According to the guidelines issued by the Agency for Health Research and Quality,
antidepressant treatment can be broken down into three stages (Table 86-10).
first stage, acute treatment, lasts approximately 12 weeks; during this time, the
clinician attempts to resolve the presenting symptoms and induce remission which is
defined as no impairing symptoms of depression and a score of ≤7 on the HAMD17
5,10 The second stage is commonly called continuation
treatment because the patient continues to receive the same antidepressant regimen
that induced the initial treatment response, and the clinician attempts to keep the acute
symptoms in remission. The duration of continuation treatment is variable (4–9
months after initial treatment or response), but it is recommended that all patients
suffering from major depression complete these first two stages. Therefore, the
minimum duration of treatment is 7 months. Alternatively, others have advocated that
the minimum duration of treatment should be for 6 months after the complete
Duration of Antidepressant Treatment
Acute treatment phase 3 months
Continuation treatment phase 4–9 months
Maintenance treatment phase Variable
minimal duration of treatment = 7 months)
Decision to prescribe maintenance treatment is based on the following:
Patient age (worse prognosis if elderly)
Persistence of environmentalstressors
Indefinite maintenance treatment is recommended if any one of the following criteria is met:
Three or more previous episodes (regardless of age)
Two or more previous episodes and age older than 50 years
One or more and age older than 60 years
The third stage of treatment, maintenance treatment or prophylaxis, is not indicated
for all patients, and the necessity of continuing medication beyond the first 6 to 7
months depends on many patient-specific factors. One must consider the number of
previous episodes, family history of depression, patient’s age, severity of presenting
symptoms, response to therapy, and persistence or anticipation of environmental
stressors. There are specific populations for whom indefinite pharmacologic
treatment is advocated: (a) individuals with three or more previous episodes of
major depression, (b) individuals older than 50 years with two or more previous
episodes, and (c) individuals older than 60 years with one or more previous
5,10 Continued antidepressant usage in the elderly is recommended to
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
Comments
Post a Comment
اكتب تعليق حول الموضوع