Because A.R. is exhibiting a full therapeutic response to escitalopram, the
recommendation would be for her to continue with the effective dosage (10 mg/day)
for at least 7 consecutive months. At the end of this time frame, the clinician should
review with the patient those considerations that enter into the decision to continue
treatment. Ultimately, the decision to continue antidepressant medications is left to
the patient’s judgment, and he/she should be well informed of the potential
consequences of stopping treatment.
In the future, if A.R. decides to discontinue her antidepressant she should fully
disclose this to her prescriber so that an appropriate taper schedule and subsequent
monitoring can occur. She should be advised of potential withdrawal symptoms
117 Abrupt discontinuation of chronic SSRI treatment (e.g., treatment
>2 months) has been associated with dizziness, headache, anxiety, lethargy,
dysphoria, and sleep problems.
5,117 The onset of these symptoms is generally within
36 to 72 hours of stopping treatment, and effects may persist for approximately a
week. Withdrawal symptoms generally are mild and self-limiting but can be
uncomfortable and alarming. Because of their relatively short half-life (and absence
of long-acting metabolites), paroxetine, fluvoxamine, and venlafaxine have been
associated with a more profound withdrawal presentation than other SSRIs and
SNRIs. Due to its long half-life (and that of its active metabolite), fluoxetine has not
been commonly associated with withdrawal symptoms. Nonetheless, it is advisable
to taper slowly off all antidepressant medications after an extended treatment course
to decrease the risk of withdrawal and subsequent relapse.
taper has not been established. Switching therapies within classes can be done
quickly (e.g., from sertraline to fluoxetine) without a cross-taper. When switching to
another class or off antidepressant completely then a 6 to 8 week taper is standard as
well as educating the patient to withdrawal symptoms and reassuring them that this is
not a life-threatening event. Because withdrawal is not life-threatening, a much faster
taper (3–7 days) can be completed with the patient’s approval.
Discontinuation of Antidepressants
Worse with paroxetine, venlafaxine
Symptoms: dizziness, nausea, paresthesias, anxiety/insomnia, flulike symptoms
Note: Risk of depression relapse is greatest 1 to 6 months after discontinuation.
Patients with major depression should always be assessed for the presence of
suicidal thoughts (e.g., “Do you ever feel like giving up?” “Are you thinking about
hurting yourself?”). Reports have noted that completed suicide rates range from 2%
to 15%. Up to 70% of suicides worldwide are persons with MDD.
made by the patients alluding to suicide (e.g., “Life is not worth living anymore,” “I
am leaving and may never see you again”) should be taken seriously. Several factors
may place a person at greater risk for a suicide attempt. These include living alone,
having a disabling illness, being unemployed, having a history of alcohol/drug abuse,
chronic pain, anxiety, or having a family history of suicide.
well, with women much more likely to attempt suicide, although men are more likely
For patients who are actively suicidal, hospitalization is often necessary and may
be facilitated against the patients will in high-risk settings. Other life-saving
interventions include establishing close contact with the patient’s family and
healthcare provider, convincing the patient to contract for his/her safety and ensuring
that firearms and other lethal means are removed from the home. Antidepressants
have different risks of lethality in overdose. Tricyclics are by far much more
dangerous than SSRIs. Duloxetine, venlafaxine, and mirtazapine are a much lower
risk than TCAs but higher than SSRIs. Among the SSRIs, citalopram has the greatest
risk of cardiotoxicity in overdose but still less than venlafaxine.
are at risk for attempting suicide, TCAs and MAOIs are contraindicated.
A.R. is at some risk for suicide, although she does not have a detailed plan at
present. She should be monitored closely during the first few weeks of therapy by
friends or family members. If her suicidal ideation becomes severe, A.R. should be
evaluated at a psychiatric emergency room for her own safety. Unfortunately, it is not
always possible to predict whether A.R. (or any depressed patient) will attempt
suicide. Even with the most conservative precautions, a small percentage of patients
successfully complete their suicide attempts.
CASE 86-1, QUESTION 4: After A.R. has been treated for a year she is asking about coming off her
appropriate way to proceed with discontinuation and treatment of depression during pregnancy?
A.R.’s escitalopram should be tapered during several weeks (e.g., decrease to 5
mg daily for 2–4 weeks, then discontinue). The risk of relapse is relatively low
during the first month off medication, but depressive symptoms often return during the
second or third months. The risk of relapse is highest during the first 6 months after
Antidepressants in Pregnancy and Lactation
The risk for depression is elevated during pregnancy and during the postpartum
121 A prospective investigation reported that women who discontinued their
antidepressant on learning, when they were pregnant, were much more likely to
relapse prior to delivery (68% relapse rate vs. 26% who continued treatment; hazard
Before deciding to treat with an antidepressant during pregnancy, one should make
a careful inventory of the benefits and risks. The consequences of maternal
depression on the mother and fetus must be compared with the potential risks of in
utero medication exposure. From the mother’s perspective, untreated depression
carries with it a great deal of distress during an emotional time. Sleep and appetite
may be compromised at a time when these functions are most important for the baby’s
development. Mothers may also be tempted to drink alcohol or abuse substances, and
studies have also shown that depressed mothers are much less likely to attend
123 Depression during pregnancy is a very strong risk factor for
Most of the SSRIs and newer antidepressants pose little risk for the development
of serious fetal malformations, and they have been subsequently categorized as Class
C by the FDA (suggesting that the risk to the fetus is not definitively known). Their
relative safety has been corroborated by two large case–control studies in which
very small increases in risks were reported.
One notable exception is with paroxetine, which was reclassified as Class D by
the FDA after the demonstration of an increased risk for congenital heart defects in
126 An additional concern with SSRIs and SNRIs in pregnancy is the risk
for a neonatal serotonin withdrawal syndrome immediately after delivery. This has
been reported with TCAs in the past as well. A small controlled investigation (n =
40) examined the effects of fluoxetine and citalopram on CNS effects in newborns
and found a significant increase in restlessness, tremor, shivering, and hyper-reflexia
during the first 4 days of life (vs. controls); these signs spontaneously remitted
127 Although some clinicians have interpreted these findings to
suggest that antidepressants should be tapered and discontinued prior to delivery,
others have argued that the delivery and the postpartum periods are major stressors
for the new mother, and the risk of relapse during this time would be unacceptably
high if the medication is withdrawn. Studies have also reported a small but
significant decrease in birthweight among babies exposed in utero to SSRI although a
prospective study found that neither depression or SSRI use effected infant growth.
Clinicians should be reminded, however, that both of these findings have been
consistently reported with depression in the absence of antidepressant treatment, and
attempts to distinguish the effects of the illness from medication effects in pregnant
women have met with mixed results.
129 The safety of bupropion in pregnancy has not
A recent review of animal studies uncovered an increased risk of congenital
abnormalities, but retrospective reviews in humans have failed to identify an
enhanced risk of fetal malformation or spontaneous abortions. Due to these findings
in animal trials, the FDA recently changed bupropion to a Class C rating. Data are
even more sparse with mirtazapine, venlafaxine, or duloxetine, but no obvious
adverse effects have been identified among infants exposed to these antidepressants
in utero. Similarly, fetal malformations have been rarely reported with TCAs and
they are generally regarded as safe in pregnant women. MAOIs, however, should be
avoided due to increased risks for hypertensive crises. Although screening for
depression is not suggested in the general population, it is recommended specifically
for those who are pregnant and postnatal.
If antidepressants need to be used, then
monotherapy is best; avoid first-trimester exposure, do not stop the antidepressant
abruptly, and do not discontinue prior to delivery due to the high risk of postpartum
For A.R., it is important to assess her risk for depression if she stops taking her
antidepressant. This was her first episode of depression (which occurred under
stressful circumstances), she is not currently symptomatic, and she does not have a
strong genetic predisposition to mood disorders. If she is committed to starting a
family, she should consider tapering off her escitalopram for several weeks before
attempting to conceive. If she becomes pregnant and her depression returns, the risk
to the fetus appears to be quite low with most SSRIs. Theoretically, this risk can be
reduced further if the antidepressant is started after the first trimester (when most
major fetal development occurs). An additional option for pregnant mothers suffering
from mild-to-moderate symptoms would be to consider psychotherapy.
Approximately 70% of new mothers report sadness or anxiety during the first few
days after delivery (baby blues), but these feelings will usually resolve within 1 to 2
weeks and do not require treatment. Approximately 10% of mothers will experience
unremitting symptoms postpartum that ultimately satisfy criteria for MDD. The onset
of these symptoms can be quite variable, ranging from the immediate postpartum
period to several months later. Although psychotherapy may be appealing and
obviate the need for medication exposure via breast milk, it is often inconvenient and
impractical for new mothers to leave the house on a weekly basis without their
infants. Antidepressant medications, therefore, are frequently prescribed to manage
depression, and if an antidepressant is the most effective option for the mother then
efforts should be placed on managing breast-feeding.
Because breast-feeding is widely advocated, the passive transfer of medication
from mother to infant must be considered. Studies with TCAs and SSRIs suggest that
concentrations of some antidepressants in breast milk are measurable. However,
subsequent concentrations in the infant’s bloodstream are relatively low, and the
sequelae from this exposure have been limited to scattered case reports of increased
infant irritability. Among the available agents, fluoxetine and the tricyclic
antidepressant doxepin have been associated with the highest concentrations in
infants, and although the clinical or developmental consequences of this finding have
not been elucidated, it has been recommended that these medications be avoided.
Recent studies with SSRIs suggest that the concentrations achieved in breast milk are
lowest with sertraline, and that paroxetine, citalopram, escitalopram, bupropion, and
venlafaxine are somewhere between the extremes of fluoxetine and sertraline.
an antidepressant is to be continued in a mother who is breast-feeding, the lowest
dosage should be prescribed. Concentrations of SSRIs in breast milk will generally
peak approximately 4 to 8 hours after oral administration. If a new mother is
particularly concerned about breast milk exposure, she can be advised to pump and
save breast milk immediately prior to taking the antidepressant.
The SSRIs are inhibitors of the cytochrome P-450 isoenzymes, but important
differences exist among the individual agents in their potency for specific metabolic
pathways (Table 86-8). For instance, the cytochrome P-450 1A2 isoenzyme (or
CYP1A2) is most sensitive to the inhibitory effects of fluvoxamine. Fluoxetine and
paroxetine have the highest impact on CYP450 2D6 with fluoxetine resulting in
approximately fourfold increase in TCAs and paroxetine a fivefold increase.
Fluoxetine’s active metabolite has weak-to-moderate inhibitory effects on the
CYP3A4 isoenzyme. In comparison, sertraline, citalopram, and escitalopram have a
much lower potential for CYP450 2D6 drug interactions but still inhibit the
metabolism of 2D6-dependent medications. The potency is typically between 30%
and 50% increases in AUC and is often clinically irrelevant. Therefore, CYP450
2D6 drug interactions are less likely to cause harm with sertraline, escitalopram,
citalopram, and fluvoxamine, but still require monitoring for a few weeks after the
antidepressant is added to the patients’ medication list.
Although in vitro affinities of antidepressants for the respective isoenzymes can be
very helpful for predicting potentially dangerous drug combinations, there is wide
interpatient variability in the intensity of these interactions. Much of this variability
can be attributed to genetic polymorphism. With CYP2D6, for example,
approximately 5% to 10% of Caucasian patients and 1% to 2% of Asian patients are
considered poor metabolizers via this isoenzyme.
139 CYP3A4 is the most abundant
CYP enzyme found in the human body. Among the SSRIs, only fluoxetine and
fluvoxamine have weak and moderate inhibitory effects on this isoenzyme,
respectively. This has resulted in approximately 50% to 150% increase in AUC of
the CYP450 3A4-dependent drug alprazolam.
Serotonin syndrome is a rare but potentially fatal interaction due to excessive and
prolonged serotonin within the synapse.
140 The syndrome includes a constellation of
symptoms, including anxiety, shivering, diaphoresis, tremor, hyper-reflexia, and
autonomic instability (increased/decreased blood pressure and pulse rate).
Fatalities have been attributed to malignant hyperthermia. It occurs due to excessive
serotonin overstimulating 5-HT1a
incoordination, and neuromuscular effects).
administration of medications that can cause the syndrome. With mild cases of
serotonin syndrome, the symptoms ordinarily resolve 24 to 48 hours after the
serotonergic agents have been discontinued. Supportive treatment may be necessary,
and for more severe reactions, the serotonergic antagonist cyproheptadine is most
140 Dantrolene has been administered successfully to manage
Excessive serotonin can occur via four mechanisms: preventing its breakdown,
preventing its reuptake into the neuron, increasing precursors or agonists, and
increasing its release. Most case reports of serotonin syndrome (and most fatalities)
have occurred with a combination of an MAOI and an SSRI, which is considered a
contraindication. Other case reports involve the combination of an MAOI (or SSRI)
with tryptophan, meperidine, SNRI, tricyclics, dextromethorphan, linezolid, and
140 One case of serotonin syndrome was reportedly induced by the
combination of clomipramine with S-adenosylmethionine (SAM-E).
the combination of an SSRI with Saint-John’s-wort may also
precipitate this pharmacodynamic interaction, but more recent evidence has
suggested that the MAOI properties of the herbal preparation are minimal with
therapeutic doses. Nonetheless, a case series of five older patients who exhibited
symptoms reminiscent of serotonin syndrome has appeared in the literature, and,
given the degree of uncertainty that persists, this combination of antidepressant agents
143 As noted by the previously described reports, the most concerning
risk is combining agents that increase serotonin via differing mechanisms such as
inhibiting the enzyme monoamine oxygenase and blocking the serotonin reuptake
pump. Serotonin syndrome has also been reported with concurrent administration of
multiple SSRIs; however, this would generally not be fatal. It is important to note that
many medications have MAO inhibitory effects although they are not classified as an
MAOI. This would include medications such as linezolid, dextromethorphan, and
The combination of trazodone with an SSRI could possibly pose some concern
because both classes of antidepressants augment serotonin activity in the CNS yet;
because both are reuptake inhibitors, it is very unlikely. Trazodone has been
associated with serotonin syndrome in two incidences, one involving the
coadministration of buspirone and the other associated with a concomitant MAOI.
However, in practice, trazodone is recommended and is commonly prescribed to
patients receiving an SSRI for the treatment of insomnia, with no confirmed cases of
serotonin syndrome that have surfaced in the medical literature thus making it a
possible risk only at very high doses.
QUESTION 1: M.G. is a 35 year old married female. She is diagnosed with MDD and has been tried on
two antidepressant trials at a therapeutic dose for a therapeutic duration?
Pooled results of clinical trials suggest that the majority of patients with major
depression receiving an adequate trial of any antidepressant will have a therapeutic
response, defined as at least a 50% reduction in depressive symptoms. However, for
a patient who is severely depressed, a 50% reduction in symptoms still leaves
him/her with significant psychopathology and associated disability. Consequently,
full remission is the preferred therapeutic end point.
5 The STAR*D trials showed that
after four stages of treatment (medication or psychotherapy), 33% of patients fail to
In addition, with each course of antidepressants, people were less
likely to achieve remission. One longitudinal investigation found that patients with
residual symptoms were 3 times more likely to suffer relapse during the 12 months
after treatment than those who had remitted.
148 Not surprisingly, patients with
treatment-resistant depression have 40% higher direct medical costs than those
without treatment-resistant depression, mainly due to medication and outpatient care
For M.G., the first step would be to confirm her diagnosis and rule out potential
medical explanations for her symptoms, specifically bipolar disorder. Bipolar
depression is diagnostically indistinguishable from MDD depressed episodes.
Because antidepressants are minimally effective in bipolar depression, it would
explain MGs lack of response if she were to have bipolar disorder. Iatrogenic causes
should also be explored, such as any new medications or substance misuse.
Assessing adherence to her previous medication trials is critical. A full therapeutic
trial is considered to be a minimum of 4 weeks of treatment at a dosage shown to be
clinically effective assuming the patient is compliant with therapy.
SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS
Because 30% to 40% of patients will effectively achieve remission and about 20%
to 25% of patients will stop an antidepressant because of side effects, many patients
started on a given antidepressant may eventually need a significant adjustment or
change to their original regimen.
In M.G.’s case, she has previously failed a therapeutic trial of sertraline and
fluoxetine. Although she had failed a sertraline trial, large controlled investigations
suggest that 50% to 70% of patients who are unresponsive or intolerant of one SSRI
will experience a therapeutic response to a different SSRI.
STAR*D trial, patients failing an initial course of citalopram were just as likely to
respond whether they were randomly assigned to a subsequent trial of a different
SSRI (sertraline) because they were to other antidepressant classes (venlafaxine and
153 Because M.G. has now failed two SSRIs, it is
recommended to try an antidepressant from a different class such as an SNRI, α 2
antagonist, or DA reuptake inhibitor.
5,10 For M.G., it was recommended to use an
SNRI and duloxetine was selected.
Venlafaxine, duloxetine, desvenlafaxine, and levomilnacipran are categorized as
serotonin/norepinephrine reuptake inhibitors (SNRIs) (Table 86-7). At dosages less
than 150 mg/day, venlafaxine’s therapeutic effects are mediated exclusively from the
blockade of serotonin reuptake. Therefore, associated adverse effects at these
dosages are qualitatively and quantitatively very similar to those found with SSRIs:
GI distress, sleep disturbances, and sexual dysfunction. At higher dosages, effects on
NE occur, and this can lead to the emergence of different adverse effects (e.g.,
tachycardia and hypertension) and insomnia. NE effects occurring with duloxetine,
desvenlafaxine, and levomilnacipran do not appear to be dose-dependent.
Levomilnacipran is an SNRI that has more potent effects on NE as compared to its 5-
HT reuptake. However, its potency at NE reuptake is similar to duloxetine, and the
ratio difference is due to its lower potency at 5-HT reuptake than the other
155,156 Venlafaxine, which is available as immediate- and extended-release
formulations, has a relatively brief plasma half-life (5–8 hours) and is demethylated
to an active metabolite (O-desmethyl-venlafaxine). This metabolite, desvenlafaxine,
was approved by the FDA in 2008 for the treatment of depression. Desvenlafaxine is
available as an extended-release tablet that has a similar mechanism of action as
venlafaxine. It has no affinity for muscarinic, histaminic, cholinergic, or adrenergic
receptors and has a terminal half-life of 11 hours.
157,158 Desvenlafaxine is not affected
by CYP2D6 inhibitors; however, CYP3A4 inhibitors may reduce clearance of the
138 Duloxetine also has a relatively short half-life (12 hours) and is metabolized
via CYP450 1A1. Levomilnacipran is mainly metabolized by CYP3A4 with a
terminal half-life of 12 hours and is available as an extended-release tablet.
Venlafaxine, desvenlafaxine, and levomilnacipran are not potent inhibitors of
cytochrome P-450 isoenzymes. Duloxetine is a moderate inhibitor of the CYP2D6
138,159 As with SSRIs, SNRIs have been associated with serotonin
syndrome. Additionally, increased BP will occur if combined with an MAOI.
As a class, all SNRIs have a risk of increasing blood pressure and heart rate
thought to be due to the increase in NE. Venlafaxine averages an increase of 1 mm Hg
160 Duloxetine averages 1 mm Hg in BP and 3 bpm.
averages an increase of 2 mm Hg and 4 bpm.
162,163 Levomilnacipran has the greatest
risk and averages an increase of 4 mm Hg in BP and 8 bpm compared to placebo.
There will be some patients who
have large changes in BP with any of the SNRIs; thus, monitoring of vital signs is
necessary a few weeks after every dose increase.
Duloxetine has also been shown to increase LFTs 3 times the upper limit of normal
by approximately 1.3% compared to 0.2% in placebo-treated patients.
these numbers are small and similar to other antidepressants, the FDA has given
duloxetine a warning that it is not to be prescribed to patients with substantial
alcohol use or evidence of chronic liver disease.
165 Levomilnacipran has also been
shown to mildly increase LFTs at initiation of therapy.
CASE 86-2, QUESTION 2: M.G. is given a prescription of duloxetine 30 mg QAM yet she has heard from
SSRI and Serotonin Receptor Modulators
Vilazodone and vortioxetine are members of a new class of antidepressant. These
medications have their primary effect on depression via inhibition of the serotonin
reuptake pump, like the SSRIs (Table 86-10). These two agents also have potency at
other serotonin receptors. Vilazodone is a partial agonist at the 5-HT1a
Vortioxetine is a 5-HT1a agonist, 5-HT1d
, 5-HT7 antagonist, and 5-HT1b
In two separate studies, vortioxetine 20 mg
showed a slightly less reduction in MADRS compared to duloxetine 60 mg QAM, –
15.57 versus –16.9, respectively and –18.8 versus 21.2, respectively.
Vilazodone should be taken with food as this increases absorption by about 50%.
It is metabolized primarily by CYP450 3A4 and secondarily through 2C19. Inhibitors
and inducers have a small effect on blood levels. Its half-life is approximately 25
171 Vilazodone seems to have no effect on CYP450 isoenzymes.
is metabolized via multiple CYP 450 pathways with 2D6 being the primary one. It
has a half-life of approximately 60 hours. It does not appear to effect the metabolism
of other drugs using CYP450 (Tables 86-7 and 86-8).
When speaking with M.G., it would be accurate to state that the new medication is
not likely to be any better than her current prescription. Monitoring vital signs is
more important with duloxetine than with vortioxetine although the change in vital
signs with duloxetine is minimal and usually clinically irrelevant. Duloxetine has a
potential for inhibiting CYP450 2D6 that is greater than vortioxetine. Duloxetine
should be titrated to 60 mg QAM; thus, a dose increase is necessary to monitor for a
therapeutic response (Table 86-9).
OTHER AGENTS: BUPROPION, MIRTAZAPINE, TRAZODONE, AND
Bupropion is an aminoketone with a mechanism of action that is clearly different
from that of any other antidepressant because its therapeutic effect is due primarily to
DA reuptake inhibition and has negligible effects on serotonin (Table 86-7).
lack of serotonin provides a benefit in regard to both a lack of sexual dysfunction and
sedation but has the negative effect in that it is definitively less anxiolytic as
compared to the proserotonergic effect of the other antidepressants.
dosages, bupropion has a different adverse effect profile compared to SSRIs and
SNRIs. Nausea, insomnia, agitation, and jitteriness are the most common, likely due
to the stimulatory effect of DA. Seizures are a risk but are unlikely with therapeutic
dosing of bupropion, provided that patients are not predisposed (e.g., history of
epilepsy, bulimia, electrolyte abnormalities, or recent history of heavy drinking).
Bupropion may decrease appetite. A randomized, placebo-controlled investigation of
bupropion in depressed obese patients observing caloric restriction found that
bupropion was much more likely to induce significant weight loss than placebo.
After 26 weeks of treatment, 40% of the bupropion-treated patients lost more than
5% of their total body weight versus 16% with placebo. This weight loss was
positively correlated with an improvement in depressive symptoms. It has little-to-no
negative effect on sexual function due to no stimulation of 5-HT receptors. For
patients who develop sexual dysfunction from the SSRI or SNRI, bupropion has
shown some benefit as an adjunctive treatment that reduces the side effect. It is also
useful for poor responders as an adjunct to SSRI/SNRI due to its unique
5 Bupropion does not seem to affect cardiac rhythm or induce
arrhythmias in susceptible patients.
175 Patients with hypertension should be monitored
for increases in BP if bupropion is initiated.
Bupropion is converted via the cytochrome CYP450 2B6 isoenzyme to an active
metabolite (9 hydroxybupropion). Bupropion (and its metabolite) appears to have a
moderate effect at inhibiting the CYP450 2D6 isoenzyme, and significant elevations
of venlafaxine and metoprolol have been demonstrated to occur with concurrent
administration (Table 86-8). Because of its short half-life (approximately 8 hours for
the parent compound and 12 hours for the active metabolite), therapeutic doses of
regular release bupropion must be administered in divided doses. The recommended
starting dose is 100 mg twice a day (BID), increasing to 100 mg 3 times a day (TID)
after at least 3 days. Individual doses must not exceed 150 mg and should be given at
least 6 hours apart. For the SR formulation, initial daily doses are 150 mg every day,
increased to 150 mg BID by the fourth day at the earliest. Individual doses of
bupropion SR can be as large as 200 mg, and divided doses should be given at least
8 hours apart. The once-daily formulation is initiated at 150 mg daily and increasing
to 300 mg daily as early as the fourth day. Maximum daily doses are 450 mg for
regular and XL products, and 400 mg for SR products (Table 86-9). Maximum doses
should be strictly followed due to the dose-dependent risk of seizures.
Mirtazapine is a novel antidepressant capable of modulating serotonin and NE
activity through a complex mechanism of action. In vitro studies reveal that
mirtazapine is an antagonist at presynaptic α2
-autoreceptors and postsynaptic 5-HT2
In addition, it appears to possess some mild inhibitory
properties at serotonin reuptake transporters. Therefore, the net effect of mirtazapine
is to enhance serotonin and NE in a manner that is clearly distinct from any other
antidepressants (Table 86-8). In a comparative randomized trial with fluoxetine for
moderate-to-severe depression, mirtazapine appeared to be much more effective than
fluoxetine after 4 weeks of treatment (58% responders vs. 30% with fluoxetine;
P<0.05), but the differences were no longer significant at 6 weeks (63% vs. 54%; P
The most common adverse effects experienced with mirtazapine are sedation and
weight gain. Because mirtazapine has potent antihistaminergic effects, it can be quite
sedating and is often used as a hypnotic similar to trazodone. Unlike trazodone,
antidepressant dosing is quite tolerable. Anecdotally, it has been reported that higher
daily doses of mirtazapine (>30 mg) are less sedating than lower doses owing to a
plateauing of antihistaminic effects at 15 mg but an increase in noradrenergic effects
up to 60 mg. In addition to the substantial risk of increasing appetite and total body
weight, mirtazapine has been associated with significant increases in total
cholesterol and triglycerides. This is likely due to its combination of H1 and 5-HT2c
antagonism, the pharmacology related to atypical antipsychotic metabolic effects.
This makes mirtazapine less preferred than SSRIs in the diabetic patient.
Mirtazapine does not appear to affect cardiac rhythm or induce arrhythmias.
recommended starting dosage is 15 mg at bedtime, and the therapeutic dosage ranges
from 15 to 45 mg/day (Table 86-9).
179 Data from controlled trials have demonstrated
safety and efficacy in doses up to 60 mg daily.
179–181 As with bupropion, mirtazapine
is considered a top choice for antidepressant combination therapy in poorly
responding patients on an SSRI/SNRI. Despite the fact that mirtazapine is increasing
5-HT and NE as do SNRIs, its unique method of doing this via α2 antagonism makes
the combination with an SNRI or SSRI recommended.
Nefazodone and trazodone have similar mechanisms of action. Both are serotonin
reuptake inhibitors but nefazodone also has a mild NE reuptake inhibitory effect
(Table 86-7). Both also block 5-HT2
17 This particular characteristic has
resulted in very little sexual dysfunction, and switching studies have shown that
patients who develop sexual side effects with SSRIs do not have this side effect with
Interestingly, trazodone does have the rare but well-documented side
184 Trazodone, which comes as immediate-release and an
extended-release caplet, is rarely used for depression due to its potency of H1
antagonism centrally resulting in significant sedation and somnolence.
Antidepressive effects with trazodone occur above 150 mg a day with most patients
requiring >300 mg a day, yet sedation occurs at low doses such as 25 mg.
has caused clinicians to use trazodone as a hypnotic with other antidepressants
instead of trying to titrate up and use it as monotherapy. It is also a potent α 1
receptor antagonist and can cause orthostasis.
10,184 A reason that nefazodone has not
been used more is due to its potential for hepatotoxicity.
common than any other antidepressant. With appropriate monitoring, such as LFTs q3
months for the first 18 to 24 months, this risk is nearly eliminated.
drugs with hepatotoxic risks such as valproic acid increase this risk making
nefazodone more difficult to use than most other antidepressants. Nefazodone is
metabolized via CYP450 3A4 and is also a moderate-to-strong inhibitor of CYP450
The SSRIs are recommended over TCAs in the treatment of mood disorders. The
popularity of SSRIs can be attributed to numerous advantages over older compounds,
including a lower side effect burden, safety in overdose, less dosage titration, and
5,10,26 Results of a meta-analysis concluded that although the overall
efficacy of the SSRI and TCA classes was comparable, primary care patients
receiving an SSRI were much less likely to discontinue therapy prematurely due to
187 TCAs cause a variety of adverse effects, ranging from bothersome
(dry mouth, sedation, constipation) to serious (cardiovascular effects), which often
prevent patients from receiving therapeutic doses of medication.
with prescribed medication may also be compromised with TCAs.
SSRIs and the newer SNRIs are preferred for treatment of depression, TCAs
continue to be prescribed at low doses for other indications that are comorbid with
depression (e.g., migraine prophylaxis, chronic neuropathic pain). This requires
careful monitoring for drug interactions as TCAs as a class are primarily
metabolized via CYP450 2D6 and, as noted previously, some SSRIs and SNRIs may
inhibit this pathway substantially increasing the risk of TCA toxicity.
Therapeutic effects of TCAs are primarily through their ability to inhibit the reuptake
of serotonin and NE, functionally an SNRI (Table 86-7).
significant effects on acetylcholine, histamine, and α noradrenergic receptors all of
which are considered potential for side effects. The intensity of these side effects has
been shown to adversely affect adherence.
26 Although patients may develop tolerance
to these effects, they may never disappear completely.
Due to the potent histamine 1 antagonism centrally, TCAs can be very sedating and
are usually administered at bedtime to minimize functional impairments. Confusion or
memory deficits may also occur with TCAs and can be particularly onerous in
elderly patients. The secondary amines may be more tolerable in this regard, but all
TCAs can impair concentration or alertness to some extent and are not recommended
10 The sedating antihistaminic effect (along with orthostasis) increases
the risk of falls. The risk of weight gain and constipation make TCAs undesirable in a
patient with comorbid diabetes.
Orthostatic hypotension is the most common and troublesome cardiovascular effect
of the TCAs (as well as MAOIs) because it can result in significant morbidity and
191,192 Major clinical consequences of orthostatic hypotension include falls
leading to bone fractures, lacerations, and even MI. Patients with CHF and the
elderly are at greatest risk for experiencing orthostatic hypotension. The tertiary
amines (e.g., amitriptyline, imipramine) may cause more severe orthostatic
hypotension than the secondary amines (e.g., nortriptyline, desipramine), and
research supports the contention that nortriptyline has the lowest risk for causing
orthostatic hypotension among TCAs.
There are substantial differences among antidepressants (and antidepressant
classes) in regard to overall cardiac safety and arrhythmogenic effects in particular.
In general, the SSRIs appear to be relatively safe in patients with a history of
In a placebo-controlled investigation, hospitalized
patients with unstable cardiac disease were randomly assigned to either sertraline or
195 Overall, both treatment arms were very well tolerated, and there was
actually a lower risk of severe cardiac events reported in the sertraline group (vs.
placebo). Retrospective data suggest that SSRIs may be somewhat cardioprotective
in depressed patients with heart disease, a benefit that might be explained by their
ability to decrease platelet activation.
TCAs increase heart rate, probably via intrinsic anticholinergic properties that
increase sinus node activity. Clinically, this effect is generally not significant,
especially in medically healthy depressed patients.
important in those with underlying conduction disease, coronary artery disease, or
CHF. TCAs, even when used at therapeutic dosages for the treatment of depression,
decrease premature atrial and ventricular contractions in both depressed and
199,200 Because TCAs have a Class 1A antiarrhythmic activity,
they have arrhythmogenic activity and thus increase the chances of ventricular
arrhythmias and even sudden death. This effect on rhythm and conduction is believed
to be related to the inhibitory effects of TCAs on the fast sodium channels and a
decrease in Purkinje fiber action potential amplitude, membrane responsiveness, and
200 Even nortriptyline, which is believed to be one of the safer
TCAs in patients with heart disease, was associated with a greater risk for adverse
cardiac events than paroxetine.
In patients with preexisting conduction defects and
in overdose, there is a greater risk for cardiac arrhythmias.
should receive a baseline electrocardiogram (ECG) before therapy, and use in
patients with preexisting cardiac conduction abnormalities should be avoided.
Other risks associated with TCAs are a lowering of the seizure threshold. This
seems to be worst with clomipramine and maprotiline compared to the others in the
10,202,203 This event is particularly risky in high doses, similar to bupropion. If
patients are at risk of seizures or have a seizure disorder, SSRIs are much safer and
10,202,203 TCAs have also been shown to produce
photosensitivity; thus, excessive exposure to sunlight has resulted in severe sunburns.
In patients who have had this reaction
or whose lifestyle requires frequent contact with sunlight (e.g., lifeguard),
switching to another class is recommended.
MAOIs are an alternative for patients who have failed multiple antidepressant trials.
MAOIs are believed to relieve depressive symptoms by enhancing the activity of
monoamines. This is done by blocking the enzyme monoamine oxidase which breaks
down serotonin, dopamine, and NE. This is in contrast to SSRI/SNRI which
increases 5-HT and/or NE by preventing its reuptake into the neuron. This may be
desirable for refractory cases. Candidates for treatment should be chosen carefully,
and MAOIs should be used only by specialist practitioners such as a psychiatrist.
Phenelzine, tranylcypromine, and isocarboxazid were commonly prescribed for the
treatment of depression in the 1970s and 1980s, and their usefulness waned primarily
because of the risks of serious drug–drug and drug–food interactions.
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