available information.

Althoufjh the survey necessarily ad­ Conclusion

dresses a sampling of conditions obtained at a given time,
an effort is made to assure that these conditions are typical.
Major factors in the accreditation decision include evidence
of overall compliance with standards, irrogressive advance­
ment toward more complete compliance, and the absence
of any serious impediment to patient safety or the quality
of care.
In the event that a facility receives a nonaccreditation
decision or its accreditation is revoked, the JCAH provides
an inipartial process by which the facility may appeal the
decision. Included in the appeals process is the facility's right
As the Joint Commission on Accreditation of Hospitals
celebrates its 25th anniversary this year, consumers and
health care professionals alike have much to reflect upon.
Problems as well as successes must be'acknowledged as signs
of change and growth. Key decisions regarding the future of
the Joint Commission must be faced and dealt with, keeping
an eye on the goals and the purpose of the JCAH. One thing
is certain—as long as this nation values its tradition, of
voluntarism and believes that positive motivation is the most
effective impetus to change, the JCAH will be an effective

Downloaded from https://academic.oup.com/ajhp/article-abstract/34/9/954/5211684 by guest on 28 October 2019

to an interview, a hearing, and formal reconsideration by the influence for improvement in the delivery of health care and
Board .of Commissioners. related human services.

Review Articles
Am J Hosp Pharm 34:954-961 (Sep) 1977

Drug therapy reviews:

Tricyclic antidepressant and monoamine oxidase inhibitor
combination therapy
Laura B. Ponto, Paul J. Perry, Barry I. Lisltow and Hazel H. Seaba
Combinations of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants
(TCAs) are discussed with regard to general toxicity, drug interactions, animal studies, clinical
reports, efficacy of combination therapy and usage conditions.
Although MAOI-TCA combinations are usually considered contraindicated, informed opin­
ion has shifted to a cautious recommendation for the combination. Only refractory patients
in whom less hazardous treatment has failed should he considered for combination therapy.
The preferred dosage regimen is administration of the MAt)I t.i.d. during the day and the en­
tire TCA dose at bedtime. Patients should he informed of the immediate need for medical ad­
vice should side effects occur.
It isconcluded that thesimultaneous administration of these agents is potentially efficacious
and safe if carefully monitored and controlled.

Key words: Antidepressants; Combined therapy; Dosage schedules; Drug interactions; Mono­
amine oxidase inhibitors

The concurrent use of a monoamine oxidase inhibitor
(MAOI) and a tricyclic antidepressant (TCA) is considered
by many authors to be contraindicated.'The combination
is listed as a "contraindication" in the product literature for
imipramine (Presamine, Imavate, SK-Pramine, Tofranil),
amitriptyline (Elavil, Endep), protriptyline (Vivactil),
nortriptyline (Aventyl), desipramine (Norpramin), tranyl­
cypromine (Parnate), phenelzine (Nardil), isocarboxazid
Laura B. Ponto is a recent pharmacy graduate. Paul J. Perry, Ph.D., is
Clinical Pharmacy Coordinator and As.sistant Profes-sor of Clinical Pharmac.v.
College of Pharmacy, University of Iowa, Iowa Cit.v 52242. Barry 1. Liskow,
M.D., is Assistant Professor of Psychiatry, College of Medicine, University
of Iowa, and Chief of Psychiatry, Iowa City Veterans Administration Hospital.
Hazel HiSeaba, M.S., isClinical Assistant Profes.sor,and Director. Iowa Drug
Information Service, College of Pharmacy, University of Iowa.
Address reprint requests to Dr. Perry.
Copyright © 1977, American Society of Ho.spital Pharmacists, Inc. All rights
reserved.
(Marplan), par^line (Eutonyl) and pargyline-methy-
chlothiazide (Eutron).® Doxepin (Sinequan) product in­
formation denotes the combination as a "warning" father-
than a "contraindiction." ® The contraindication is derived
from observations of potential drug toxicity in four areas;
(1) the general toxicity occurring with either agent admin­
istered singly; (2) the proposed drug-drug interaction; (3)
the animal toxicity studies conducted on the combination;
and (4) the clinical observations of serious toxicity, some­
times resulting in death.
General Toxicity
The tricyclic antidepressants, administered alone, have
a wide range of reported side effects, including psychiatric
(delirium and hypomania), neurologic (tremors, headache,
extrapyramidal symptoms, seizures), anticholinergic (dry

954
 DIUK: THKRAPY RF:VIKWS

mouth, constipation, blurred vision, mydriasis, cycloplegia, Table 1. Tyramine-containing Foods

urinary retention, etc.), allergic (jaundice, agranulocytosis), Precipitating Hypertensive Crisis in Patients
gastrointestinal (nausea, vomiting) and cardiovascular (or­ Receiving MAOi Therapy*'*^"*®
thostatic hypotension, cerebrovascular accidents, myocardial
Tyramine Content Number of
infarction, tachycardia, palpitations) manifestations. Product (Mg/g or ml) Cases Reported
The cardiac effects are considered to be especially dangerous •
Cheese 0-1,416 67
since they allegedly have caused suddeij death in patients English Cheddar 0-953
both with and without previous heart disease.^" Canadian Cheddar 231-535
New York State Cheddar 1,416
The monoamine oxidase inhibitors exhibit a similar array
New Zealand Cheddar 417-500
of side effects,^'®'^"® plus the potentially fatal interaction with Kraft, Cheshire ND^
foods containing the pressor substance tyramine.'"'^'"'''' This Camembert 86
Stilton 466
interaction may occur unexpectedly because of the unpre­
Brie 180
dictable quantities of tyramine in foods.'*-'®-''^ Thg tyramine

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Emmenthaler 225
content of foods known to have caused hypertension in pa­ Gruyere 516
tients receiving MAOI therapy are listed in Table I.4.12-16 Cottage cheese NS"
Cream cheese NS"
Table 2'';i2-i6 Ustg other foods and amines that have pre­ Processed American ND^
cipitated hypertensive reactions.
Yeast products 0-1.6 3
Tyramine, 6 mg, can cause a moderate rise in blood pres- Yeast ND"
sure,i3 10 mg may exhibit a marked pressor effect,'* and 25 Yogurt NS"
"Marmite" 1.6
mg can produce a severe hypertensive crisis.*^ In Great
Britain, phenelzine (Nardil) therapy has been associated Aicohol 0-25.4 5
Beer 1.8-4.4 •
with 26 deaths over a seven and one-half-year period, with
Wines 0-25.4
jaundice being the cause in 15 cases.*" In addition, three Sherry 3.6
cases of nonfatal intracranial hemorrhage have been docu­ Sauterne 0.4
Reisling 0.6
mented.*^ Seventeen cases of interactions between phenel­
Chianti 25.4
zine and foodstuffs were reported between January 1964, and Port ND^ -
June 1973, none of which was fatal.*"* Tranylcypromine
Pickled herring 0-3,030 2
(Parnate) therapy has been reported to bave caused 21 Fermented sausage (Summer, etc.) 8-=
deaths*'*'? and 14 instances of nonfatal intracranial hemor­
Liver 50-274
rhage over a seven and one-half-year period.*'* Of the deaths Fresh chicken ND®
two were attributed to jaundice, five to "cbeese reactions," *" Aged chicken 94-113
three to combination with amphetamines and three to Fresh beef 50-65
Aged beef 274
intracranial hemorrhage caused by an unknown precipi­ Cream 0-8"= 3
tant.*^ Eight of the deaths were unexplained. Tranyl­
Bananas 0-65
cypromine's higher incidence of adverse reactions with ty- Skin 65
ramine-cqntaining foods is most likely a result of its efficacy Fresh pulp NS"
Rotten pulp S<=
in inhibiting intestinal MAO.***
Avocados NS-S^
Bickel*® reviewed 106 cases of intoxication with tricyclic Canned figs NS-S=
antidepressants resulting in severe or fatal reactions. In
® ND = tyramine levels were not detectable.
adults, imipramine proved fatal in doses ranging from 10 to "1*13 = tyramine levels were not significant.
88 mg/kg and amitriptyline proved fatal in doses ranging 8 = tyramine levels were significant, but no specific value was given.

Tfie Drug 'Therapy Reviews column is edited by Russell R. Miller,
Pharm.D., Ph.D., and David J. Greenblatt, M.D. The objective of
the column Is to present critical reviews in pharmacotherapeutics.
The principal type of contribution is papers on the current status of
the clinical use of a'drug or group of drugs. Articles on the current
status of drug therapy in selected diseases are also published.
Drug Therapy Reviews is a service of the Department of Ptiarmacy
of the New England Medical Center Hospital, Boston. Redactorial
expenses Involved in the publication of Drug Therapy Reviews are
funded by a grant from the Bingham Associates Fund. Contributions
also appear In the Journal of the Maine Medical Association, gen­
erally one month before their publication in the American Journal
of Hospital Pharmacy. Authors who have prepared papers thought
. to be appropriate for this column are invited to submit them to:
Russell R. Miller, Pharm.D., Ph.D.
Box 420
New England Medical Center Hospital
Boston, Massachusetts 02111
from 15 to 69 mg/kg.***
Gander*** found that in more than 80% of patients treated
with a combination of an MAGI and TCA, side effects were
either absent or inconsequentially mild. In 10% of the pa­
tients on combination therapy and 7% of those receiving one
drug alone, side effects warranted a modification of dosage
or discontinuation of therapy.
•
Drug Interactions
Three mechanisms of interaction have heen proposed in
the literature;'-*'
1. MAOI inhibits the enzymes responsible for the metabolic
inactivation of TCA.

American Journal of Hospital Pharmacy Vol 34 Sep 1977 955

 Table 2. Other Amines which Precipitate Hypertensive
Crisis in Patients Receiving MAGI Therapy^'^^'^^
Number of
Product Amine Cases Reported
Chocolate vanillin 1
Broad beans dopa 2 and no fatalities occurred with trimipramine. Furthermore,
R^inanaQ serotonin
2. MAOI acts on liver enzymes to alter TCA catabolism such
that abnormal but active TCA metabolites are produced.
3. The interaction causes an intensification of the action of
amines present in the central nervoussystem by stimulating
, further release or by augmenting the pharmacologic activity
of existing amines.
The third mechanism appears most valid because, unlike
the first, it accounts for the difference between the toxic
reactions encountered in a single-entity and combination
drug overdose cases. For example, death from an overdose
of imipramine stems from respiratory depression with only
a mild hyperpyrexia (approximately fC), whereas death
after administration of the combination of an MAOI and
imipramine stems from hyperpyrexia in rabbits.^o Intra­
ventricular administration of 5-hydroxytryptamine resulted
in a fall or no change in the rectal temperature in rabbits, but
intraventricular administration of norepinephrine (levart-
erenol or noradrenaline) resulted in a rise or no change in the
rectal temperature.^ Imipramine^-^^'^i and amitriptyline^i
predominantly influence the reuptake of norepinephrine.
Clomipramine^' has a greater effect on the reuptake of 5-
hydroxjdryptamine. The hyperpyrexic response observed
from thecombination of an MAOI and a TCA are due to the
increased brain amine levels caused by the MAOI and the
more selective inhibition of the reuptake of norepinephrine
resulting in enhanced levels of norepinephrine in the
brain.^'^" This third mechanism also explains the increased
cardiovascular toxicity of the combination because of the
augmentation of the pressor effect of norepinephrine.22
Animal Studies
Studies on albino rabbits by Loveless and MaxwelP" are
representative of other animal investigations of the
MAOI-TCA combination. An MAOI (tranylcypromine,
phenelzine or nialamide) was given intraperitoneally 42 Md
18 hours prior to intravenous infusion of a TCA (imipramine,
amitriptyline, or trimipramine). The doses of all drugs were
close to or exceeded the dosages usually associated with 50%
mortality (LD50) in this species. Imipramine consistently
produced fatal hyperpyrexia. With a 5-mg/kg dose of this
drug, seven of 13 animals died with ICQ mg of concurrent
tranylcypromine, five of six died with concurrent phenelzine
(50 mg), and six of six died with concurrent nialamide (100
mg). Amitriptyline appeared to be less toxic. One fatality
occurred witb tranylcypromine (100 mg) together with am­
itriptyline (10 mg). A 5-mg dose of amitriptyline proved to
be fatal in 11 of 14 animals when given with 50 mg of phe­
nelzine; with nialamide (100 mg), amitriptyline, 5 mg, was
956
fatal in five of six animals.
Animal studies such as thjs were the major documentation
for the severe restrictions on combination tberapy. The
consistent lethality of imipramine was considered conclusive,
even though amitriptyline appe^ed substantially less toxic
th^nvestigators noted that the MAOI doses used were
greater than those needed for MAO inhibition in vivo and
were in themselves potentially toxic. The TCA doses also
were very high;
Clinical Observations
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Fatal Overdose Caused by Single Drugs. The most con­
vincing evidence against antidepressant drug combinations
is tbe serious and sometimes fatal toxicity often reported
following overdosage of either taken alone. In 1968, the na-
tiond Poisons Information Service in Great Britain reported '
that the antidepressant drugs, especially amitriptyline,
nortriptyline, protriptyline and imipramine, alone and often
with other products, were significant contributors to in­
tentional and accidental poisonings.23 In Great Britain, the
number of successful suicides caused by TCA overdose in­
creased from 127 to 167 between 1973 and 1974. These fig­
ures represent 7.3 and 9.0%, respectively, of the total suicidal
poisonings in England.^-'-^s
Fatal Overdoses Involving Combination Therapy. Sar-
gant,^® Schuckit,^^ and Sethna^ have reviewed the literature
describing cases of toxicity attributed to combined therapy.
In all such cases the morbid and fatal events were caused by
an overdose, a "cheese reaction," another medical problem
or tbe sequential use of TCA shortly after an MAOI. Except
in the overdose cases or where another medical problem
intervened, all tbe patients recovered.^''
'Davies^® in 1960 reported a 23-year-old female wbo was
ingesting high doses (40 tablets/day) of phenmetrazine
(Preludin). She was "withdrawn" using chlorpromazine over
a three-week period. Phenelzine, 45 mg/day, was substituted
for another 21 days, then imipramine, 75 mg/day, was added.
She took 200 to 300 mg imipramine instead of the prescribed
dose and subsequently died four hours after hospital ad­
mission. Clinical findings included profuse diaphoresis,
extreme restlessness and hyperexcitability, collapse, and
death secondary to hyperpyrexia (109 F).
Babiak®" in 1961 reported a 26-year-old male who ingested
600 mg of imipramine and 13 Parstelin (130 mg of tranyl­
cypromine and 13 mg of trifluoperazine). His temperature
rose to 107.8 F, and his blood pressure, which was 180/60 mm
Hg on admission, fell to 70 mm Kg systolic. Death occurred
approximately six hours after admission.
• Bowen®' in 1964 reported a 41-year-old female who was
hospitalized with tachycardia (150 beats per minute) and
fever (104 F). The cause of death was diagnosed as heart
failure secondary to myocardial degeneration precipitated
by tbe combined action of antidepressant drugs. Controversy
surrounds this report. The woman's husband claimed that
she was faithfully taking phenelzine, 45 mg/day. Although
desipramine had been presribed six weeks earlier, she was

not taking the drug on a regular basis, and it was alleged that
the patient had not taken desipramine within 48 hours of her
death. On the morning of her death, she had taken chlor-
promazine, although she usually took this only as a sedative
at bedtime..The pathologist found "therapeutic" levels of
chlorpromazine and desipramine in tissues, but no phenel­
zine. Although no phenelzine could be found, it was sug­
gested by the pathologist that this could still have produced
the serious reaction even if it had not been taken for a
number of days. The pathologist concluded that death was
caused by a combination of the MAOI and TCA. Sargant^^
replied to the Bowen case report, indicating that the woman
had been successfully treated with phenelzine, 45 mg/day,
and amitriptyline, 150 mg/day, on two separate occasions
without side effects. He also questioned the pathologist's
conclusion since phenelzine was not found in the body. The
only evidence that a desipramine overdose had not occurred
was the number of tablets remaining in the bottle. Hall,^^
the pathologist for the case, replied to the criticism and re­
stated his position that no overdose existed.
Stanley^^ in 1964 described a 22-year-old male alcoholic,
apparently abstinent, for whom phenelzine, 45 mg/day, was
prescribed. Because he began drinking again, imipramine
was substituted. However, the imipramine therapy made
him excessively drowsy and phenelzine was restarted. He was
instructed not to start the phenelzine until he had discon­
tinued the imipramine for a total of four days. Instead, he
ingested between 450 and 600 mg of phenelzine, approxi­
mately 20 imipramine tablets of an unknown strength and
resumed drinking heavily. He died one hour after hospital
admission. Clinical findings included a heart rate of 150
beats/min, blood pressure of 160/100 mm Hg, temperature
of 110 F, and potentially toxic blood levels of phenelzine and
imipraihine.
Saunders^® in 1965 reported a 37-year-old male who had
taken etryptamine (Monase), 45 mg/day for 10 days. It was
discontinued and replaced with amitriptyline, 75 mg/day for
the next five days. Because.he experienced visual halluci­
nations, the patient was admitted to the hospital and initially
treated with promazine, phenobarbital and paraldehyde.
The patient apparently was a heavy drinker and had expe­
rienced episodes of transient jaundice four years earlier and
two weeks prior to admission. Between 24 and 60 hours after
admission the patient experienced hyperexcitability, fluc­
tuations in blood pressure and body temperature, congestive
heart failure, and anuria. The patient died approximately
60 hours after admission. Autopsy revealed damage to the
liver and kidneys.
Sargant^'*-^ reported two patients on combination therapy
who died with findings suggestive of drug toxicity. However,
an autopsy on the first patient^'' revealed a volvulus of the
small intestine which proved to be the cause of death. The
second patient, who had three months of therapy with
tranylcypromine-trifluoperazine combination (Parstelin)
together with trimiparmine, died suddenly. At autopsy, a
large volume of macaroni and cheese, ingested an hour before
hospital admission, was found in the stomach.
In each of these cases, with the exception of the contro­
American Journal of Hospital Ptiarmacy Vol 34 Sep 1977
DRUG THERAPY REVIEWS
versial Bowen case, an overdose was taken, a complicating
medical problem intervened, or a tyramine-induced hy-
pertensiye crisis was the precipitating factor. The Saunders^®
case emphasizes the interaction of all the physiological fac­
tors. Since both hydrazine-MAOI and TCA may produce
jaundice as a nondose-related side effect,!'^'"^ a patient with
a history of jaundice or heavy drinking, or both, is probably
predisposed to this toxicity. A final consideration in the
Saunders^^ case and the Bowen^^ case, is the possible in­
teractions of alcohol, barbiturates and phenothiazines with
MAOI and TCA. Numerous anecdotal reports have sug­
gested possible adverse interactions among these
agents.^'^'^'^® The combination of amitriptyline and alcohol
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has apparently resulted in two deaths.®®
Near-fatalities Involving Combination Therapy. Near-
fatal reactions have involved three types of situations: (1)
attempted suicide with overdoses of antidepressants and
other drugs or foods (or both) containing high tyramine
levels; (2) adverse reactions associated with multiple drug
abusers; and (3) adverse reactions occurring with therapeutic
doses.
(7) Deliberate Self-poisoning. Luby et aH® reported a
30-year-old female, who, after suicide attempts with aspirin,
was treated with tranylcypromine, 75 mg/day. Following a
fight with her husband, resulting in a return of her depres­
sion, imipramine, ICQ mg/day was substituted for tranyl­
cypromine. Within one week she made a third suicide at­
tempt by ingesting 175 mg tranylcypromine and 275 mg of
imipramine. Vital signs were: blood pressure 120/60 mm Hg,
heart rate 124 beats/min, respiratory rate 32/min and tem­
perature 105.6 F. Within 24 hours, she regained conscious­
ness, but memory loss and confusion persisted for two
weeks.
Jarecki"*! reported a 38-year-old female who attempted
suicide with phenelzine 180 mg, amitriptyline 800 mg, an
unknown but small amount of aspirin and chlorpheniramine.
She had been taking amitriptyline 150 mg/day for 12 weeks.
Her vital signs were variable with blood pressure ranging
from 150/80 to 90/60 mm Hg, heart rate 90 to 100 beats/min
and temperature ranging from normal to 100 F. She was alert
by the third day after hospital admission.
Simmons'"® reported a 19-year-old male who ingested 25
Parstelin (250 mg tranylcypromine and 25 mg trifluopera­
zine) tablets, lOO mg of protriptyline and two cheese rolls.
Upon admission, vital signs were: temperature 101 F, heart
rate 130 beats/min and blood pressure 190/90 to 260/0 mm
Hg. He was comatose for 48 hours. Twenty-four hours after
regaining consciousness, all signs were normal.
In each of these cases, the reaction was attributed to the
improper usage of the antidepressant drugs.
(2) Multiple Drug Use. Adverse reactions have also oc­
curred in multiple drug users. ChappelP® reported a 43-
year-old female who developed hypothermia and hypoten­
sion seven days after the substitution of amitriptyline, 100
mg/day, for isocarboxazid (Marplan), 30 mg/day, with three
days of "washout" in between. She was also taking sodium
amobarbital, perphenazine, and unspecified amounts of wine
and other alcoholic beverages.
957
 Hjrpertension, hyperpyrexia and convulsions were re­
ported by Man"*^ in a 43-year-old female taking15 drugs si­
multaneously, including chlorpromazine, trihexiphenidyl,
phenobarbital, phenelzine and amitriptyline. Her toxic
manifestations were attributed to the "MAOI and other
psychotropic drugs.""*'* This conclusion has been disputed
in the literature.*®
Delirium tremens was mistaken for an adverse reaction
of combined therapy with tranylcypromine and trimipra-
mine.®® The patient experienced hallucinations, twitching
of the limbs, fever, tachycardia and profuse sweating. The
physician and the patient's mother were insistent that no
other drugs had been taken in excess, and the only drugs
used were those prescribed. It was later determined that he
had been taking high doses of carbromal with pentobarbital
and was in his fourth day of sedative withdrawal.®®
(3) Therapeutic Doses. Nonfatal adverse reactions have
occurred when therapeutic doses of MAOI were given first
and then followed by a TCA administered parenterally. In
. all three reported cases,®®-*®-*'' the MAOI was phenelzine and
the tricyclic was imipramine. The reaction occurred within
16 hours after the initial dose.
Toxic, nonfatal reactions manifested by agitation, trem-
ulousness, restlessness, delirimn, generalized clonic con-
vulsioiK, hyperthermia and increased pulse, respiration and
blood pressure have also followed oral administration of an
MAOI and TCA. McCurdy and Kane*® reported a woman
receiving pargyline who took one 25-mg imipramine tablet
from a prior prescription. Ayd*® reports of two instances of
toxicity. The first involved the use of iproniazid, 75 mg/day,
with a later addition of imipramine, 75 mg/day. Toxic re­
actions occurred after the third dose of imipramine. The
second case involved the use of isocarboxazid by a patient
for three months. After discontinuing the isocarboxazid,
imipramine was started without interruption of therapy.
Toxicity developed after six doses of imipramine. Howarth®®
reported a 76-year-old female, who after three weeks of
phenelzine therapy, was given a 50-mg dose of imipramine
with 15 mg of phenelzine simultaneously because of an error.
A toxic reaction ensued. Brachfeld et al®* suggested that
three weeks of tranylcypromine discontinued for three days
can still precipitate a toxic response after "one tablet" of
imipramine.
TVo instances of toxicity have been reported involving the
use of a tricyclic followed by an MAOI. The first report®®
involved a female taking imipramine for several weeks; after
one 15-mg tablet of etryptamine (Monase) she developed a
toxic reaction. The other report®® involved the use of im­
ipramine for 19 days which was discontinued and immedi­
ately followed by tranylcypromine. Six days after discon­
tinuation of the imipramine, toxic reactions occurred.
Nonfatal toxic reactions have developed under all sets of
circumstances and with all combinations of agents. The time
interval between dosage and onset of toxicity appears to be
important. When a tricyclic is added to an MAOI regimen,
toxicity appears to develop within at least three doses,
whereas when an MAOI is added to a tricyclic regimen, the
toxicity appears to he delayed up to six days.
958
Efficacy of Combination Therapy
In numerous studies involving nearly 600 patients with
refractory depression or phobic anxiety states, the combi­
nations of MAOIs and TCAs have proved to he bothsafe and
effective''-*®-®*-®''-®®-®*-®* (Table 3). The incidence of side ef­
fects is approximately the same as with single drug thera­
py 7,19,27,33 The most significant side effect reported from
the combination is-exceSsive weight gain because of an in­
crease in appetite and serum insulin levels.®®
The Food and Drug Administration has granted investi­
gational status for further study of this combination.®® The
American Pharmaceutical Association, in its Evaluations
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of Drug Interactions (second edition),®* has reclassified the
combination. It is no longer contraindicted, and recom­
mendations for safe usage are given. Hansten®'' views the
combination as safe if the following precautions are ob­
served:
1. Avoid large doses,
2. Give the drugs orally,
3. Avoid tranylcypromine,
4. Avoid imipramine and clomipramine, and
5. Monitor the patient closely.
Usage Conditions
The following considerations appear pertinent to the use
of MAOI-TCA combinations. ,
Patient Selection.^ Only refi:actory patients in whom less
hazardous treatment measures have failed should be con­
sidered for combination therapy. Safer treatment measures
consist of an adequate trial (at least four weeks) of an MAOI
or a TCA individually at therapeutic doses. At least 14 days
of "washout" should ^lapse when changing from an MAOI
to a TCA, and at least 10 days between a TCA and an MAOI.
Patients should be evaluated medically to ensure good
general physical health, particularly normal hepatic and
cardiac function. Only those patients who are responsible
enough to take their medication exactly as prescribed and
who will adhere to dietary restrictions should be considered.
Alcoholics, drug "abusers," and individuals taking multiple
medications should be excluded.
Dosage Schedule. Although all of the currently marketed
drugs have been combined safely, some drugs appear better,
candidates for combination. Amitriptyline is recommended
over imipramine®*-®®-®® because it has a sedative effect
whereas imipramine is stimulating.®*-®® Amitriptyline is less
likely than imipramine to sensitize the patient to norepi­
nephrine because its norepinephrine reuptake inhibition is
countered by a blocking effect on the norepinephrine re­
ceptor sites.®* The use of hydrazine MAOI rather than a
nonhydrazine agent also is indicated. Tranylcypromine use
is considered more hazardous®® because of the higher inci­
dence of hypertensive crises and tyramine reactions asso­
ciated with its use. Isocarboxazid has been suggested as
potentially safer because it is a "pure MAOI" as compared
to tranylcypromine and phenelzine, which exhibit "amine
releasing" properties in addition to their MAOI inhibition.
 DRUG THERAPY REVIEWS

Table 3. Studies of Combined MAOl and Tricyclic Antidepressant Therapy

Number of Dosage Dosage Number Discontinued
Study Patients Tricyclic Drug (mg/day) MAOI (mg/day) Because of Side Effects

Schuckit^s 36 Imlpramlne 50-100 Isocarboxazld 10-40 0/50

6 Amitriptyllne 50-100 Isocarboxazld 23-30
3 Amitrlptyllne 75 Tranylcypromine 30
2 Nortriptyline 75 Isocarboxazld 30
1 Oesipramlne 100 Tranylcypromine 30
2 Protrlptyllne 20 tranylcypromine 20
Winston®" 13 Amitrlptyllne 25-100 Isocarboxazld 5-30 4/20
6, Amitrlptyllne 10-100 Tranylcypromine 10-30
1 Imlpramlne 10-100 Tranylcypromine 10-30
Sethna^' 12 Amitrlptyllne 75 Phenelzine 45 2/12
Ayd«" 55 Doxepin 150-200 Tranylcypromine 50
Gander' 98 Amitrlptyllne 150 max. Phenelzine 45 max. 8/157

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22 Amitrlptyllne 150 max. Isocarboxazld 45 max.
19 Amitrlptyllne 150 max. Ipronlazld 45 max.
9 Imlpramlne 150 max. Phenelzine 45 max.
5 Imlpramlne • 150 max. , Isocarboxazld 45 max.
7 Imlpramlne 150 max. Ipronlazld 45 max.
11 . Other combination
Splker"' 8 Amitrlptyllne 150 max; Isocarboxazld 12/201
41 Amitrlptyllne 150 max. Phenelzine 45
28 Amitrlptyllne 150 max.. Tranylcypromine
77 Imlpramlne 150 max. Isocarboxazld
14 Imlpramlne 150 max. Phenelzine 45
14 Imlpramlne 150 max. Tranylcypromine
2 , Other Isocarboxazld
5 Other Phenelzine
7 Other Tranylcypromine
Sargant®^ 51 Amitrlptyllne 75-150 Isocarboxazld 30 0/88
51 _ Amitrlptyllne 75-150 Ipronlazld 75-150
5 Imlpramlne 150 Ipronlazld 75-150
5 Amitrlptyllne Phenelzine 45
-1- Imlpramlne

thus predisposing the patient to hypertensive attacks.®^
Phenelzine has also caused problems because of genetic
„ variability in rates of clearance by acetylation. The response
to phenelzine therapy is better in slow acetylators than in
fast6v.68 because of higher drug levels in the slow acetylators.
However, the incidence of side effects also is higher.®'^ In one
study it was found that most patients with severe side effects
were slow acetylators.®®
The preferred dosage regimen constitutes administration
of the MAOI during the day, usually on a t.i.d. regimen, while
the entire dose of the TCA is administered at bedtime to take
advantage of sedative effects.^®-®®-®®
The route of administration should be oral.®'^ The safest
approach to initiate therapy is tostop all drugs, wait an ap­
propriate length of time, such as 10 to 14 days,® '* then begin
the drugs together.®® A beginningdosage of 25 to 50 mg/day
of the TCA and 15 mg/day of the MAOI can be slowly in­
creased over the next two to three weeks to maximum doses
of 150 and 45 mg/day, respectively. The dosages used are
generally slightly lower than the recommended individual
therapeutic dose.
Patient Education. Patients should be informed of po­
tential side effects and the immediate need for medical ad­
vice should side effects occur. Schildkraut and Klein®® rec­
ommend having the patient carry 300 mg of chlorpromazine
at all times, with the directions to take it orally if a "sudden.
throbbing, radiating, occipital headache" occurs, and to seek
medical help immediately. Clinicians should also consider
obtaining written informed consent from the patient. In
cases of severe hypertensive crisis, alpha adrenergic blocking
agents, i.e., phentolamine, are the drugs of choice.®"*
Conclusion
Refractory depression is a debilitating disease. An alter­
native to the present methods of treatment can be the
combination of an MAOI and a TCA. Carefully monitored
combination therapy in appropriately selected patients is
potentially beneficial and has an acceptably low potential
for serious toxicity.
References
1. Byck R: Drugs and the treatment of psychiatric disorders, In
Goodman LS and Gilman A (eds): The pharmacological basis of
therapeutics, 5th ed, The Macmillan Company, New York, New
York, 1975, p 174-184.
2. Corrigan LL (ed): Evaluations of drug interactions 1973,1st
ed, American Pharmaceutical Association, Washington, D.C., 1973,
p259.
3. Anon: Drugs for psychiatric disorders, Med Letter Drug Ther
18:89-96 (Oct) 1976.
4. Sjoqvist F: Psychotropic drugs, ii: interaction between
monoamine oxidase (MAO) inhibitors and other substances, Proc
R Soc Med 58:967-978 (Nov) 1965.

American Journal of Hospital Pharmacy Vol 34 Sep 1977 959

 5. Cohen SN and Armstrong MF: Drug interactions; a handbook
for clinictd use, Williams & Wilkins Co., Baltimore, Maryland, 1974,
p 127.
6. Barker CD (ed): Physicians' desk reference, 30th ed, Litton
Industries, Oradell, New Jersey, 1976.
7/Gander DR: The clinical value of monoamine oxidase m-
hibitors and tricyclic antidepressants in combination. In Garattini
S and Dukes MNG (eds): Antidepressant drugs: proceedings of the
first international symposium, Elxcerpta Medica Foundation, New
York, New York, 1967, p 336-343.
8. Hollister LE: Toxicity of psychotherapeutic drugs. Practi­
tioner 134:72-83 (Jan) 1965.
9. Ayd FJ Jr: A critique of antidepressants, Dis Nerv Syst 22:
32-36 (May suppl) 1961.
.10. Mofr DC: Tricyclic antidepressants and cardiac disease. Am
Heart J 86:841-842 (Dec) 1973.
11. Hartshorn EA: Handbook of drug interactions, 2nd ed. Drug
Intelligence PubUcations, Hamilton, Illinois, 1973, p 131-138.
12. Anon: Foods potentially harmful to patients taking MAO
inhibitors, Med Letter Drug Ther 18:32 (Mar) 1976.
13. Blackwell B, Marley E and Price J: Hypertensive interactions
between monoamine oxidase inhibitors and foodstuffs, Br J Psy­
chiatry 113:349-365 (Mar) 1967.
14. Bdulton AA, Cookson B and Paulton R: Hypertensive crisis
in a patient on MAGI antidepressants following a meal of beef liver.
Caw Med Assoc J 102:1394-1395 (Jun 20) 1970.
15. hjcGilchrist JM: Interactions with monoamine oxidase^in­
hibitors (letter), Br Med J 3:591-592 (Sep 6) 1975.
16. Saigant W: Interactions with monoamine oxidase inhibitors
. (letter), Br Med J 4:101 (Oct 11) 1975.
17. (jirdwood RH: Death after taking medicaments, Br Med J
1:501-504 (Mar 10) 1974.
18. Bickel MH: Poisoning by tricyclic antidepressant drugs:
general and pharmacokinetic considerations, Int J Clin Pharmacol
11:145-176 (Mar) 1975.
19. Gander DR: Combining the antidepressants (letter), Br Med
cll:521(Feb20)1965.
20. Loveless AH and Maxwell DR: A comparison of the effects
of imipramine, trimipramine, and some other drugs in rabbits
treated with a monoamine oxidase inhibitor, Br J Pharmacol 25:
158-170 (Aug) 1965.
21. Ashcroft GW: Psychological medicine: management of de­
pression, Br Med J 2:372-376 (May 17) 1975.
22. Raisfeld IH: Cardiovascular complications of antidepressant
therapy. Am Heart J83:129-133 (Jan) 1972.
23. National Poisons Information Service: Fifth annual report
for the year ended 31 December 1968, Br Med J 3:408 (Aug 16)
1969.
24. Sargant W: Psychotropic drugs (letter), Br Med J 3:861 (Sep
30) 1967.
25. Brewer C:Suicide with tricyclic antidepressants (letter), Br •
Med J 3:110 (Jul 10) 1976.
26. Sargant W: Treatment of the phobic anxiety state (letter),
Br Med J 3:118 (Jul 12) 1969.
27. Schuckit M, Robins E and Feighner J: Tricyclicantidepres­
sants and monoamine oxidase inhibitors: combination therapy in
the treatment of depression. Arch Gen Psychiatry 24:509-514 (Jun)
1971.
28. Sethna ER: A study of refractory cases of depressive illnesses
and their, response to combined antidepressant treatment, Br J
Psychiatry 124:265-271 (Mar) 1974.
29'.. Davies G:Side effects of phenelzine (letter), Br Med J2:1019
. (Oct 1) 1960.
30. Babiak W: Case fatality due to overdosage of a combination
of tranylcypromine (Parnate) and imipramine (Tofranil), Can Med
Assoc J 85:377 (Aug 12) 1961.
* 31. Bowen LW: Fatal hyperpyrexia with antidepressant drugs
(letter), Br Med J 2:1465-1466 (Dec 5) 1964.
32. Sargant W: Combining the antidepressant drugs (letter), Br
Med d1:251 (Jan 23) 1965.
33. H^ GFM: Combining the antidepressant drugs (letter), Br
Med J 1:384 (Feb 6) 1965.
34. Stanley B and Pal NR: Fatal hyperpyrexia with phenelzine
and imipramine (letter), Br Med J 2:1011 (Oct 7) 1964.
35. Saunders J: Adverse drug reaction following treatment with
monoamine oxidase inhibitors and imipramine and similar drugs:
reporton twocases—one successfully treated with chlorpromazine.
960
dffansas Med Soc 66:471^76 (Oct) 1965.
36. Sargant W: Safety of combined antidepressant drugs (letter),
Br Med J1:555-556 (Mar 6) 1971.
37. Hansten PD: Drug interactions: clinical signiRcance of
drug-drug interactions and drug effi^ on clinical laboratory results.
Lea & Fehiger, Philadelphia, Pennsylvania, 1975, p 156,170^175,
191.
38. Jefferson JW: A reyiew of the cardiovascular effects and
toxicity of tricyclic antidepressants, Psychosom Med 37:160-179
(Mar-Apr) 1975.
39. Lockett MF and Milner G: Combining the antidepressant,
drugs (letter),"Br Med J1:921 (Apr 3) 1965.
40. Luby E and Domino EF: 'Toxicity from large doses of im­
ipramine and a MAO inhibitor in suicidal intent, J Am Med Assoc
177:68-69 (Jul 8) 1961.
41. Jarecki HG: Combined amitriptyline and phenelzine poi­
soning, Am J Psychiatry 120:189 (Avig) 1963.
Downloaded from https://academic.oup.com/ajhp/article-abstract/34/9/954/5211684 by guest on 28 October 2019
42. Simmons AV, Carr D and Ross EJ: Case of self-poisoning with
multiple antidepressant drugs. Lancet 1:214-245 (Jan 31) 1970.
43. Chappell AG: Severe hypothermia due to combination of
psychotropic drugs and alcohol (letter), Br Med J 1:356 (Feb 5)
1966.
44. Man PL and Aleem A: Are MAOI and other psychotropic
drugs really compatible? (letter), Br J Psychiatry 120:120-121 (Jan)
1972.
45. Simpson GM: Combined antidepressant therapy (letter), Br
J Psychiatry 120:695 (Jim) 1972.
46. Hills NF: Combining the antidepressant drugs, Br Med J
1:859 (Mar 27) 1965.
47. Singh H: Atropine-like poisoning due to tranquilizing agents.
Am J Psychiatry 117:360-361 (Oct) 1960.
48. McCurdy RL and Kane FJ: Transient brain syndrome as a
non-fatal reaction to combined pargyline-imipramine treatment.
Am J Psychiatry 121:397-398 (Oct) 1964.
49. Ayd FJ: 'Toxic somatic and psychopathologic reactions to
antidepressant drugs, J Neuropsychiatry:119-122 (Feb; suppl 1)
1961.
50. Howarth E: Possible synergistic effects of the new thson- •
oleptics in connection with poisoning, JMent Sci 107:100-103 (Jan)
1961.
51. Brachfeld J, Wirtschafter A and Wolfe S: Imipramine-tran-
ylcypromine incompatibility, J Am Med Assoc 186:1172-1173 (Dec
28)1963.
52. Kane FJ and Freeman D: Non-fatal reaction to imipram-
ine-MAO inhibitor combination. Am J Psychiatry 120:79-80 (Jul)
1963.
53. Grantham J, Neel W and Brown RW: Reversal of imipram-
ine-monoamine oxidase inhibitor induced toxicity by chlorproma­
zine, J Kansas Med Soc 65:279-280 (Jun) 1964.
54. Randall J: Combining the antidepressant drugs (letter), Br
McdJ 1:521 (Feb 20) 1965.
55. Pare CMB: Combining the antidepressant drugs (letter), Br
Med J 1:384 (Feb 6) 1965.
56. Sargant W: Antidepressant drugs (letter), Br Med tl 1:1495
(Jun 5) 1965.
57. Kelly D, Guirguis W, Frommer E et al: Treatment of phobic
states with antidepressants: a retrospective study of 246 patients,
Br J Psychiatry 116:387-398 (Apr) 197().
58. Ayd FJ: Doxepin with other.drugs. South Med J 66:465-471
(Apr) 1973.
59. Winston F: Combined antidepressant therapy, Br J Psychi­
atry 118:301-304 (Mai) 1971.
60. Spiker DG and Pugh DD: Combining tricyclic and mono­
amine oxidase inhibitor antidepressants. Arch Gen Psychiatry
33:828-830 (Jul) 1976.
61. Sargant W, Walter CJS and Wright N: New treatment of
some chronic tension states, Br Med J1 -.322-324 (Feb 5) 1966.
62. Winston F and McCann ML: Antidepressant drugs and ex­
cessive weight gain (letter), Br J Psychiatry 120:693-697 (Jun)
1972.
B3. Kline N: Questions and answers, J Am Med Assoc 227:807
(Feb 18) 1974.
64. Corrigan LL (ed): Evaluations of drug interactions, 2nd ed,
American Pharmaceutical Association, Washington, D.C., 1976, p
104.
65. Pare CMB: Treatment of depression. Lancet 1:923-925 (May
1) 1965.
 66. Dally PJ: Combining antidepressant drugs (letter), Br Med
J 1:384 (Feb 6) 1965.
67. Evans DAP, Davison K and Pratt RTC: The influence of
acetylator phenotype on the effects of treating depression with
phenelzine, Clin Pharmacol Ther 6:430-435 (Jul-Aug) 1965.
68. Johnstone EC and Marsh W: The relationship between re­
sponse to phenelzine and acetylator status in depressed patients,
Proc R Soc Med 66:947-948 (Sep) 1973.
69. Schildkraut JJ and Klein DF: The classification and treat­
ment of depressive disorders. In Shader R1 (ed): Manual of psy­
chiatric therapeutics. Little, Brown, & Co., Boston, Massachusetts,
1975, p 61.

Am J Hosp Pharm 34:961-965 (Sep) 1977

High-dose methotrexate with folinic acid rescue

John F. Bender, Wliiiam R. Grove and Ciarence L. Partner

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A brief review of the pharmacology of methotrexate is presented, and the rationale for the
administration of high-dose methotrexate and the necessity of a folinic acid rescue to prevent
methotrexate toxicity are discussed.
. Critical factors concerning the use of this therapy, as well as unusual toxicities associated
with the use of high-dose methotrexate, are presented. Several drug-and patient-related vari­
ables which may affect the toxicity of this dual drug administration are discussed to better en­
able pharmacists to monitor patients receiving this form of therapy.
High-dose methotrexate with folinic acid rescue has improved the therapeutic index of
methotrexate. The optimal dosage and duration of the two agents are yet to be determined.
Key words: Antineoplastic agents; Dosage; Leucovorin; Methotrexate; Toxicity

Intensive investigation into the use of antifolates—and
in particular methotrexate—as anticancer agents was
spurred by Farber's demonstration of the efficacy of anti-
folate therapy for inducing complete remissions in childhood
acute lymphocytic leukemia in 1948.1 Since that time, ex­
tensive information concerning the mechanism of action,
pharmacology, pharmacokinetics, toxicology and indications
for the use of methotrexate has been accumulating. Appli­
cation of this information to the clinical situation has pro­
duced signiHcant advances in the therapy of malignant
diseases, including the first chemotherapeutic cures. Most
recently, high-dose methotrexate followed by folinic acid
rescue has been reported to improve the therapeutic index
of.methotrexate.2 It is the intention of this paper to discuss
the rationale and clinical implications of this therapeutic
regimen.
Pharmacology
Methotrexate reversibly binds to dihydrofolate reductase,
thereby inhibiting the enzyme that reduces folic acid to
tetrahydrofolic acid.^-^ Tetrahydrofolic acid and related
derivatives function as carriers of one-carbon units which
John F. Bender is Clinical Pharmacist; William R. Grove is Assistant Di­
rector; and Ciarence L. Partner, M.S.,' is Director, Clinical Research
Pharmacy Service, Baltimore Cancer Research Center, National Cancer In­
stitute, National Institutes of Health, University of Maryland Hospital,
Baltimore 21201.
The autHors thank Dr. Peter Wiernik for his assistance in reviewing this
manuscript. The authors thank Maggie Potts for typing the manuscript.
Copyright © 1977, American Society of Hospital Pharmacists, Inc. All rights
reserved.
are used iff the synthesis of thymidylic acid and in the de
novo synthesis of purines. Without these, deoxyribonucleic
acid (DNA) replication and consequently cell division would
be severely impaired.'' In human cells, the reaction most
sensitive to depletion of tetrahydrofolic acid is thymidylic
acid biosynthesis.^ Not only is DNA synthesis halted, but
ribonucleic acid synthesis, although somewhat protected by
purine salvage mechanisms, is also seriously impaired.''
Goldman has shown that complete inhibition of DNA
synthesis is dependent on the presence of free intracellular
methotrexate in excess of that which is stoichiometricallp
bound to the high affinity sites on dihydrofolate reductase.
The excess methotrexate is required to bind to new dihy­
drofolate reductase being synthesized, but more importantly,
to saturate binding sites on dihydrofolate reductase that
have a low affinity for methotrexate.®''' In the absence of free
intracellular methotrexate, biosynthesis of tetrahydrofolate
and consequently processes which are dependent on te­
trahydrofolate are able to continue, despite saturation of the
high affinity sites on dihydrofolate reductase with metho­
trexate.''
Continuous infusion experiments have established the fact
that the cytotoxic effects of methotrexate are more a func­
tion of the duration of exposure of cells to levels of metho­
trexate that completely inhibit DNA synthesis rather than
peak serum levels achieved.®
Absorption, Distribution and Excretion
Methotrexate may be administered orally, intramuscu­
larly, intravenously and intrathecally. It is essentially
completely absorbed in small oral doses (0.1 mg/kg) while

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