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).

1691