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.
treatment of depression, MAOIs are not recommended except for the treatment of
atypical depression where this class appears to have a small efficacy advantage over
5,10 Data comparing TCAs with SSRIs for atypical depression suggest
that the two classes are comparable in efficacy and both are superior to placebo and
so SSRIs should still be tried first due to safety concerns.
The “cheese reaction,” which can manifest as a hypertensive crisis, is so named
because it occurred in patients who were taking nonselective MAOIs and ingested
foods high in tyramine, a by-product of tyrosine metabolism that is found in certain
foods and beverages, such as aged cheese or Chianti wine (Table 86-12). When
tyramine is ingested in the absence of an MAOI, it is rapidly metabolized by the
MAO enzyme in the GI tract before systemic absorption. In the presence of an MAOI,
more tyramine is absorbed and relatively high concentrations of tyramine may be
achieved in circulation, resulting in the displacement of NE (and other
catecholamines) from presynaptic storage granules. NE surges into the synapse, and
as metabolic degradation is inhibited by the MAOI, a profound pressor response is
207 A slightly safer version of the MAOI class is the once-daily selegiline
transdermal. By avoiding the GI tract, selegiline has less effect on the MAO that
reduces tyramine from entering the bloodstream via food. Despite the improved
safety of selegiline transdermal to oral MAOIs, there still remains a risk of food–
drug interactions resulting in hypertensive reactions, particularly at higher doses, and
so the FDA has recommended diet restrictions for doses over 6 mg/24 hours.
Additionally, there are application site reactions that occur in approximately 35% of
5,208,209 This agent is available in 6, 9, and 12 mg strengths. Selegiline
transdermal as well as oral MAOIs are reserved for refractory cases and should be
used only by skilled clinicians.
Smoked, aged, or pickled meat or fish
Aged cheeses (e.g., Stilton, blue cheese)
Yeast extracts (e.g., marmite)
Beer (microbrewed > commercial)
inhibitors. J Clin Psychopharmacol. 1989;9:397.
Orthostatic hypotension, weight gain, edema, and sexual dysfunction are common
191 As is the case with the TCAs, the nonselective MAOIs can
cause clinically significant postural decreases in BP. However, with the MAOIs, the
mechanism is believed to be a direct sympatholytic effect because both the lying and
the standing systolic BP readings are decreased.
210,211 Phenelzine seems to cause
orthostatic hypotension more commonly than does tranylcypromine.
orthostatic hypotension appears to be dose-related, a reduction in dosage may be
213 Sexual dysfunction occurs in up to 20% of patients taking MAOIs but may
diminish and disappear spontaneously over time.
214,215 A switch into mania has been
reported in up to 10% of patients with a history of bipolar disorder. Therefore,
MAOIs should be avoided in this population.
191 Although MAOIs are not known as
antimuscarinic medications, some patients complain of anticholinergic-like side
effects, including blurred near vision and urinary retention. Dosage reduction may be
helpful, but these effects may also diminish over time. The nonselective MAOIs are
not associated with proarrhythmic, antiarrhythmic, or contractility effects when used
in therapeutic dosages. Like other MAOIs, selegiline can be quite activating, and
insomnia is frequently reported.
Several potentially fatal drug–drug interactions occur with nonselective MAOI
antidepressants. Like the reaction with tyramine, indirect sympathomimetics such as
phenylpropanolamine and pseudoephedrine (common ingredients in over-the-counter
cold preparations and diet pills) can cause a precipitous rise in BP that can result in
The potential for serotonin syndrome with the combined use of SSRIs and MAOI
antidepressants or other medications with MAOI effect is well documented. A
washout period of at least 14 days should separate the use of an SSRI and an MAOI.
Because fluoxetine (and its primary active metabolite norfluoxetine) has a much
longer half-life, the recommended washout period is at least 5 weeks after
60 mg QAM. An increase to 90 mg resulted in intolerable insomnia. She has had a partial response
Antidepressant Augmentation with NonAntidepressants
Treatment refractory depression (TRD) is considered to be a failure to reach
remission with 2 or more antidepressant monotherapy trials that were given at a
for an appropriately therapeutic period. Generally, a therapeutic dose is for 4 to 8
weeks. This would not include the time it takes to titrate to a therapeutic dose.
common strategy for TRD includes combining antidepressants such as an SSRI with
bupropion or mirtazapine, as mentioned previously. Other strategies are augmenting
an antidepressant with a medication from another class, or somatic treatments,
There are many options to augment an SSRI/SNRI if the patient has not achieved a
full response. Some atypical antipsychotics, lithium and triiodothyronine, all have
studies showing efficacy. Buspirone has less robust data but is still
5,216,217 The use of atypical antipsychotics for the management of
treatment-resistant depression has become relatively common among mental health
providers due to well-designed and replicated studies. Four atypical antipsychotics
(olanzapine in combination with fluoxetine, aripiprazole, brexpiprazole, and
quetiapine) have received FDA approval as adjunctive agents with SSRIs or SNRIs
for depression that has poorly responded to monotherapy, and others have been
reported to be effective as well.
5,216,217 Generally, lower doses of second-generation
antipsychotics have been successfully used in trials for depression (vs.
schizophrenia), and relatively rapid improvement was evident. Given the significant
risk of metabolic side effects that have been reported, clinicians must carefully weigh
the risks and benefits of recommending this augmentation strategy prior to maximizing
antidepressant monotherapy trials and antidepressant combinatioms.
recommended that nonbehavioral health specialists use caution when using the
atypical antipsychotics for poorly responding patients.
One instance where the use of an atypical antipsychotic adjunct is given during the
acute phase is with psychotic depression. Patients with psychosis during the
depressed episode, as with multiple previous episodes and depression severity, are
at greater risk of chronicity and suicidality.
10 Multiple studies have shown benefit of
antipsychotic and antidepressant combination better than either monotherapy. Despite
the fact that monotherapy may be appropriate for the maintenance phase, it is
recommended to start an antipsychotic with the antidepressant during the acute phase
and slowly taper off after the persons depression and psychosis remits.
least preferred antidepressant is bupropion. Its prodopaminergic effect could worsen
10 ECT is also a recommended treatment.
Lithium’s antidepressant properties as an augmenting agent have primarily been
217 Seven of nine antidepressant augmentation trials with
lithium have reported positive therapeutic effects, usually within 1 week of achieving
steady state dynamics (i.e., 3–7 days of daily dosing).
levels are generally within the range used to treat bipolar disorder (0.5–1.2 mEq/L).
Lithium has a very narrow therapeutic index along with multiple significant drug
interactions and should only be used by a clinician skilled in its use.
) also has a long history of use in psychiatric circles for
patients exhibiting partial or suboptimal responses to antidepressant monotherapy.
Five of six RCTs support the use of T3 supplementation for antidepressant
augmentation, with an average effect size of 0.58 reported.
dosage of 25 mg/day, can accelerate as well as augment antidepressant response, and
superior effects have been reported in female patients, in particular. The response to
the thyroid supplementation should be noticeable within 1 to 2 weeks, much like that
found when lithium is used to augment therapy. Thyroxine (T4
with typical daily doses of 75 to 100 mcg daily often used. In the STAR*D trials, T3
was compared to lithium for antidepressant augmentation with citalopram in patients
with two previous treatment failures.
221 Remission rates were modest for both agents
in this challenging population (24.7% with T3 vs. 15.9% with lithium), and there was
no significant difference between these two therapies.
In the STAR*D trial, augmentation with bupropion was compared to buspirone and
both adjunctive treatments showed 30% remission rates.
benefit to patients with residual symptoms of anxiety, in particular, and titration up to
daily doses of 30 to 60 mg daily is often required.
5,182 Stimulants and modafinil have
generally shown no benefit on depressive symptoms overall.
provide temporary relief from excessive fatigue and somnolence while waiting for
the full antidepressant effect of the primary treatments.
Because M.G. had a failure to two monotherapies and some response to
duloxetine, the option of adding a medication to the SNRI is the next step.
Combinations of duloxetine with another antidepressant (mirtazapine or bupropion)
or with an atypical antipsychotic are both recommended. Mirtazapine, quetiapine,
and olanzapine would help if there is any insomnia and would protect against this
side effect if duloxetine were to be increased in the future. Bupropion would
possibly worsen the insomnia. Aripiprazole, brexpiprazole, mirtazapine, quetiapine,
and olanzapine (least to most) all could cause weight gain worsen cholesterol.
Discussing the risks of each option is critical and letting M.G. help decide which
choice fits her lifestyle will ensure better adherence. M.G. decided to start
aripiprazole 2 mg QAM and will increase her exercising to mitigate the possible
weight gain and cholesterol increase.
What are the recommendations for the treatment of pediatric depression?
Rates of pediatric depression are less than in adults. As a person ages, the risk of
depression increases with rates of 0.5% in 3- to 5-year-olds increasing to 3.5% in
10,223 Diagnosing pediatric depression uses the same criteria from
the DSM 5 as for adults; however, the interview questions may be slightly different.
For example, poor concentration may be mislabeled as procrastination or anhedonia
might be described as “being bored.”
9 Treatment guidelines do differ compared to
adults. One reason for this is that placebo rates are much higher in pediatric studies
resulting in the medication not having as dramatic a difference when compared to the
difference between placebo and drug in adult studies. Thus, there are many studies
where SSRIs had strong response rates but placebo also did and the medication was
not considered to be statistically different.
224–226 Due to this high response rate from
placebo and the support given by being a subject in a research study, the expert
guidelines recommend supportive care and formal talking therapy be the first option
for mild-to-moderate depression.
227,228 Medications can be used if symptoms are
moderate to severe. Pharmacotherapy options are limited, though, compared to
adults. Fluoxetine is FDA-approved down to age 8, escitalopram to age 12.
older), fluvoxamine (8 and older), and sertraline (6 and older) are FDA-approved
for obsessive compulsive disorder but not depression. The SNRI duloxetine is
approved for 7 years old and above for generalized anxiety disorder, and imipramine
is approved for 6 and older for enuresis. To summarize, only two antidepressants are
FDA-approved for depression in children although some other antidepressants do
have nondepression indications in children.
CASE 86-3, QUESTION 2: The child psychiatrist’s initial recommendation is to have A.A. meet with a
medication. Which medication is the preferred agent?
Unlike adults where all antidepressants are similarly effective, pediatric
depression guidelines have recommended that SSRIs particularly fluoxetine and
escitalopram be the treatments of choice.
227,228 Fluoxetine’s starting dose is 10 mg
QAM with a target dose of 20 to 40 mg a day. Escitalopram’s starting dose is 5 to 10
mg QAM with a target dose of 10 to 20 mg a day. Interestingly, the separation from
placebo increases as the child ages for many of the SSRIs. For example,
escitalopram did not statistically differ from placebo in the under 12 year old age
group but did so in the adolescent age group.
224,229 Paroxetine is not recommended for
depression due to overall lack of efficacy in any age group when studies are
combined and a high dropout rate in the younger patient.
mirtazapine, venlafaxine and duloxetine have recommendations as treatment options
but after failures to the SSRIs.
227 TCAs are not recommended primarily due to a high
risk of harm being much greater than the small benefit on symptoms.
CASE 86-3, QUESTION 3: A.A. is started on fluoxetine 10 mg QAM. What safety monitoring is required
when starting a young adult or pediatric patient on an antidepressant?
Generally, the SSRIs are well tolerated in children. One black box warning is for
suicidal thinking. As with adults, the clinician needs to monitor for suicidality, but in
children there is a doubling of suicidal thoughts, not suicide attempts or completions,
from 2% in the placebo arms to 4% in medication arms. It is important to note that
actual suicides are much higher in untreated depressed youth compared to those
94,231–233 This risk diminishes as age groups increase. For
patients over age 24, it is not required to be so vigilant regarding suicidal thinking
although many guidelines recommend continuing to monitor throughout the age ranges
due to the possibility of disease-related risk. In pediatrics and young adults, the
experts recommend the use of antidepressants with the FDA-sanctioned monitoring
for suicidal thinking of every week for the first week, every other week for the next 4
weeks, then monthly or as decided by the patient and clinician.
may have some protection against the side effect of increased suicidal thoughts.
Depression in late life is typically more difficult to recognize than depression in
younger adults. Clinicians and patients may inappropriately attribute depressive
symptoms to the “aging process” and minimize their significance. In addition,
functional expectations are often lowered after retirement, making the degree of
impairment difficult to evaluate. Because medical comorbidities are also more
common in the elderly, depressive symptoms may be overlooked or misinterpreted in
In general, the elderly present with the same depressive
target symptoms as younger adults, which is reflected in the fact that DSM-5
diagnosis for major depression in adults is not specific for age. However,
qualitatively, the presentation of depression among the elderly may be quite different.
For instance, older patients are more likely to present with psychomotor retardation
and are less likely to acknowledge “depression” per se, preferring instead to dwell
on somatic concerns (e.g., poor sleep, low energy, changes in bowel function, bodily
10 They are also much less likely to share or admit suicidal thoughts,
and because elderly men have the highest suicide completion rate, an accurate
assessment of depression and attendant risks is critical.
nonspecific behavioral and cognitive symptoms in the elderly, a careful differential
diagnosis between medical and other psychiatric disorders is essential because
numerous medical illnesses can mimic depressive symptoms. Anemia, malignancies,
congestive heart failure (CHF), and endocrine abnormalities may all present in a
manner similar to that in depressive illness.
Aging does result in decreased monoamine depletion as well as increased
116 One of the more difficult differential diagnoses in this
setting involves the distinction of depression from dementias.
patients with dementia may present with apathy, poor memory or concentration,
reduced facial expression, and lack of spontaneous interaction. The illnesses are
often comorbid, as 30% to 70% of patients with dementia also suffer from major
239 Some experts have suggested, in fact, that new-onset depression in
elderly patients may actually be part of a prodrome toward the manifestation of
239,240 A longitudinal cohort study found that among elderly
patients suffering from an acute episode of major depression, 57% were ultimately
diagnosed with Alzheimer dementia within the next 3 years.
are three notable differences between dementia and depression: (a) the symptoms
(slow and subtle changes with dementia, rapid with depression), (b) orientation
(markedly impaired with dementia, intact with depression), and (c) principal CNS
impairment (short-term memory with dementia, concentration with depression).
A therapeutic trial of an antidepressant in a depressed individual with cognitive
impairment may reverse the symptoms of the affective illness and restore functional
capacity. Depression-related cognitive dysfunction will also improve to some
degree. Moreover, because primary degenerative dementia is largely a diagnosis of
exclusion, a successful trial of an antidepressant may help clarify the underlying
pathologic condition and is strongly recommended in patients with a positive
personal or family history of mood disorders.
antidepressants in elderly patients is believed to be comparable to that observed in
younger subjects, although the response to treatment is somewhat slower (i.e., 6-
week therapeutic trial usually warranted).
5 Psychotherapy may be somewhat more
effective in the elderly particularly due to the emotional impact of medical
comorbidities and neurodegeneration effects as long as there is no dementia
hindering talking therapy’s effect.
5 Similarly, the comparative therapeutic effects of
individual antidepressants do not appear to differ qualitatively between elderly
patients and the general population. The selection of antidepressants for geriatric
depression is the same as the process for younger patients. The elderly are much
more sensitive to side effects compared to the younger patient, and the presence of
medical comorbidities and concurrent medications will have a greater influence on
antidepressant selection. For example, the anticholinergic effects of TCAs preclude
their use in elderly patients particularly if they are suffering from narrow
angle glaucoma, chronic constipation, or urinary hesitancy. Anticholinergic impact on
memory and the cardiac-related effects such as arrhythmias, orthostasis, and
tachycardia are other critical reasons not to use the TCAs in the elderly. As noted
previously, the risk of falls from TCAs due to antihistaminic, anticholinergic, and α
receptor antagonistic properties is another reason not to use them in the elderly
SSRIs are recommended as first line but among this list paroxetine is considered
the worst option due to its anticholinergic effects (albeit mild) compared to no effect
from the others. SNRIs also have data showing efficacy.
more dropouts with venlafaxine compared to the SSRIs.
antidepressants such as mirtazapine may serve to promote sleep in depressed patients
suffering from insomnia, other geriatric clients may be candidates for more activating
medications that can increase energy or enhance alertness (e.g., bupropion).
All antidepressants have a risk of causing the syndrome of antidiuretic hormone
secretion (SIADH) with SSRIs being the group with the highest reported cases.
Elderly patients, compared to younger patients, are at a much greater risk of this
event with some reviews reporting hyponatremia up to 32%.
medications used in the elderly, the antidepressants should be started at lower initial
5,10,116 Titration to a known therapeutic target dose has the
best evidence even if the geriatric seems to be responding to a subtherapeutic dose.
Therapeutic Blood Level Monitoring
Attempts to demonstrate an association between plasma concentrations and
therapeutic response for SSRIs and SNRIs have been largely unsuccessful. In
contrast, the serum concentration of some TCAs correlates well with clinical
response. Nortriptyline exhibits a curvilinear effect, whereas imipramine
demonstrates a sigmoidal relationship between serum levels and clinical
243,244 Maximum benefit of imipramine is usually associated with serum
levels of imipramine plus its demethylated metabolite, desipramine, in excess of 250
ng/mL. The relationship between plasma concentration of desipramine and clinical
response is less clear, but a linear relationship is likely.
surrounds amitriptyline; studies have shown a linear relationship, a curvilinear
relationship, and no relationship between serum concentration and outcome.
The APA Task Force on the Use of Laboratory Tests in Psychiatry recommends
plasma concentration monitoring of TCAs when patients are elderly, not responding
to therapy, nonadherent, experiencing adverse effects, or on multiple medications that
may result in a possible drug interaction.
249 Plasma concentrations of imipramine,
nortriptyline, and desipramine should be obtained after at least 1 week of a constant
dosage when steady state has been achieved. Samples should be drawn 12 hours after
the last dose has been administered. Routine therapeutic blood monitoring of other
antidepressants is not recommended because information concerning their usefulness
is limited; however, serum levels may be useful for evaluating adherence in some
patients or ruling out serious toxicities.
Antidepressants and Chronic Pain
moved in with her. When asked, she also notes significant decreases in energy and concentration, and
difficulties in falling and staying asleep.
meantime, she has continued to see her therapist on a weekly basis during this time frame.
There is a strong and complex association between chronic pain syndromes and
mood disorders. Epidemiologic investigations report that 50% of patients with
chronic pain will satisfy the criteria for a depressive disorder.
are also commonly reported in this population as well. On the other hand, 65% of
individuals with major depression will experience some symptoms of somatic pain,
often presenting with pain as their chief complaint. Researchers have theorized that
this comorbid phenomenon can be explained by deficiencies in the neurotransmitters
serotonin and NE, which influence mood disorders in the prefrontal cortex and
limbic system, as well as module pain sensitivity via descending projections down
the spinal column. Other theories implicate elevations in cytokine activity, which
commonly occur during the course of mood disorders, as well as mediating
inflammatory activity occurring within the context of chronic pain.
Treatment plans for depressed patients with chronic pain should target both of
these conditions in order to achieve optimal outcomes. In regard to the selection of
antidepressants, preference is often given to medications that can address both sets of
symptoms associated with these comorbid conditions. For instance, antidepressant
agents with pain-relieving properties and agents that promote sleep and relieve
anxiety are often preferred. Antidepressants that enhance 5-HT and NE (TCAs and
SNRIs) have proven to be quite effective for the management of neuropathic pain
conditions, in addition to their benefits on anxiety and depression.
much less effective primarily due to the lack of NE enhancement which is critical for
Drug interactions are often a major consideration in the selection of
antidepressants. For example, the combination of SNRI antidepressants with the
analgesic tramadol has been linked to a few case reports of serotonin syndrome, and
concomitant use of these agents should be discouraged. Certain opioid analgesics are
prodrugs and require metabolic transformation to generate the active species. These
analgesics include codeine (metabolized to morphine), hydrocodone (active
antidepressants that do not effect CYP 450 (Table 86-8).
D.C. meets the criteria for an acute episode of major depression, and medication is
clearly indicated. Among the alternatives, SSRIs have not proven to be effective for
neuropathic pain. SNRIs and TCAs are effective for neuropathic pain conditions, as
well as depression and anxiety. However, there are substantial tolerability and
toxicity risks with TCAs not shown with the SNRI class. Additionally, she has
experienced significant weight gain with a low-dose TCA (50 mg amitriptyline). An
SNRI would be a good choice for the treatment of her depression and chronic pain.
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