT inhibitor (Ki=0.1 nMol) and a 5-HT1A receptor partial agonist (half-maximal inhibitory concentration [IC
(Hughes et al. 2005). It has low (although not trivial) affinity for the NET and the
dopamine transporter (Ki=56 and 37 nMol, respectively) and extremely low binding
to other receptors (Hughes et al. 2005). It is approved in the United States for the treatment of MDD. Partial-agonist actions at 5-HT
receptors are similar to those of bu-
1A
spirone; therefore, vilazodone is expected to have significant antianxiety and antidepressant effects. This is supported by studies in some (but not all) anxiety models
(Treit et al. 2001). The clinical benefit in patients with generalized anxiety disorder
was shown in three well-designed controlled trials with a total of 844 participants
(Zareifopoulos and Dylja 2017). However, the development of vilazodone for this indication was suspended by the manufacturer. Nevertheless, vilazodone appears to be
effective for anxiety symptoms in patients with MDD (Thase et al. 2014).
Comparative effectiveness against other antidepressants is unknown. One important outstanding question is whether vilazodone is more effective than simply combining an SSRI, such as escitalopram, with buspirone, both of which are generic and
very inexpensive, unlike the branded vilazodone. Vilazodone has a higher affinity for
5-HT
receptors than buspirone (IC50=0.2 vs. 24 nMol), but whether this translates
1A
into superior efficacy is unknown.
]=0.2 nMol)
50
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Side effects commonly associated with vilazodone include nausea, diarrhea, vomiting, dry mouth, dizziness, and insomnia. The FDA-approved product information
includes warnings regarding acute pancreatitis and hyponatremia related to the syn
drome of inappropriate antidiuretic hormone secretion (SIADH). However, the frequency of these more serious reactions is low. It is metabolized by CYP3A4 and does
not inhibit CYP enzymes.
Vortioxetine
Vortioxetine (Trintellix) is approved for the treatment of MDD in the United States (Pae
et al. 2015a). It is a complex and unique medication in that it is a potent SERT inhibitor
(1.6 nMol), but it also has significant affinity for a number of serotonin receptors. It is
a 5-HT
antagonist at 5-HT
clinical implications of some of these binding effects are unknown, some actions can
be predicted on the basis of both preclinical and clinical pharmacology. For example,
actions at 5-HT
this is supported by both animal studies (Mørk et al. 2012) and human clinical trials
(Pae et al. 2015b). A recent meta-analysis of four randomized controlled trials in generalized anxiety disorder showed a significant, albeit modest, clinical effect (Pae et al.
2015b), although a second meta-analysis drew the opposite conclusion (Fu et al.
2016). It is not currently approved for the treatment of generalized anxiety disorder.
as the frontal cortex and nucleus accumbens (Huang et al. 2012). Increases in both norepinephrine and dopamine have been shown with vortioxetine in the medial prefrontal
cortex, nucleus accumbens, and hippocampus. These actions may improve attention
and executive function. One well-done controlled trial showed a significantly greater
effect of vortioxetine on the digit symbol substitution test (DSST) compared with placebo (Mahableshwarkar et al. 2015). Path analysis showed that vortioxetine had an
effect on the DSST that was independent of its effect on depression. The DSST taps
into a number of cognitive domains, including attention, memory, and executive
function, and the clinical significance of improvement on this test is unknown. Other
trials did not show a significant difference between vortioxetine and SSRIs on cogni
tion (Baune et al. 2018b; Nierenberg et al. 2019; Vieta et al. 2018); however, a recent
meta-analysis suggested that vortioxetine may have a greater effect than SSRIs,
TCAs, and placebo on the DSST (Baune et al. 2018a).
tion, dizziness, and sexual dysfunction. With the exception of nausea, these effects occur in less than 10% of patients in clinical trials, although, as noted earlier, sexual
dysfunction may be underreported in clinical trials. Vortioxetine is a CYP2D6 substrate and does not inhibit CYP enzymes.
receptor agonist (Ki=15 nMol), a partial agonist at 5-HT
1A
, 5-HT3, and 5-HT7 receptors (Sanchez et al. 2015). Although the
1D
and 5-HT3 receptors are expected to produce antianxiety effects, and
1A
Both 5-HT
agonists and 5-HT7 antagonists increase dopamine efflux in areas such
1A
receptors, and an
1B
Common side effects of vortioxetine include nausea, vomiting, diarrhea, constipa-
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Reboxetine and Atomoxetine
Both reboxetine (Edronax, Vestra) (Brunello et al. 2002; Kasper et al. 2000) and atomoxetine (tomoxetine; Strattera) (Kratochvil et al. 2003) are potent and relatively selective norepinephrine reuptake inhibitors. Therefore, these drugs are similar in their
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therapeutic potential to TCAs such as desipramine. Although the effectiveness of reboxetine for MDD is supported by several studies, and it is available outside of the
United States, FDA-regulated controlled registration trials were negative, and the
drug was never approved (Page 2003). This may be the result of failed rather than
negative trials—that is, caused by a relatively high placebo response rate. On the
other hand, atomoxetine has received FDA approval in the United States for ADHD
as a result of significant controlled trials. Atomoxetine has not been approved for de
pression; it was shown in at least one published Phase II clinical trial to be effective in
depression (Chouinard et al. 1984), although subsequent depression trials have been
negative. In addition, atomoxetine is not effective as an adjunct to SSRIs (Michelson
et al. 2007), and it does not effectively improve depression in children with ADHD
(Bangs et al. 2007).
Special Considerations
Serotonin Reuptake Inhibitor Discontinuation Syndrome
Abrupt termination of treatment with SERT inhibitors can result in a rapid onset of
one or more characteristic symptoms now associated with the discontinuation syn
drome: anxiety, crying, dizziness, headache, increased dreaming, insomnia, irritability, myoclonus, nausea (with occasional vomiting), paresthesias (including “electrical
sensations”), and tremor. This phenomenon appears to be linked to three significant
factors: SERT blockade, short half-life, and a relatively rapid decrease in dosage or
termination of the medication. The anticholinergic effects of TCAs also have been
touted as contributing to the problems associated with these drugs, especially in the
face of symptoms that are more consistent with cholinergic rebound (including gastrointestinal hypermotility, movement disorders such as akathisia, and arrhythmias).
However, this is a consistent property of SERT inhibitors, although half-life is key:
long-half-life drugs such as fluoxetine seldom produce significant discontinuation
syndrome, whereas short-half-life drugs such as paroxetine or venlafaxine very often
do (Michelson et al. 2000; Rosenbaum et al. 1998).
Serotonin reuptake inhibitor discontinuation syndrome is not peculiar to the
newer generation of agents, such as venlafaxine. In fact, the phenomenon has been reported with TCAs such as imipramine and clomipramine and with MAOIs (Lejoyeux
and Adès 1997). The highest relative rates of discontinuation symptoms have been
with TCAs (21.5%–100%) (Lejoyeux and Adès 1997), although this has not been confirmed in head-to-head comparisons. Prevention is the ideal approach to managing
the syndrome. When patients are being treated with shorter-half-life agents, slow tapering typically prevents significant symptoms. Furthermore, patients on any serotonin reuptake inhibitor should be warned about the incidence of discontinuation
symptoms after abrupt withdrawal. However, even with very slow tapering, some
patients experience intolerable symptoms. Slowing the tapering process sometimes
helps, but at times the substitution of another drug with a longer half-life is needed.
Fluoxetine can be added to shorter-half-life medications, followed by tapering of the
first medication and then by tapering of fluoxetine (Haddad 2001).
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In utero exposure to antidepressants and subsequent postpartum discontinuation
effects in infants also are of concern (Costei et al. 2002). One study showed an en
hancement of perinatal complications, particularly respiratory distress, in infants
born to mothers taking paroxetine at the time of delivery relative to infants exposed
to paroxetine earlier in pregnancy but not at delivery (Costei et al. 2002). This advo
cates avoiding short-half-life SERT inhibitors late in pregnancy. Alternative strategies
include discontinuation of the antidepressant well before delivery (although this
risks the return of depression) or substitution of a longer-half-life drug early in preg
nancy. Pregnancy issues should be considered when prescribing short-half-life drugs
in women of reproductive potential.
Sexual Dysfunction
Sexual dysfunction is a side effect common to all SERT inhibitors; although these
drugs have other chemical properties including α-adrenergic blockade and anticho
linergic effects, the most consistent theme is the blockade of SERT. Sexual side effects
were reported with serotonergic TCAs in the past. Common side effects of serotonin
reuptake inhibitors include decreased libido, impairment in erection (in men) or labial engorgement (in women), and inhibition of orgasm. Therefore, patients taking
these medications must be monitored carefully for persisting sexual side effects, be
cause this class of adverse reactions contributes significantly to premature discontinuation. Reported rates of sexual dysfunction with serotonin reuptake inhibitors have
varied widely, depending more on the ascertainment method than on the type of
drug. Conservatively, about half of the patients treated with serotonin reuptake inhib
itors experience significant dysfunction, with 15% or more having persistent symptoms (Ferguson 2001).
Caution needs to be exercised when evaluating sexual dysfunction associated with
serotonin reuptake inhibitors. Decreased sex drive and arousal are common in de
pression; about half of patients with depression report significantly decreased sexual
interest. Therefore, a baseline sexual history is an important part of information gath
ering in the evaluation of depression. Persistent sexual dysfunction may be a side
effect of antidepressant therapy but may also be a residual symptom of depression,
and, if so, should be addressed accordingly.
Management of sexual dysfunction can involve several different possible ap-
proaches. As noted, many individuals experience some improvement with time.
However, it often is an intolerable side effect and should be managed aggressively to
prevent premature termination of treatment. Decreasing the dosage or discontinuing
the medication for a short period has been recommended, although this typically is
ineffective and risks a return of depressive symptoms or discontinuation syndrome.
One alternative is switching to a drug with fewer side effects: for example, switching
from the serotonin reuptake inhibitor to bupropion, nefazodone, or mirtazapine has
been reported to be effective. However, some patients experience a significant return
of depressive symptoms on tapering of the serotonin reuptake inhibitor and therefore
must be restarted on the original drug. Adding bupropion to the serotonin reuptake
inhibitor is one management strategy; the addition of bupropion in the dosage range
of 100–300 mg/day has been reported to be somewhat effective, although relatively
few controlled clinical trial data are available (Safarinejad 2011).
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Suicide Risk
In 1990, Teicher et al. (1990) reported on a series of six inpatients who, at baseline, had
reported no suicidal ideation but developed intense suicidal preoccupation after ini
tiating treatment with fluoxetine. According to the authors, this state persisted for periods of between 3 days and 3 months after discontinuation. This set off a firestorm of
controversy about the potential of SSRIs to induce suicidal ideation in patients who
did not previously have thoughts of self-harm. Furthermore, allegations arose that
the risk of suicidal ideation with SSRIs has been downplayed by researchers due to
economic interests that are the product of financial relationships between pharmaceutical companies and universities (Healy 2003).
Some epidemiological data suggest that SSRIs do, in fact, enhance suicidal ideation
in certain patients. For example, Donovan et al. (2002) retrospectively evaluated 2,776
cases of deliberate self-harm that presented to the emergency department of the
Derbyshire Royal Infirmary in the United Kingdom. The incidence of self-harm by
drug was estimated from the number of prescriptions written for either a TCA or SSRI
in the Southern Derbyshire district for the same time interval. Donovan and colleagues
found a higher incidence of deliberate self-harm among the patients taking SSRIs than
among those taking TCAs. The relative risk of overdose (setting imipramine at 1.0)
was highest for fluoxetine, at 2.8, followed closely by flupentixol (an antipsychotic), at
2.6. The mean relative risk for SSRIs was 2.3, and for TCAs was 1.7. However, as the
authors noted, the SSRI-related risk was skewed by the risk for fluoxetine; for exam
ple, the risk with sertraline was 1.4, and the risk with paroxetine was 1.9, whereas the
risk for the TCAs clomipramine and lofepramine was 2.0 and 2.5, respectively. These
kinds of data have led some to conclude that the risk of self-harm is increased with
SSRIs, especially fluoxetine (Healy 2002). However, as the authors noted:
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Equally relevant, however, is the pragmatic consideration that prescribers are heeding
advice to prescribe safer-in-overdose antidepressants to patients who are perceived to
be at greater risk of [deliberate self harm]. This effectively “loads the dice” against anti
depressants such as the SSRIs, so that this manifests as an apparent excess of self-harm
behaviour in patients who had been prescribed these antidepressants. (Donovan et al.
2002, p. 556)
That is, people at higher risk of suicide are more likely to be prescribed medications
that are safer in overdose.
Data from controlled clinical trials generally have not indicated that SSRIs enhance
risk relative to non-SSRI antidepressants or placebo, with the exception of adolescents
and young adults (discussed later). Khan et al. (2000) assessed the frequency of sui
cides and suicide attempts along with symptom reduction derived from adult clinical
trial information for seven drugs in the FDA database: fluoxetine, sertraline, paroxetine, venlafaxine, nefazodone, mirtazapine, and bupropion. A total of 19,639 participants were included. The authors found no differences between the three groups
compared collectively, or within any given drug dataset; however, fluoxetine information was not available for that analysis. Therefore, no comment could be made in
regard to the suicide risk for fluoxetine per se, but this has been assessed by other
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261 Selective Serotonin Reuptake Inhibitors and Related Antidepressants
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studies. Beasley et al. (1991) conducted a meta-analysis of 17 controlled clinical trials
comparing fluoxetine (n=1,765 exposures) with TCAs (n=731), placebo (n=569), or
both. The pooled incidence of suicidal behavior did not differ between groups (sui
cidal acts: fluoxetine 0.3%, TCAs 0.4%, placebo 0.2%; suicidal ideation: fluoxetine
1.2%, TCAs 3.6%, placebo 2.5%). Together, these data make a compelling case for a
lack of association between SSRIs and an increase in suicidal potential.
More recently, small differences in rates of suicidal ideation, attempts, or nonsuicidal self-injury from individual clinical trials have led the FDA and other regulatory
authorities to issue warnings about the potential for certain SSRIs to enhance suicide
risk in adolescents. The FDA issued an initial warning based on a meta-analysis of
three unpublished controlled trials in depressed adolescents that failed to show differences between paroxetine and placebo (Wooltorton 2003). In these studies, suicidal
thoughts, suicide attempts, and episodes of self-harm were more frequent among
adolescents taking paroxetine (5.3% of 378) versus placebo (2.8% of 285). A similar
result was demonstrated in studies of adolescents with social anxiety disorder (paroxetine 2.4% of 165 vs. 0% of 157). In this review, the author stated that “Paroxetine is
contraindicated for patients under the age of 18...any pediatric patient currently tak
ing paroxetine should be screened for suicidal thoughts, suicide attempts or episodes
of self-harm” (Wooltorton 2003, p. 446).
Based on similar data, clinicians have been warned about the risk of suicidal behavior in adolescents treated with venlafaxine XR. This FDA warning came from an
analysis of children and adolescents between the ages of 6 and 17 years treated in both
open and controlled clinical trials. In a “Dear Healthcare Professional” letter, Wyeth,
the manufacturer of venlafaxine, outlined adverse event information from trials in
depression and generalized anxiety disorder conducted in children and adolescents.
The company noted an excess of discontinuations for adverse events in three categories—hostility (venlafaxine 2% vs. placebo <1%), suicidal ideation (2% vs. 0%), and
abnormal or changed behavior (1% vs. 0%)—and concluded: “Effexor and Effexor XR
have not been and are not now recommended for use in pediatric patients” (Wyeth
Pharmaceuticals 2003).
Subsequent, more comprehensive assessments of the FDA clinical trials databases
indicated that the risk of suicidal ideation and self-injury (although not completed
suicides) was highest in pediatric populations and progressively declined with age
(McCain 2009). Setting the suicide rate of 25- to 30-year-old subjects as the comparator, the odds ratio for suicidality was highest among pediatric patients (OR 2.22) and
lowest among subjects age 65 and older (OR 0.39) (McCain 2009).
Clinical trials databases are not the best for evaluating risk of increased suicidal potential, because patients with active suicidal ideation typically are excluded from outpatient trials and subsets of patients who may be at greater risk, such as those with
borderline personality disorder, are routinely excluded as well. One of the better datasets for evaluating risks in adolescents comes from the Treatment of Adolescent Depression Study (TADS; Emslie et al. 2006), given that adolescents with suicidal ideation
were not systematically excluded from participation. Adolescents with MDD were
randomized to treatment with fluoxetine, cognitive-behavioral therapy (CBT), combined treatment, or placebo. Notably, in the TADS, as in the FDA-analyzed studies
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