HaCKeRz Kr0nlcKLeZ 1/HaCKeRz Kr0nlcKLeZ.iso/drugs/tricyclic.antidepressants

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Broadly speaking, there are three classes of antidepressant
medications in use - - the tricyclics (or heterocyclics), the
monoamine oxidase (MAO) inhibitors and the newer, so-called
second-generation agents by and large developed in the 1980 's.  While
there is considerable overlap in their actions and uses,  these diffe
rent categories of antidepressants work by distinct mechanisms, have
different s ide effect profiles, and may be favored for varying
indications.  For these reas ons, they will be discussed separately
below.

The tricyclics began to see broad use in psychiatry in the early
 1950's with the introduction of imipramine (Tofranil and others),
 still one of the most-used me dications in this group.  Other
 tricyclics (see table 1) include amitriptyline ( Elavil, Endep),
 desipramine (Norpramin, Pertofrane), nortriptyline (Pamelor and
 Aventyl), trimipramine (Surmontil), protriptyline (Vivactil), and
 doxepin (Adapi n, Sinequan). Clomipramine (Anafranil) is a somewhat
 specialized tricyclic agen t only recently introduced into the United
 States and approved specifically for the treatment of
 obsessive-compulsive disorder, in contrast to the other members of
 this class which have a broader range of accepted uses. Tricyclics
 also app ear in fixed-dose combination with other agents (Etrafon,
 Triavil, Limbitrol) al though many psychiatrists frown on these
 preparations as not allowing enough ind ividual titration of the
 doses of the component medications.

For what are the tricyclics used? The tricyclics, while accepted first
and foremost for the treatment of depressiv e conditions and primarily
referred to as "antidepressants," are useful in a wid e range of
disorders.  Their effectiveness is agreed upon for major depressive e
pisodes, some so-called atypical depression (see further discussion of
this belo w under the monoamine oxidase inhibitors), panic disorder,
social phobia, bulimi a, narcolepsy, attention deficit disorder (ADHD)
with or without hyperactivity, migraine headache and various other
chronic pain syndromes, enuresis in children , and
obsessive-compulsive disorder.  Depressive symptoms occurring in the
conte xt of other major mental illnesses such as manic depressive
disorder, schizophre nia and schizoaffective disorder, are also
treated with tricyclics, with certain caveats discussed below.  These
medications  are possibly useful as well for a broader range of
depressive conditions not meeting strict criteria for major dep
ressive episodes (such as so-called "dysthymia" or depressive
neurosis; and even prolonged or pathological mourning), for
agoraphobia without panic attacks, and for some of the symptoms (such
as intrusive nightmares) in post-traumatic stres s disorder.

What will it feel like to be taking a tricyclic? It is a common
supposition that taking an antidepressant produces some kind of "
high."  In fact, this is not the case; usually the recipient will not
be aware a t all subjectively of being on a medicine except that one's
depression, panic di sorder, etc. will be lessened in intensity or
one's ability to function in the f ace of it (including in one's
therapy) will be enhanced.  Except for the side ef fects, a person who
does not have a disorder treatable with an antidepressant wi ll not
feel any different when taking one.

Often, the benefits will not be apparent except in retrospect over
some time.  I n other cases relief, especially from depressive
symptoms, may be more dramatic; only in the sense of this dramatic
relief do responders feel elated.  Certainly , one does not "escape,"
ignore or become numb to one's problems or sadnesses th rough taking
an antidepressant.  Being aware of this in advance will often be of
great assistance in the realistic appraisal with one's caregivers of
whether it is advantageous to take an antidepressant medication.  To
know this will be a r elief to some and may well be disappointing to
others!

Two corollaries of the above are that the antidepressants are not
"addictive" an d that they have low abuse potential.  Taking more than
the prescribed dose of a tricyclic is not an attractive but rather a
disagreeable experience.  In additi on, patients do not describe
craving or yearning for the experience of being on the medication
after it is stopped. (Of course, it is possible to have a reboun d of
depressive symptoms, especially if the medication is stopped
prematurely. Furthermore, there is a "withdrawal" syndrome, with
malaise, nausea and headache s, if the medication is stopped too
abruptly, although this is not indicative of dependency.)


When a person benefits from a tricyclic in the treatment of
depression, some of the discernable effects include sounder or more
restful sleep, decreased dreamin g (particularly a decrease in
troubling dreams), increased energy and ability to concentrate, and
correction of appetite disturbance.

How do these medicines work? Over time, the tricyclics enhance the
concentrations in certain regions of the C NS of two neurotransmitter
chemicals, norepinephrine and serotonin, whose undera ctivity has been
implicated in depression and other disorders.  When these neuro
transmitters, known as monoamines, have been secreted,  they must then
be inacti vated by a variety of mechanisms including reuptake into the
secreting cells.  T ricyclics impede this reuptake process so that the
monoamines remain active long er after secretion, presumably affecting
the preexisting underactivity which was responsible for the target
symptoms. Some tricyclic side effects relate to the fact that these
medications have similar effects on other neurotransmitters in the
CNS, notably histamine and acetylcholine.

What side effects can I expect if I take a tricyclic? While there are
individual differences among the agents in terms of degree, they
produce quite similar and troubling side effects (see tables 2 and 3).
With ma ny tricyclics, the most troublesome effect with ongoing use is
sedation.  They a re often administered at bedtime so that this effect
is bearable, but it may per sist into the following day.

Commonly, they cause enduring anticholinergic effects including dry
mouth or eye s (of concern particularly in patients with dental
problems and contact lenses, respectively); a peculiar taste in the
mouth; and dilation of the pupils with re sultant sensitivity to
bright light.  Disturbances in visual accommodation (the rapid
adjustment in focus necessary when the gaze is shifted from near to
far or vice versa) can cause blurry vision. Constipation or urinary
hesitancy are com mon.  These effects can occasionally be quite
serious or exacerbate underlying p roblems or tendencies in the
affected organ system, occasionally precipitating c onditions
requiring immediate medical attention such as acute glaucoma, paralyti
c ileus of the bowel or acute urinary retention.

Weight gain is a common complaint of which patients should be made
aware at the outset so that they can anticipate controlling their
intake.  It seems that the weight gain comes from a mechanism distinct
from the mere correction of the appe tite suppression that often
coincides with depression.  In men, erectile dysfunc tion or, more
rarely, difficulty achieving an ejaculation may be important and u
nderreported barriers to compliance with the tricyclics.

At the outset of treatment, people taking these medications often are
restless o r anxious, may be tremulous or feverish, may report
increased perspiration or ni ght sweats, can experience difficulty
falling asleep or restless disturbed sleep , and may report some
clouded thinking or interference with their concentration. These
symptoms are usually transitory although they may be so uncomfortable
th at they cause the patient to discontinue the drug during the first
few days or w eeks of treatment.  At about the point where the
therapeutic benefits of the med ication begin to be apparent several
weeks into the course of treatment, this cl ass of adverse reactions
has usually resolved or become tolerable.

Cardiovascular effects are also associated with these medications.
Orthostatic hypotension, i.e. dizziness upon arising or otherwise
rapidly changing posture, is common.  A rapid heartbeat is often
reported, sometimes with palpitations.  T he medications can have
deleterious effects on an unhealthy heart, e.g. causing EKG
(electrocardiogram) changes or arrhythmias (disturbances in cardiac
rhythm o r conduction); or, rarely, worsening or precipitating angina
or heart failure or precipitating a myocardial infarction (heart
attack).   These cardiac effects m ay eliminate the tricyclics from
consideration for some patients, although with close ongoing
monitoring they may often be employed to good effect.  A thorough
evaluation of their safety in the presence of reported history of
cardiac diseas e, especially a cardiac conduction defect, is always
warranted and may involve a referral for a consultation with a
cardiologist.  In all patients from middle a dulthood, it is prudent
to obtain an EKG prior to treatment and with dosage incr eases beyond
a certain extent.

It is the cardiac effects which make the tricyclics so dangerous in
overdose.  T aken at one time, a one- to two-week supply can cause
serious, potentially letha l, cardiac complications.  Tricyclic
antidepressants are now the leading cause o f death by drug overdose
in the United States. It is ironic that such effective medications for
conditions which often involve serious suicidal intent have such
potential lethality.

The tricyclics can occasionally cause seizures in patients with a
history of hea d injury, especially those with a preexisting seizure
history.  In these cases, collaboration of care between your
psychiatrist and a neurologist is often warra nted.  As with all
medications to which one has not previously been exposed, the
possibility of an allergic reaction should be borne in mind.  Once
allergy to o ne of these medications has been established, it must be
avoided by that individ ual.  Certain of these medications are very
closely related and there may be cro ss-sensitivity among imipramine,
clomipramine, desipramine and trimipramine; or among amitriptyline and
its derivatives nortriptyline and protriptyline.

As with other antidepressants, the tricyclics can cause a swing from
the depress ed to the manic state when given to a depressed patient
with manic-depressive il lness.  In someone whose manic-depressive
illness has not been recognized, it ca n declare itself in just such a
fashion when the individual presents for treatme nt of a depressive
episode.  There is some debate about whether the antidepressa nts can
precipitate mania in someone who would not otherwise have a manic
component to their affective disease.

The elderly are particularly susceptible to the range of side effects
noted above.  They often require treatment on lower dosages of these
medications for comfort and safety; fortunately, such lower doses can
also be therapeutic for them. The tricyclics should be used in
pregnancy, as the Physician's Desk Reference puts it, "only if the
clinical condition clearly justifies potential risk to the fetus."  A
woman taking these medications should not nurse an infant, as the medi-
cation may be excreted in the breast milk.

With what other medications that I may be taking will the tricyclics
interact?

You should always inform any physicians involved in prescribing for
you of what medications you are already taking.  Your primary care
doctor, any specialists, surgeons and dentists involved in your care
should be aware of the fact that you are taking a tricyclic; your
prescribing psychiatrist should know all the other medications you
take.

The effects of anticholinergic and sympathomimetic medications
(employed in anae sthesia, treatment of gastrointestinal disturbances
and certain ophthalmological conditions, allergy and cold remedies)
may be additive with the side effects of the tricyclics described
above.  Certain blood pressure medications may interact with them as
well, or their effectiveness may be inhibited by the presence of the
tricyclic. Cimetidine (Tagamet), ranitidine (Zantac) and other similar
medi cations used in peptic ulcer disease may raise the tricyclic
levels in your body and thus increase the frequency and severity of
adverse reactions.  If you are receiving thyroid supplements for
hypothyroidism, tricyclics may make you more sensitive to their
adverse effects, especially on the heart and circulatory syste m, and
should be more closely monitored.

The tricyclics amplify the CNS depressant effects of alcohol and other
sedatives (tranquilizers and sleeping medications), so these
medications should be used cautiously by someone receiving a
tricyclic.  You may find a reduced tolerance for excess caffeine
while taking these medications. Except for the cold remedies noted
above, no difficulty is presented by combining the tricyclics with
any over-the-counter remedies, vitamin and other food supplements,
or foods.

What are the preliminaries to starting on a tricyclic? A thorough
medical screening including bloodwork is required to be sure that a m
edical illness is not being mistaken for the psychiatric diagnosis.
It is cruci al as well to determine whether you have the types of
cardiac conduction disease which would make the use of a tricyclic
dangerous.  These can be detected with an EKG, which should be a
routine precursor to beginning on a tricyclic for pati ents over 40
years of age or anyone with a history of heart disease.  When doubt s
about the safety of these drugs arise, a cardiology consultation is
prudent.


Other medical conditions which can make the use of the tricyclics
dangerous, suc h as narrow-angle glaucoma, should be ruled out in
preliminary history, examinat ion and if necessary consultation.

 How will my doctor choose among the various tricyclics? None of the
antidepressants has been proven more effective or more rapidly-actin g
than another, although this is a marketing claim that is often made
for variou s ones. The grounds for choice among them is therefore
largely based on their si de effect profile. There are two broad
chemical classes of tricyclics. The tert iary amines (amitriptyline,
imipramine, trimipramine and doxepin), which have pr oportionally more
effect in boosting serotonin than norepinephrine, produce more
sedation, anticholinergic effects and orthostatic hypotension.
Amitriptyline an d doxepin are especially sedating. Secondary amines
(nortriptyline, desipramine, and protriptyline) tend more toward
enhancement of norepinephrine levels and he nce toward irritability,
overstimulation and disturbance of sleep.  The tertiary amines, thus,
are more useful where depression is accompanied by sleep disturba nce,
agitation and restlessness; whereas the secondary amines may be
preferable where the depressed patient is fatigued, withdrawn,
apathetic and inert.  The p sychiatrist's initial evaluation,
therefore, must go into extensive detail about the pattern of
depressive symptoms you have experienced, to tailor the agent to the
condition.  An impression about which side effects you would best
tolerate (or even benefit from) will enter into the physician's choice
of tricyclic as we ll.  Overall, desipramine and nortriptyline are
perhaps the most benign in term s of patient tolerance, and are often
the initial tricyclic of choice.

However, these are just the broadest guidelines, and treatment must be
individua lized in terms of agent and dose in a trial-and-error
fashion. Since there is r eason to believe that many of the
tricyclic-responsive conditions have a heredit ary component, all
other things being equal, starting on the same agent to which a
genetically-related family member with the same disorder has responded
favora bly in the past will usually be apt.  You may wish to make
inquiries about this within your family if you are under consideration
for medication treatment.  Of course, where you yourself have
previously responded favorably and tolerably to a particular agent, it
should generally be the drug of choice again.

How should the medication be taken? As with any medication, if your
physician's instructions are unclear, you should ask for
clarification. You and your prescribing doctor will individualize a
treatment plan for you.  However, some generalizations can be made.
The medication will be started at a low dose to make sure you can
tolerate it and to acclimatize your body to its effects.  If you are
in good health, the dose will be incre ased every two to four days as
tolerated until it is in the therapeutic range. For the elderly or
infirm, the interval between dosage increases is lengthened, generally
to between seven and ten days as tolerated.  Your doctor should do a t
horough review with you of what side effects to anticipate.  For
example, knowin g of the risks of orthostatic hypotension may mean the
difference between becoming faint on arising, falling and injuring
yourself; and merely taking the care to move slowly when standing up.

During this period of acclimatization to the medicine, it is important
for your psychiatrist to be available by phone or frequent follow-up
appointment to check on your progress, answer questions about the
effects you may be feeling, and reassure you.  Your comfort with the
medicine will be enhanced if you have a low threshold for contacting
your doctor if you are puzzled or troubled by anything y ou are
experiencing.

Generally, the medication is taken all at once at bedtime so that side
effects will peak overnight and so that sedation will be less
inconvenient.  If necessary , the dose can be divided into two or more
portions taken at different times of the day, where peak side effects
after a single dose have been intolerable.

The recipient should not expect to respond at once after starting on
an antidepr essant.  A one- to three-week interval to therapeutic
effect is the rule and a four- to six- week lag is conceivable.
Unfortunately, there is no corresponding delay in the onset of adverse
reactions, so it may even be useful to anticipate feeling worse on the
medicine before you will feel better!  Where bearable, it i s
necessary to persist in the face of the discomfort of the side effects
(some o f which will attenuate) and of the lack of quick symptom
remission to give the m edicine a chance to be effective.
Furthermore, responsiveness to a particular a gent or a particular
dosage range is variable. While there are acknowledged "therapeutic
dosage ranges" and some basis for individualizing choice of agent, an
element of trial and error prevails and you and your doctor may have
to make seve ral dosage increases or go on to a second or third
medication before an effectiv e regimen is found.

It should be stressed that the tricyclics must be taken regularly and
consistent ly to be beneficial.  They cannot be used on an "as-needed"
basis only on the da ys when you are feeling worst.  The need to
persevere with the medication during the two-to-four week lag time
until it takes effect must be borne in mind.

What if I don't respond? Because it takes some time for a tricyclic at
sufficient blood level to bring ab out the changes in the CNS that
cause resolution of target symptoms, a patient m ust have a trial of
adequate duration at effective dosage.  Even if you are taki ng the
recommended dose, poor absorption or rapid elimination of the
medication from your system may necessitate a higher dose, especially
if side effects are m inimal or being tolerated well.  Occasionally,
it will be useful to monitor the blood level of the medication, but
the inaccuracy in measuring such miniscule co ncentrations limits the
usefulness of the tests, and the range of effective bloo d levels has
not been meaningfully defined for all the agents in this class. As
mentioned above, when high doses of a tricyclic are employed, serial
EKGs should be followed as well.

After an adequate but ineffective trial, you and your doctor will make
a decisio n about switching to a different medication or attempting to
potentiate your cur rent medication with agents such as lithium
carbonate, thyroid hormone, or on oc casion the addition of a second
antidepressant.

Will I have to take the medication for the rest of my life? On the
basis of clinical experience and research, there is a consensus that
pati ents with major depression can typically be taken off their
antidepressant medic ation after six to eight months of clinical
response without doing worse than pa tients who continue on the
medication.  In contrast, premature discontinuation a fter fewer
months or after a less complete treatment response can often lead to a
relapse.  However, a patient who initially does well after
discontinuing an an tidepressant may have a recurrence months or years
later, as evidence suggests t hat up to 50% of patients who have had a
single major depressive episode will ha ve subsequent episodes. The
value of longer-term antidepressant maintenance to prevent recurrence,
as opposed to episodic treatment of any relapses, is uncerta in.

Much less evidence bears on the proper length of a course of tricyclic
therapy f or other conditions, either the attenuated (non-major)
depressive syndromes or t ricyclic-responsive non-depressive syndromes
such as panic disorder.  Often, pat ients with panic disorder require
open-ended treatment courses to avoid relapse, and
medication-responsive chronic depression or dysthymia may also relapse
if medication is not maintained. Attempts to discontinue medication
should take pl ace in a measured way under regular ongoing followup
with a sensitivity to the c hance that resumption of medication use
will be merited.

As noted above, there is sometimes a withdrawal syndrome when
tricyclic use is a bated abruptly.  This consists mainly of headache,
general malaise, and GI distress and can last several days.  Over the
weeks following discontinuation of an a ntidepressant, a patient may
experience REM rebound, in which the frequency and intensity of his or
her dreams is increased.

...eliot  [Eliot Gelwan M.D.]                            |
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