LETTERS

elevated interferon-alpha in chronic fatigue syndrome patients is no longer statistically significant when an appropriate Bonferroni correction is made for the multiple comparisons undertaken. The finding did not correlate with duration of symptoms

or severity

ofdisability,

and in their discussion

that other investigators had either or demonstrated it in only a small syndrome patients. Klimas et al.

noted

the variability

in findings

Lloyd et al. noted

not found this abnormality subgroup of chronic fatigue (Dr. Bell’s reference 3) also

between

investigators.

Gold-

Pharmacotherapy

of Agitation

SIR: We

the

mcnt,

subtle neurological abnormalities although not examined by a consultant neurologist,

they

epidemic which has unclear relevance for the current sporadic form of the illness. There are no replicated studies that have convincingly demonstrated a viral etiology for the disorder. As with Epstein-Barr virus, it now appears that the primary infection with HHV-6 occurs in most individuals in early life, and the meaning of HHV-6 reactivation in approximately 70% of the subjects of Buchwald et al. (Dr. Apfelbaum’s reference 3) is unclear. As they note, it may be an epiphenomenon, secondary to immune dysfunction or have no relation at all to a patient’s symptoms. To date, there has been a failure to replicate the retroviral findings. Significant abnormalities of neuropsychological functioning have not been reported in peer-reviewed publications (4). Our own work has documented abnormalities

on SPECT

scanning

tigue syndrome Moldovsky’s focused on a underway in ofabnormal

adequate

in a subgroup

of patients

with chronic

fa-

but the significance ofthis finding is unclear(S). report (Ms. Saltzstcin and associates’ reference 6) small number of patients, and studies arc currently a number of centers that document a wide range sleep findings. No studies in the literature have used

psychiatric

control

groups,

which

would

be an impor-

tant consideration given the documented abnormalities in immunology, neuroimaging, and neuropsychobogy that have been found in major depression (3). We are currently pursuing investigations of patients with chronic fatigue syndrome and those with major depression on a variety of immunologic measures in order to help clarify this issue. Clearly, it is important to study this syndrome further from an integrative biopsychosocial approach using well-designed studies. In this paper, we sought to emphasize the importance

of studying fatigue

social

factors

in the genesis

and shaping

of chronic

syndrome.

carefully

study by Emil F. the relative efof agitation

designed

( 1 ) that reported pharmacotherapics

in dementia. The authors mustered a large sample of well-assessed patients with severe dementia, screened them meaningfully for the independent variable, allowed for dosage adjustvalidity

were on an

EDITOR

in Dementia

Coccaro, M.D., and associates ficacy and side effects of three

stein’s report (Dr. Goodrich’s reference 1 ) and Bastien’s report (cited by Ms. Saltzstein and associates) have yet to be described in a peer-reviewed forum. Hyde’s study (Dr. Goodrich’s reference 3) involved a nonblind assessment of patients, emphasized

the patients and focused

appreciate

TO THE

maintained

double-blind

of the

ground review

rating

conditions,

process.

Their

and results anticipated (2) that provides useful

Despite

the

have

tients. patient

strengths

major

the universe his patient included

whether dictive

the mean

studies

in application

screened

outcome

in this

area,

to individual

and included

data

in his situation.

pa-

in this study.

forms he would

of the whole

He also

study (as these of “no difference

individual

back-

cager to use these results for a difficult to know whether his patient belonged to

of patients

parallel-group their finding to any

of parallel-group

had one of the less common (for instance, Korsakoff’s),

value

to the

of the

the publication of a scholarly context for such discussion.

drawbacks

A physician would need

and attended

discussion

would

authors between

group not

If

of dementia not know

had pre-

know

pointed out) medications”

from

a

whether applied

case.

We recently completed a series of intensive (N-of-i ) studies (3) designed to avoid the problems of using extensive study results (paper in preparation). Like Dr. Coccaro and associates,

we treated

dementia

hydraminc and also maintained ratings

(shift-by-shift

between

optimal

provide

We cepted free of patient

several

patients

oxazepam

ratings

dosages

ofresistiveness).

of each

presentations

diphen-

We crossed

medication

of the

and

of haloperidol. We and used frequent

most

often

over

enough

to

effective.

found that this strategy was practicable and well acin our setting. Of iO patients admitted, seven remained serious medical illness long enough to analyze. One was dropped due to improvement during placebo ad-

ministration.

Another

did

pam, or diphenhydramine. spondcd best to thiothixene, equally to diphenhydramine, None

with

used thiothixenc instead double-blind conditions

were

improved

on

not

respond

Of the 2-4

to thiothixene,

remaining

mg/day,

150 treatment

and

oxaze-

five, one

mg/day

and

with

oxazepam.

four

re-

responded

thiothixene. Global

ratings before and after these trials confirmed that improvement was not achieved by sedation. These findings were transmitted to the clinical team as medication recommendations. Born of long and methodological observation, they survived the inevitable next episodes of resistiveness. In I to 2-year follow-up, these medication assignments have, in general, been followed. Our aggregate results closely mirror those of two reviews of medication trials for agitation in demented patients (4, 5). Antipsychotics have the best, but modest, efficacy, whereas benzodiazcpinc sedatives have little to offer. We believe clinical decisions should be guided by the widest experience with similar patients, but behavior disorders in dementia often pose challenges that defeat this guidance. Under such circumstances, an N-of-i trial may be a reasonable approach. For research use, it may provide (as in this case) treatmcnt evaluation that is economical; for clinical purposes, it may instill confidence that the final treatment is indeed optimal in the long run. -

REFERENCES 1 . Abbey SE, Garfinkel PE: Chronic fatigue syndrome and the psychiatrist. Can J Psychiatry 1990; 35:625-633 2. Kleinman A: The Illness Narratives: Suffering, Healing and the Human Condition. New York, Basic Books, 1988 3. Abbey SE, Garfinkel PE: Chronic fatigue syndrome and depression: cause, effect or covariate. Rev Inf Dis 1991; 13(suppl 1): S73-S83 4. Altay HT, Toner BB, Brooker H, Abbey SE, Salit IE, Garfinkel PE: The neuropsychological dimensions of postinfectious neuromyasthenia: a preliminary report. IntJ Psychiatry Med I 990; 20: 14 1-149 S. Ichise M, Salit IE, Abbey SE, Chung D-G, Gray B, Kirsh JC, Freedman M: Assessment of regional cerebral perfusion by technetium-99m HM-PAO SPECT in chronic fatigue syndrome. Nucl Med Commun (in press)

PAUL

Am

J

Psychiatry

149:12,

December

SUSAN E. ABBEY, M.D. E. GARFINKEL, M.D. Toronto, Ont. , Canada

1992

REFERENCES 1. Coccaro Giordani

EF, Kramer E, Zemishlany Z, Thorne A, Rice CM B, Duvvi K, Patel BM, Torres J, Nora R, Neufeld

III, R,

1757

LETTERS

2.

3. 4.

S.

TO THE

EDITOR

Mohs RC, Davis KL: Pharmacologic treatment of noncognitive behavioral disturbances in elderly demented patients. Am J Psychiatry 1990; 147:1640-1645 Schneider LS, Pollock VE, Lyness SA: A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc 1990; 38:553-563 Barlow D, Kersen M: Single Case Experimental Designs. New York, Pergamon Press, 1984 Salzman C: Treatment of agitation in the elderly, in Psychopharmacology: The Third Generation of Progress. Edited by Meltzer HY. New York, Raven Press, 1987 Wragg RE, Jeste DV: Neuroleptics and alternative treatments. Psychiatr Clin N Am 1988; 11:195-213 LAWRENCE R. HERZ, LADISLAV VOLICER, M.D., VIRGINIA ROSS, YVETTE RHEAUME, Bedford,

Dr. Coccaro SIR:

and Dr. Mohs

We agree

of demented tion may

with

Reply

Dr. Hcrz

patients be highly

M.D. PH.D. PH.D. R.N. Mass.

and associates

to various individual.

that the response

pharmacotherapics Given our current

for agitastate of

knowledge, the N-of- 1 crossover pose may be the most practical ment for a single patient. The however, is a reflection of our tated” behavior both biologically tients included in our study and

treatment studies they proway to identify the best treatneed for such an approach, poor understanding of “agiand behaviorally. The pain others undoubtedly had a

variety

neurochcmical

The

of neuropathologic

associated

physical

and

behavioral

aggressiveness,

pacing,

other behaviors. Whether agnostic variables could agent for a given patient be determined. At present ing such

treatment

own study of use

indicates

for at least

problems wandering,

and

We

would

that oxazepam

like

and Delirium

our

are

Disease

and associates (1) described the delirium in seven of 1 1 patients treated with ECT for “psychiatric

to be discontinued.

They

was

considered

so severe

The response of Parkinson’s disease be related to an increase in dopaminc pamine

receptor

sensitivity

erature

supports

this hypothesis

mission, delirium

or or

levels of psychosis,

brain toxic

(2).

that

ECT

the possibility

ticular vulnerability to the cognitive side this patient population. They, however, medication status of their patients, which their observations.

Evidence

had

of “a par-

effects of ECT” did not report may be a factor

in the in

to ECT is reported levels or enhanced from

the

animal

dopaminc

to dolit-

trans-

dopamine, become excessive, a such as the one observed with

excessive dosages of dopaminc agonists, may be precipitated (4). Our preliminary results indicate that coadministration of ECT and antiparkinson agents increases the likelihood of de-

1758

the delirium tions

seen

following

in a patient

( 1 ), we reneurotrans-

to the Journal dopaminergic

taking

completion

M. ZERVAS, M.D. MAX FINK, M.D. Stony Brook, N.Y.

unpublished this could

dopaminergic

of ECT.

Illustrating

work explain

medicaour

point

is

the patient series reported recently by Dr. Oh and associates. They described a retrospective analysis of i i patients with Parkinson’s disease who underwent ED’ for associated mood disorders. Although most patients benefited from the treatment, they demonstrated an unexpectedly high (64%) mcidence of post-ECT delirium, requiring the discontinuation of ECT

in six patients.

One explanation for this untoward reaction to convulsive therapy could lie in the concurrent L-dopa-carbidopa combination taken by most of the patients. Enhanced responsivity of dopaminc receptors, which has been demonstrated following ECT in parkinsonian as well could excessively potentiate the

precursor, cinosis

L-dopa. and

Moreover,

as depressed effects of

the patients

unpublished medications brain

mania

may

work),

the impact

the

with

patients (2), dopaminc

organic

hallu-

had excessive dopaminergic transmission at baseline. While ECT typically exerts an antipsychotic clinical effect, presumably through direct or indirect inhibitory actions on mesolimbic dopaminc pathways (our

whether

(3). Should

In a recent communication the evidence for enhanced

mission following a course of ECT (2, and of Rudorfer et at.) and wondered whether

patients.

with Parkinson’s disease illness.” In six patients, delirium

IANNIS

and

that

prior

1. Oh JJ, Rummans TA, O’Connor MK, AhlskogJE: Cognitive impairment after ECT in patients with Parkinson’s disease and psychiatric illness (letter). Am J Psychiatry 1992; 149:271 2. Andersen K, Balldin J, Gottfries CG, Grancrus AK, Modigh K, Svennerholm L, Wallin A: A double-blind evaluation of ECT in Parkinson’s disease with “on-off” phenomena. Acta Neurol Scand 1987; 76:191-1 99 3. Nomikos GG, Zis AP, Damsma G, Fibiger HC: Electroconvulsive shock produces large increases in interstitial concentrations of dopaminc in rat striatum: an in vivo microdialysis study. Neuropsychopharmacology 1991; 4:65-69 4. Klawans HL: What to do when Sinemet fails: part one. Clin Neuropharmacol 1984; 7:121-133 S. Zervas IM, Fink M: ED’ for refractory Parkinson’s disease. Convulsive Therapy 1991; 7:87-92

anxious

to add

dosage

REFERENCES

SIR:

Jachoon J. Oh, M.D., development of a reversible SIR:

to one-halftheir

viewed

and diphenhydraminc

in Parkinson’s

agents

and

EMIL F. COCCARO, M.D. RICHARD C. MOHS, PH.D. Philadelphia, Pa.

ECT

these

prevented the occurrence of such toxicity without compromising the motoric improvement of Parkinson’s disease. We suggest that standing dosages of dopaminc agonists be reduced prior to initiating ECT in order to decrease the mcidence of delirium described by Dr. Oh and associates.

verbal

included

biologic, behavioral, or clinical dibe used to select the most effective or subgroups of patients remains to we know of no studies demonstrat-

specificity. some

abnormalities.

lirium (5). Reducing to initiating ECT

have

is unknown.

ECT-associated barrier

of simultaneous

Also

increased

could

influence

the

at

issue

dopaminergic is the

permeability rate

question

of

of the blood-

or extent

of entry

of

concurrent medications into the central nervous system. While Dr. Oh and associates limited their references of ECT use in Parkinson’s disease to case reports from the i970s, the more recent literature includes two highly successful trials of ECT in depressed patients with Parkinson’s disease (one reported in the Journal [3]), including the only sham-ECT controlled trial (4). While the primary clinical intent was treatment of the mood disturbance, significant concomitant

Am

J

Psychiatry

149:12,

December

1992