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 predicators of suicide. There has been a
long-standing concern 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
trails 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 18-24) 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.
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.
| Table 1
|
Age Range
| Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
|
| Increases Compared to Placebo
|
less than 18
| 14 additional cases
|
18-24
| 5 additional cases
|
| Decreases Compared to Placebo
|
25-64
| 1 fewer case
|
greater than or
equal to 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 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 should be written for the
smallest quantity of tablets 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 nortrityline 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, inasmuch as 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, since 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.
The concomitant administration of quinidine and nortriptyline may result in a
significantly longer plasma half-life, higher AUC and lower clearance of
nortriptyline.
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.
