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 18–24) 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 Cas es of Suicidality per 1000
||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 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
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 Nardil 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 Nardil is not approved for use in treating bipolar depression.
It should be noted that NARDIL is not approved for use in treating any indications in the pediatric
The most serious reactions to NARDIL involve changes in blood pressure.
The most important reaction associated with NARDIL administration is the occurrence of hypertensive
crises, which have sometimes been fatal.
These crises are characterized by some or all of the following symptoms: occipital headache which
may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with
fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or
bradycardia may be present and can be associated with constricting chest pain.
Intracranial bleeding has been reported in association with the increase in blood pressure.
Blood pressure should be observed frequently to detect evidence of any pressor response in all patients
receiving NARDIL. Therapy should be discontinued immediately upon the occurrence of palpitation or
frequent headaches during therapy.
Recommended Treatment In Hypertensive Crisis
If a hypertensive crisis occurs, NARDIL should be discontinued immediately and therapy to lower
blood pressure should be instituted immediately. On the basis of present evidence, phentolamine is
recommended. (The dosage reported for phentolamine is 5 mg intravenously.) Care should be taken to
administer this drug slowly in order to avoid producing an excessive hypotensive effect. Fever should
be managed by means of external cooling.
Warning To The Patient
All patients should be warned that the following foods, beverages, and medications must be avoided
while taking NARDIL, and for two weeks after discontinuing use.
Foods And Beverages To Avoid
Meat and Fish
Dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna)
Broad bean pods (fava bean pods)
Cheese (cottage cheese and cream cheese are allowed)
Beer and wine
Alcohol-free and reduced-alcohol beer and wine products
Yeast extract (including brewer's yeast in large quantities)
Excessive amounts of chocolate and caffeine
Also, any spoiled or improperly refrigerated, handled, or stored protein-rich foods such as meats, fish,
and dairy products, including foods that may have undergone protein changes by aging, pickling,
fermentation, or smoking to improve flavor should be avoided.
OTC Medications To Avoid
Cold and cough preparations (including those containing dextromethorphan)
Nasal decongestants (tablets, drops, or spray)
Asthma inhalant medications
L-tryptophan containing preparations
Also, certain prescription drugs should be avoided. Therefore, patients under the care of another
physician or dentist should inform him/her that they are taking NARDIL.
Patients should be warned that the use of the above foods, beverages, or medications may cause a
reaction characterized by headache and other serious symptoms due to a rise in blood pressure, with the
exception of dextromethorphan which may cause reactions similar to those seen with meperidine. Also,
there has been a report of an interaction between NARDIL and dextromethorphan (ingested as a
lozenge) causing drowsiness and bizarre behavior.
Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms.
Concomitant Use With Dibenzazepine Derivative Drugs
If the decision is made to administer NARDIL concurrently with other antidepressant drugs, or within
less than 10 days after discontinuation of antidepressant therapy, the patient should be cautioned by the
physician regarding the possibility of adverse drug interaction.
A List Of Dibenzazepine Derivative Drugs By Generic Name Follows
perphenazine and amitriptyline hydrochloride
NARDIL should be used with caution in combination with antihypertensive drugs, including thiazide
diuretics and β-blockers, since exaggerated hypotensive effects may result.
Use in Pregnancy
The safe use of NARDIL during pregnancy or lactation has not been established. The potential benefit
of this drug, if used during pregnancy, lactation, or in women of childbearing age, should be weighed
against the possible hazard to the mother or fetus.
Doses of NARDIL in pregnant mice well exceeding the maximum recommended human dose have
caused a significant decrease in the number of viable offspring per mouse. In addition, the growth of
young dogs and rats has been retarded by doses exceeding the maximum human dose.