Letters to the Editor Mirtazapine and Breast-Feeding Reference
1. Burt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E:
TO THE EDITOR: Postpartum depression occurs in approxi-
The use of psychotropic medications during breast-feeding.
mately 10% of childbearing women, and for many of them,
treatment with an antidepressant may be necessary. The ben-
efit of breast-feeding for the infant and the mother is well es-
tablished; clinicians are therefore asked to make a careful
risk-benefit decision on the use of antidepressants. The liter-
ature on antidepressants and breast-feeding consists mainlyof case series of selective serotonin reuptake inhibitors and
Bradycardia at Low Doses of Risperidone
tricyclics, whereas information on newer antidepressants isscarce (1). We describe what we believe to be the first reported
TO THE EDITOR: Risperidone is a selective antagonist of dopa-
data on mirtazapine treatment in a breast-feeding woman.
mine and serotonin receptors and is widely used for the treat-ment of schizophrenia. The cardiac side effects of risperidone
Ms. A, a 27-year-old woman, was admitted to a psychi-
relate to a prolonged QT interval, orthostatic hypotension,
atric hospital 3 weeks after delivery of her daughter. She
and tachycardia. Recently, an article described a case of
was suffering from a severe depressive episode with sui-
symptomatic bradycardia secondary to risperidone in a
cidal thoughts. Ms. A had a history of a first depressive ep-
young man undergoing alcoholic withdrawal (1) but only af-
isode at age 18 that was not treated. At the time of admis-
ter increases to moderately high levels of risperidone. We de-
sion to the mother-child unit, Ms. A was breast-feeding her
scribe here the dramatic finding of acute sinus bradycardia
child and had so far not received antidepressive treat-
with frequent premature ventricular complexes in a pattern
ment. A routine diagnostic assessment, including a physi-
of bigeminy in a geriatric patient taking an initial low starting
cal examination, laboratory studies, and a cerebral com-
dose of risperidone. He had normal sinus rhythm before the
puterized tomography scan were normal. Treatment with
addition, and the bradycardia and ventricular bigeminy re-
sertraline, 150 mg/day for 11 weeks, was not effective.
solved after termination of risperidone, suggesting that ris-
Therefore, Ms. A was switched to mirtazapine, 30 mg/day
peridone was the etiological agent in the arrhythmia. at 9:00 p.m. She fed her infant six times a day. Concentra- tions of mirtazapine were determined in breast milk and Mr. A was an 80-year-old widowed white man with a his- in the serum of mother and infant by using mass spec- tory of coronary artery disease and cerebrovascular dis- trometry after Ms. A provided written informed consent ease who was transferred to our clinic from an outside fa- and the study was approved by the local ethics committee cility for treatment of dementia not otherwise specified. for measurement of her and her infant’s serum levels of He was originally hospitalized for an inability to care for the drug. Samples were taken after reaching steady state himself, with confusion, delusions, and poor orientation. At the outside facility, an ECG revealed a normal sinus before breast-feeding, the first time at 7:00 p.m. (22 hours rhythm at 74 bpm, a P-R interval of 171, a QRS interval of postdose) and a second time at 12:00 a.m. (15 hours post- 81 msec, and a QT/QTc of 362/402. His CBC, liver function tests, thyroid function tests, and basic metabolic panel At 7:00 p.m., the maternal plasma level of mirtazapine were all normal. Mr. A was not taking any medication ini- was 7 ng/ml (therapeutic range=5–100 ng/ml); the same tially; during the stay, the following medications were level was found in the foremilk (the early portion), whereas given to him: risperidone, 0.75 mg/day (for agitation and in the hindmilk (the later portion), a concentration of 18 delusions), and donepezil, 10 mg/day. Five days afterward, ng/ml was detected. On the next day at 12:00 a.m., the Mr. A was admitted to our facility, and a diagnosis of de- maternal plasma concentration was 25 ng/ml; in the mentia not otherwise specified was made. As part of our foremilk, a concentration of 28 ng/ml and in the hindmilk, evaluation, we also performed an ECG and repeated the 34 ng/ml were found. The infant’s plasma concentration tests and studies. All laboratory values and studies, includ- ing calcium, phosphate, and magnesium were normal, ex- was 0.2 ng/ml. The body weight of the infant was 6.8 kg at cept for borderline diabetes. Of interest was that his ECG this time. now displayed marked sinus bradycardia with frequent Ms. A was discharged in remission after 6 weeks of mir- premature ventricular contractions in a bigeminy pattern. tazapine treatment. The psychomotor development of the His ventricular rate, including bigeminy, was 70 bpm. Dis- infant was normal, as rated by an experienced neuropedi- counting the confounding premature ventricular contrac- atrician. No adverse events related to the mother’s mir- tions, his heart rate was 38 bpm. His P-R interval was 180 tazapine intake could be detected; especially, there was msec, his QRS interval was 80 msec, and his QT/QTc was no sedation or abnormal weight gain. 481/451 msec. Pending evaluation by the cardiology ser- vice and because of Mr. A’s increased agitation and delu-
The results of this case report demonstrate that mirtaza-
sional status, we increased his risperidone to an oral dose
pine is excreted into the milk of a nursing mother. No accu-
of 1.5 mg at bedtime. Seven days after being admitted to
mulation of mirtazapine in the milk was found. Measured
our service and 12 days after drug initiation, we discontin- ued risperidone. An ECG revealed a normal sinus rhythm,
serum concentration in the infant was below therapeutic
with a rate of 67 bpm within 1 day of discontinuation.
concentration. We would like to add this information to still
Throughout this time, Mr. A reported no syncope or palpi-
incomplete evidence on the safety of antidepressants and
tations. All major laboratory values and studies were nor- mal before, during, and after the addition of risperidone. Am J Psychiatry 161:12, December 2004LETTERS TO THE EDITOR
Current research suggests that risperidone acts in a fashion
Ms. A was a 51-year-old nonsmoking woman with breast
similar to a class III antiarrhythmic, causing concentration-
cancer, lung metastases, and brachial plexopathy, with no
dependent blockage of the rapid component of the delayed
history of chemical or alcohol dependence. She was re- ferred to the outpatient clinic because of severe pain. She
Kr) in ventricular monocytes and possibly
had been taking tramadol for 2 years: 50 mg t.i.d. increas-
explaining the QTc prolongation in some patients (2). As an
ing to 100 mg t.i.d., plus 50 mg intramuscularly as
atypical antipsychotic, risperidone is an attractive agent be-
needed. Switching to a strong opioid was proposed, but
cause of the relatively low side effect profile and decreased ex-
Ms. A refused for 2 months, notwithstanding her uncon-
trapyramidal effects. However, it is important to note that
trolled pain, because she said she became very agitated
death secondary to risperidone overdose and symptomatic
when delaying or skipping the tramadol administration,
cardiac side effects have been noted but at moderate to high
and she had learned to recognize the onset and then fear
levels of risperidone (6–24 mg/day) (3). Geriatric patients may
this nervousness, which reversed only by taking tramadol.
be more susceptible to the cardiac side effects of risperidone,
One day she did not take tramadol twice in a row. After
perhaps because of cardiac comorbidities or metabolic differ-
a few hours of having missed the first administration, she
ences. Although our patient reported no symptoms of syncope
became very nervous. Upon missing the second dose, she
or palpitations, it was difficult to assess his ability to report
began to have anxiety, anguish, a feeling of pins and nee- dles all over her body, sweating, and palpitations. She
such symptoms because he was demented. We emphasize
knelt down and rolled on the floor, pressing her hands
that elderly patients like our own, with coronary artery and
against her head so as “not to feel and not to understand
cerebrovascular disease, require more careful monitoring. what was happening” and begged her husband to take
Since QTc prolongation and ventricular arrhythmias can po-
her back home immediately so she could have her trama-
tentially result in fatal cardiac processes, we suggest that ris-
dol dose. When we asked about her pain on that occasion,
peridone use should be monitored with ECG, especially with
she replied, “I do not know because I felt too bad.” She
the elderly, who are more susceptible to decompensation. described what happened very clearly and with great pre- occupation because she felt like a “drug addict,” and References when we suggested changing the opioid, she agreed so as
1. Goyal RS, Goyal SB: Symptomatic bradyarrhythmia secondary
not to undergo another similar experience. We stopped
to risperidone (letter). Am J Psychiatry 2003; 160:2243
tramadol and prescribed oral methadone, 5 mg t.i.d., re-
2. Magyar J, Banyasz T, Bagi Z, Pacher P, Szentandrassy N, Fulop L,
ducing it to 3 mg t.i.d. after a week, which resulted in an-
Kecskemeti V, Nanasi PP: Electrophysiological effects of risperi-
algesic benefit and no adverse effects.
done in mammalian cardiac cells. Naunyn Schmiedebergs
“Physical dependence” is the term used to describe the
phenomenon of withdrawal when an opioid is abruptly dis-
3. Kopala LC, Day C, Dillman B, Gardner D: A case of risperidone
overdose in early schizophrenia: a review of potential compli-
continued. The severity of withdrawal is a function of the pa-
cations. J Psychiatry Neurosci 1998; 23:305–308
tient’s prior opioid exposure. Here we have a case of with-drawal due to physical dependence on tramadol even if no
tolerance had developed over 2 years. The patient became
nervous and agitated if the tramadol intake was merely de-
layed. When the patient missed the dose twice in a row, her
withdrawal symptoms became severe, with an overwhelmingneed to take the drug that could appear as psychologicaldependence. Withdrawal Syndrome
We believe that 1) patients must be advised to take trama-
After Delayed Tramadol Intake
dol regularly and to stop gradually especially after long treat-
TO THE EDITOR: Tramadol is a centrally active synthetic analge-
ment periods, 2) physicians should consider the potential
sic drug with opioid and nonopioid properties (norepineph-
physical dependence when they prescribe tramadol for pain,
rine and serotonin reuptake inhibition). Its widespread use in
and 3) any form of “dependence” of cancer patients taking
benign and malignant painful conditions is due to the follow-
tramadol, however, needs to be further explored. In fact, we
ing: 1) tramadol is a nonscheduled medication, 2) most peo-
are observing some patients who continue to take tramadol in
ple are unaware of its opioid nature, 3) its name does not
order “to achieve a feeling of well-being,” even though their
produce “opiophobia” like morphine does, and 4) it is not
pain is controlled after disease regression or switching to
considered a drug that produces severe adverse effects, de-
strong opioids. This may be related to the inhibition of seroto-
pendence, or abuse. However, some studies have reported
tramadol abuse, respiratory depression in patients with renal
References
failure, cerebral depression, and even a fatal outcome in asso-ciation with a benzodiazepine (1, 2).
1. Lee CR, McTavish D, Sorkin EM: Tramadol: a preliminary review
of its pharmacodynamic and pharmacokinetic properties, and
In patients with or without a history of drug abuse who
therapeutic potential in acute and chronic pain states. Drugs
were treated with tramadol for chronic benign pain, also in
therapeutic doses (up until 400 mg/day), dependence and
2. Freye E, Levy J: Acute abstinence syndrome following abrupt
withdrawal syndrome after abrupt discontinuation have been
cessation of long-term use of tramadol: a case study. Eur J Pain
reported (3, 4). Tramadol is the third active principle most fre-
quently involved in withdrawal syndromes (5). We could not
3. La Farmacovigilanza. http//:www.farmacovigilanza.org
locate in the literature any case of withdrawal in cancer pa-
4. Withdrawal syndrome and dependence: tramadol too. Am J Psychiatry 161:12, December 2004
One reason some parents don’t vaccinate their children against the hepatitis B virus (HBV) is their belief that their child has no risk of ever coming in contact with the virus. “My child will never be sexually promiscuous or addicted to drugs! Why does he or she need to be protected against hepatitis B?” Of course, it is impossible to predict which children will grow up and engage in risky