LE1TERS
TO THE
EDITOR
(halopenidol, 2 mg/day; amantadine, 300 mg/day; benztropine, 2 mg/day) remained unchanged. After a cumulative bupropion dose of 450 mg over 72 hours, Mr. A became disoriented and agitated, with visual and auditory hallucinations, impaired attention and memory, and a fluctuating level of awareness. His gait was unsteady, resuiting in a fall. Bupropion was discontinued, but the other medications were unchanged. Neurological examination revealed impaired cerebellar function, including dysdiadochokinesia, dysmetria, and positive Romberg’s sign. An EEG demonstrated only diffuse bilateral slow wave activity. Laboratory measures and a head CT scan were unremarkable. The patient’s delirium resolved over the next 4
days. Agitation, disorientation, impaired attention, hallucinaand acute loss of cerebellar function with EEG changes indicative of encephalopathy clearly define delirium. These symptoms began with the initiation of bupropion and resolved when it was discontinued. Cerebellar dysfunction has been associated with bupropion (according to the package insert), but there have been no reports of delirium. One cxpianation for the delirium is synergism between bupropion and amantadine. Bupropion inhibits dopamine reuptake; amantadine facilitates release of presynaptic dopamine. Together they may cause dopaminergic overdrive (despite the use of a competitive inhibitor such as halopenidot), with subsequent delirium. In addition, antichohinergic agents (e.g., benztropine) may further enhance dopaminergic transmission or cause delirium on their own. Last, pharmacokinetic interactions between bupropion and amantadine or benztropine could have produced elevated serum levels of these agents, resulting in delirium. Bupropion’s favorable side effect profile makes it appealing in treating elderly depressed individuals. However, this same population also frequently suffers from parkinsonism and is often treated with dopaminergic agents; their combination with bupropion may result in delirium. We suggest caution in the concurrent use of bupropion and dopamine agonists, even at the lowest doses.
tions,
however, they have limitations. In the first two studies, maximum response was observed at trough bupropion concentrations under 100 ng/mt. A similar trend was observed by Golden et al. (2), but it did not reach statistical significance,
perhaps because of the small sample size. The latter study did report that high plasma levels of the metabolites, particularly hydroxybupropion,
catty
active
associated 142:1459-
ISRAEL LIBERZON, JOHN R. DEQUARDO,
M.D. M.D. KENNETH R. SILK, M.D. Ann Arbor, Mich.
Therapeutic
Drug
Monitoring
As
with
reflected
half-life metabohites
less
antidepressant
by
changes
in plasma
of 4-24 hours (3). In contrast, can be as long as 43 hours.
While bupropion plasma concentration may be high 1-4 hours after a dose, it can fall by 75% over the next 4 hours. In contrast, metabohites reach concentrations more than 10 times that of bupropion and remain high over the entire dosing
interval.
achieve
steady
After
state
a dose
in 3-S
adjustment,
days,
bupropion
white
metabolites
will
may
take
10 days. These facts raise the question of when plasma should be sampled in relation to duration of therapy and time of dose, since the relative contributions of bupropion and its metabolites to efficacy and safety are unknown. For seizure, the principal safety concern with bupropion, there is a correhation with bupropion dose, but there are insufficient data to
correlate seizure levels (4). Furthermore, ohites exist, but
pending
risk
with
bupropion
or metabohite
reliable assays for bupropion they are complicated. Results
on the capability
of the laboratory
plasma
and its metabmay vary de-
employed.
Also,
bupropion is unstable in plasma (5). More experience is needed in transferring these assays from the experimental to the reference laboratory. The goal of therapeutic drug monitoring is to improve
and
reduce
reliance
toxicity.
goal is not feasible. drug
monitoring
just
the dose
450
mg/day,
formation toring
Given
on monitoring for
bupropion
inappropriately which
is not
is available, for bupropion
be used solely employed.
the paucity
of bupropion
that
might
in practice
as a compliance
clinicians
raise
recommended.
Until
is limited
to ad-
the dose drug
(perhaps,
and must
above
definitive
of therapeutic
check)
this
use of therapeutic
lead
or even
the value
of informa-
to accomplish
We are concerned
of Bupropion
SIR: Therapeutic drug monitoring is an accepted tool in practice and is readily available from commercial haboratonies. Given its availability and its usefulness for some classes of antidepressants, there is a tendency to rely on therapeutic drug monitoring for new antidepressants before it has been adequately tested. Such is the case with bupnopion, first of a new class (aminoketones). There have been three studies relating plasma concentrations of bupropion alone (one with 61 subjects [11 and one with 15 subjects [Preskorn et al., unpublished]) or with its metabolites (10 subjects [2]) to its antidepressant effects;
1690
metabolites.
a beta (elimination) half-hives for the
tion,
1. Golden RN, James SP, Sherer MA, et at: Psychoses with bupropion treatment. Am J Psychiatry 1985; 1462
associated
concentration, the half-life (time required to eliminate onehalf of the amount of drug in the body) of bupropion has two components: an alpha (disposition) half-life of 1 #{189} hours and
efficacy REFERENCE
were
response. Stilt, reliance on therapeutic drug monitoring to guide bupropion dose adjustment is premature and potentially dangerous for the following reasons. Bupropion is extensively metabolized to pharmacologi-
in-
moni-
it should
be cautiously
REFERENCES 1. Preskorn SH: Antidepressant response and plasma concentrations of bupropion. J Clin Psychiatry 1983; 44(5, section 2): 137-139 2. Golden RN, DeVane CL, Laizure SC, et at: Bupropion in depression, II: the role of metabolites in clinical outcome. Arch Gen Psychiatry 1988; 45:145-149 3. Laizure SC, DeVane CL, Stewart iT, et at: Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose. Chin Pharmacol Ther 1985; 38:586-589 4. Davidson J: Seizures and bupropion: a review. J Chin Psychiatry
1989; S. Laizure
50:256-261
SC, DeVane
Am
J
CL:
Stability
Psychiatry
of bupropion
147:12,
and
December
its major
1990
LETfERS
metabolites 450
in human
plasma.
Ther
Drug
Monit
SHELDON
1985;
7:447-
H. PRESKORN,
M.D.
Wichita,
Kan.
RICHARD J. FLECK, PHARM.D. DAVID H. SCHROEDER, PH.D. Burroughs Wellcome Co. Research Triangle Park, NC.
oxetine.
This
of Psychological
SIR:
We
concept readers The
but
that
the
of psychological of the Journal. concept
psychiatric widely
believe
following,
trauma,
minds
origin
of the
be of interest
the
to the
since
trauma
the
late
with
of the
stress
taxed
the
best
century.
Breuer
and
unconscious,
trauma had earlier antecedents. We ing them because of their continuing
ogy of posttraumatic
has
nineteenth
originated
concept
It is
Freud
(1),
psychological
feel it is worth mentionrelevance for the nosot-
disorder.
den vehement emotions such as terror or anger, could better be called psychic trauma. He regarded this “sudden action of vehement emotions” as an actual molecular concussion of the brain, which he likened to the commotio cerebri postulated in physical trauma. Since then, other German
these stress rather
appears
in patients
equated the concepts of psychic (5). It is only recently, however,
into
drug,
a new
devoid
person.
of side
effects,
Curiously,
when
that
neurotransmitters.
that
they will need
make efforts to change they will have to treat pression” was not the Increasing the dose of the increased dysphonia (One might speculate
to find jobs,
that
VAN DER HART, PH.D. Utrecht, The Netherlands
PAUL BROWN,
excellent
responses
to fluoxetine,
with other antidepressants. scribing fluoxetine; they adoxicat phenomenon.
Preston,
Victoria,
M.D.
Australia
of Fluoxetine
Am
J
Psychiatry
increasingly seen with
1 47: 1 2, December
with have
to
seen
this
Caution is urged for those should be on the alert for this
just
as we have
prepar-
REFERENCES 1. Cowley G, Springen K, Leonard EA, et at: The promise of Prozac. Newsweek, March 26, 1990, pp 38-41 2. Klerman GL: The psychiatric patient’s right to effective treatment: implications of Osheroffv Chestnut Lodge. Am J Psychiatry 1990; 147:409-418
Fluoxetine SIR:
and
the
common but antidepressant
1990
underflu-
and In
Suicidal
HIERHOLZER,
M.D.
a recent
colleagues
Ideation
article,
Martin
(1 ) presented
H.
six case
experienced increased suicidal ideation oxetine treatment. While acknowledging in a “small minority” of their patients,
Teicher,
reports
M.D.,
Ph.D.,
of patients
coincident that this
who
with fluoccurred
they commented that “the purpose of this report is to suggest the surprising possibility that fluoxetine may induce suicidal ideation.” In my opinion, this is not well substantiated and may introduce a medical-legal precedent. Tnicychic antidepressants and monoamine oxidase inhibitons (MAOIs) lack receptor specificity. These side effects (2) limit dose titration, patient compliance, and safety in somatic disease (e.g., cardiac disease) and represent a major concern
about
an
they
Fresno, Calif.
1. Breuer J, Freud 5: Studies on Hysteria (1895 [1893-18951): Complete Psychological Works, standard ed, vol 2. London, Hogarth Press, I 955 2. Janet P: L’automatisme psychotogique: essai de psychologie cxp#{233}rimentale sur les formes inf#{233}rieures de l’activit#{233}humaine. Paris, Felix Alcan, 1889; Paris, Soci#{233}t#{233} Pierre Janet/Payot, 1973 3. van der Kolk BA, van der Hart 0: Pierre Janet and the breakdown of adaptation in psychological trauma. Am J Psychiatry 1989; 146:1530-1540 4. Eulenburg A: Lehrbuch der Nervenkrankheiten, vols 1, 2. Bertin, August Hirschwald, 1878 S. Groeningen GH: Ueber den Shock. Wiesbaden, JF Bergmann, 1885
SIR: I wish to report appreciated phenomenon
is
Happily, in our clinic we have happened upon a somewhat novel approach to this phenomenon: psychotherapy. Admittedly, we have had to resort to techniques regarded as “unscientific” by some headers in the field (2), but we have found this approach to be of tremendous help. Like others, we have seen some patients who have had
ROBERT
Limitations
with
their attitudes toward people, that their spouses decently, that their “deroot cause of their alcohol abuse, etc. fluoxetine does not appear to improve that accompanies these realizations. that this medication imparts a measure
REFERENCES
East
which
fluoxetine
indicated and prescribed, after it begins to exert its therapeutic effects, many patients realize that the medication wilt not change the problems in their lives. They realize, for cx-
shock
ideas regarding the molecular basis of posttraumatic disorders have begun to find a basis in scientific fact than fancy, as exemplified in research on trauma and
ONNO
who
of insight.)
The nineteenth-century French psychiatrist Janet (2) saw psychic trauma as crucially mediated by vivid or “vehement” emotions. These were further prompted by traumatic memones and exerted a disintegrating effect on the mind (3). The first to introduce the term “psychic trauma,” however, was the German neurologist Albert Eulenburg in 1878 (4, p. 589). He believed that “psychic shock,” in the form of sud-
physicians have also and psychic trauma
is a wonder
one
ample,
to have
the
on
may
of psychological
believed
as with
make
Trauma
typically
have recently heard about fluoxetine from a television talk show, from the lay press, as in the recent cover story in Newsweek (1 ), on from a friend who heard about the mcdication from one of these two sources. Typically, the patient has a long history of dysphonia and interpersonal difficulties and has several psychosocial stressors. The patient comes to the clinic and asks for “Prozac” by name. There is an expectation, spread about by the sources I have named, that fluoxetine
Concept
phenomenon
TO THE EDITOR
overdosage.
In contrast,
second-generation
sants are equally effective, are usually well exhibit a favorable therapeutic index. While ment modality merits vigilance for unexpected should not lose sight of its beneficial addition
peutic
armamentarium
antideprestolerated, and any new treatsequetae, we to our thera-
(3).
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