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 shortterm
placebo-controlled trials of antidepressant drugs (selective serotonin re-uptake
inhibitors [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 (drugplacebo
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
||Increases Compared to Placebo
||14 additional cases
||5 additional cases
||Decreases Compared to Placebo
||1 fewer case
||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
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
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 NORPRAMIN 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 NORPRAMIN
is not approved for use in treating bipolar depression.
The development of a potentially life-threatening serotonin
syndrome has been reported with serotonin norepinephrine re-uptake inhibitors (SNRIs) and
SSRIs, including NORPRAMIN, alone but particularly with concomitant use of other
serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol,
tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of
serotonin (in particular, MAOIs both those intended to treat psychiatric disorders and also
others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g.,
tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal
symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the
emergence of serotonin syndrome.
The concomitant use of NORPRAMIN with MAOIs intended to treat psychiatric disorders
is contraindicated. NORPRAMIN should also not be started in a patient who is being
treated with MAOIs such as linezolid or intravenous methylene blue. All reports with
methylene blue that provided information on the route of administration involved
intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved
the administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking
NORPRAMIN. NORPRAMIN should be discontinued before initiating treatment with the
MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of NORPRAMIN with other serotonergic drugs including triptans,
tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s
Wort is clinically warranted, patients should be made aware of a potential increased risk for
serotonin syndrome particularly during treatment initiation and dose increases.
Treatment with NORPRAMIN and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic treatment
should be initiated.
The pupillary dilation that occurs following use of many
antidepressant drugs including Norpramin may trigger an angle closure attack in a patient
with anatomically narrow angles who does not have a patent iridectomy.
Extreme caution should be used when this drug is given in the following situations:
- In patients with cardiovascular disease, because of the possibility of conduction defects,
arrhythmias, tachycardias, strokes, and acute myocardial infarction.
- In patients who have a family history of sudden death, cardiac dysrhythmias, or cardiac
- In patients with a history of urinary retention or glaucoma, because of the anticholinergic
properties of the drug.
- In patients with thyroid disease or those taking thyroid medication, because of the
possibility of cardiovascular toxicity, including arrhythmias.
- In patients with a history of seizure disorder, because this drug has been shown to lower
the seizure threshold. Seizures precede cardiac dysrhythmias and death in some patients.
This drug is capable of blocking the antihypertensive effect of guanethidine and similarly
The patient should be cautioned that this drug may impair the mental and/or physical
abilities required for the performance of potentially hazardous tasks such as driving a car or
In patients who may use alcohol excessively, it should be borne in mind that the potentiation
may increase the danger inherent in any suicide attempt or overdosage.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to antidepressants, including NORPRAMIN, during pregnancy. Healthcare
providers are encouraged to register patients by calling the National Pregnancy Registry for
Antidepressants at 1-844-405-6185 or visiting online at
Safe use of NORPRAMIN during pregnancy and lactation has not been established;
therefore, if it is to be given to pregnant patients, nursing mothers, or women of childbearing
potential, the possible benefits must be weighed against the possible hazards to mother and
child. Animal reproductive studies have been inconclusive.
Clinical studies of NORPRAMIN did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly
and younger patients. Lower doses are recommended for elderly patients (see DOSAGE AND ADMINISTRATION).
The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most
likely due to decreased renal elimination with aging.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions
to this drug may be greater in patients with impaired renal function. Because elderly
patients are more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.
NORPRAMIN use in the elderly has been associated with a proneness to falling as well as
confusional states (see ADVERSE REACTIONS).