Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation
and behavior (suicidality) or unusual changes in behavior, whether or not they
are taking antidepressant medications, and this risk may persist until significant
remission occurs. Suicide is a known risk of depression and certain other psychiatric
disorders and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have
a role in inducing worsening of depression and the emergence of suicidality
in certain patients during the early phases of treatment. Pooled analyses of
short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
showed that these drugs increase the risk of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults (ages 18 to 24) with
major depressive disorder (MDD) and other psychiatric disorders. Short-term
studies did not show an increase in the risk of suicidality with antidepressants
compared to placebo in adults beyond age 24; there was a reduction with antidepressants
compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents
with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders
included a total of 24 short-term trials of 9 antidepressant drugs in over 4400
patients. The pooled analyses of placebo-controlled trials in adults with MDD
or other psychiatric disorders included a total of 295 short-term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There
was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger patients for almost all drugs studied. There
were differences in absolute risk of suicidality across the different indications,
with the highest incidence in MDD. The risk differences (drug vs placebo), however,
were relatively stable within age strata and across indications. These risk
differences (drug-placebo difference in the number of cases of suicidality per
1000 patients treated) are provided in Table 1.
||Drug-Placebo Difference in Number of Cases
of Suicidality per 1000 Patients Treated
||Increases Compared to Placebo
| < 18
||14 additional cases
|18 to 24
||5 additional cases
||Decreases Compared to Placebo
|25 to 64
||1 fewer case
| > 65
||6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in
the adult trials, but the number was not sufficient to reach any conclusion
about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e.,
beyond several months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants
can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should
be monitored appropriately and observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of
a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, and mania, have been reported in adult and pediatric patients being
treated with antidepressants for major depressive disorder as well as for other
indications, both psychiatric and nonpsychiatric. Although a causal link between
the emergence of such symptoms and either the worsening of depression and/or
the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients whose depression is persistently
worse, or who are experiencing emergent suicidality or symptoms that might be
precursors to worsening depression or suicidality, especially if these symptoms
are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of pediatric patients being treated with antidepressants
for major depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of agitation,
irritability, unusual changes in behavior, and the other symptoms described
above, as well as the emergence of suicidality, and to report such symptoms
immediately to health care providers. Such monitoring should include daily observation
by families and caregivers. Prescriptions for nortriptyline hydrochloride
oral solution should be written for the smallest quantity consistent with good
patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode
may be the initial presentation of bipolar disorder. It is generally believed
(though not established in controlled trials) that treating such an episode
with an antidepressant alone may increase the likelihood of precipitation of
a mixed/manic episode in patients at risk for bipolar disorder. Whether any
of the symptoms described above represent such a conversion is unknown. However,
prior to initiating treatment with an antidepressant, patients with depressive
symptoms should be adequately screened to determine if they are at risk for
bipolar disorder; such screening should include a detailed psychiatric history,
including a family history of suicide, bipolar disorder, and depression. It
should be noted that nortriptyline hydrochloride is not approved for use in
treating bipolar depression.
Patients with cardiovascular disease should be given nortriptyline hydrochloride
only under close supervision because of the tendency of the drug to produce
sinus tachycardia and to prolong the conduction time. Myocardial infarction,
arrhythmia, and strokes have occurred. The antihypertensive action of guanethidine
and similar agents may be blocked. Because of its anticholinergic activity,
nortriptyline hydrochloride should be used with great caution in patients who
have glaucoma or a history of urinary retention. Patients with a history of
seizures should be followed closely when nortriptyline hydrochloride is administered,
because this drug is known to lower the convulsive threshold. Great care is
required if nortriptyline hydrochloride is given to hyperthyroid patients or
to those receiving thyroid medication, because cardiac arrhythmias may develop.
Nortriptyline hydrochloride may impair the mental and/or physical abilities
required for the performance of hazardous tasks, such as operating machinery
or driving a car; therefore, the patient should be warned accordingly.
Excessive consumption of alcohol in combination with nortriptyline therapy
may have a potentiating effect, which may lead to the danger of increased suicidal
attempts or overdosage, especially in patients with histories of emotional disturbances
or suicidal ideation.
Use in Pregnancy--Safe use of nortriptyline hydrochloride during
pregnancy and lactation has not been established; therefore, when the drug is
administered to pregnant patients, nursing mothers, or women of childbearing
potential, the potential benefits must be weighed against the possible hazards.
Animal reproduction studies have yielded inconclusive results.