Prcg. NeumPsychopharmaml &B&l Psychfat. 1993. Vol. 17. PP. 861-873 Printed tn Great Britatn. AU tights reserved

0278 - 5846/93 $24.00

0 1993 Pergamon Press Ltd

1. 2. 3. 3.1. 3.1.1. 3.1.2. 3.1.3. 4. 4.1. 4.2. 4.3. 5.

CAN ECT-INDUCED COGNITIVE EFFECTS BE ALTERED PBARMACOLOGICALLY?

ARIFULLAKHAN,MARYHELENMIRCI0, HUGHA.MIR0I.C a.ndSHKREEMIILER

Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA

(Final form, October 1992)

Contents

Abstract Introduction Methodology Results General Rmarks Type I Study Design Type II Study Design Type III Study Design Discussion General R-marks Pitfalls in Study Design Future Directions for Research Conclusions Acknowledgements References

861 862 864 864 864 865 866 866 867 867 867 869 870 871 871

Abstract

Khan, Arifulla, Mary Helen Mirolo, Hugh A. Mirolo and Sheree Miller: Can M;T-Induced Cognitive Effects be Altered Pharmacologically ? Prog. Neum-Psychopharmacol. & Biol. Psychiat.1993,17(6):861-873.

1. A systematic review of tne literature revealed twelve clinical trials that evaluated nine different drugs, and used three different conceptual models to prevent, restore or treat ECT-induced cognitive deficits.

2. This review indicated inconclusive results regarding clinical utility of any of the drugs.

3. Major factors discussed include the complexities involved in the evaluation of ECI-induced cognitive deficits, and the techniques of evaluating changes in cognitive functions.

4. Cur conclusion is that future research should emphasize understanding the neural mechanisms related to m-induced cognitive deficits. We suggest several areas for future exploration.

Keywords: cognitive deficits, electroconvulsive therapy, research models.

Abbreviations: Alzheimer's Disease (AD), blood-brain barrier (BBB), central nervous system (CNS), choline acetyltransferase (CHAT), electroconvulsive therapy (ECI'), electroconvulsive shock (ECS), electroencephalogram (EM;), high affinity choline

861

862 A. Khan et al.

uptake (BACU), long-term potentiation (LTP), N-methyl-D-aspartate (RMDA), Weschler Memory Scale (WMS).

1. Introduction

Despite more than 50 years of controversy, electroconvulsive therapy (EXIT) remains

a principal treatment of the severely mentally ill (Fink, 1988). The major contro-

versy regarding ECT is its effect on cognition. Although no evidence exists of

structural damage to the nervous system (Coffey et al, 1991), multiple cognitive

deficits do occur with ECL'. ~epr~~n~ts~t~isl~sof~~. This appears

within a few treatments as shown by both objective measures and patient reports

(Freeman and Kendell, 1980; Squire and Slater, 1983). Other forms of cognitive im-

pairment also occur with FCI'. These also tend to appear after several treatments.

They include disturbances in language (Kahn and Fink, 1958), verbal fluency (Kronfohl

et al, 1978), naming abilities (Rochford and Williams, 1962), perceptual learning

(Robbins et al, 1959; Daniel et al, L984), and choice reaction tims (Pascal and

Zeaman, 1951).

A major focus of interest in diminishing cognitive effects of ECT has been in alter-

ations in the procedure itself. Two technical issues have received considerable at-

tention: placement of electrodes (unilateral vs. bilateral.), and stimulus waveform

(brief pulse square wave vs. sine wave).

The early suggestion that unilateral placement of electrodes may spare memory func-

tions (Lancaster et al, 1958) has not gained favor among many clinicians. Several

factors have contributed to this. kng the 12 studies conducted in recent years

that compared sham ECI' to true MLT, I.1 used bilateral placement of electrodes and

showed efficacy for true ECT. One study using unilateral placement of electrodes

(Lambourn and Gill, 1978) was unable to show significant effect for true ECf (Abrams,

1986). Missed seizures are significantly more frequent with unilateral placement of

electrodes (63%) -ared to bilateral placement of electrodes (2Q%), as shown by

EEG monitoring techniques (Pettinati and Nilsen, 1985). Using unilateral placement

of electrodes results in two or msre procedural sessions compared to bilateral place-

ment of electrodes for equivalent effect (Squire et al, 1979; Frcznn-Auch, 1982;

St-en, 1984; Tandon et al, 1988). Right unilateral ECT has a more sparing effect

on tests of verbal memory, but not on tests of nonverbal memory, mared to bilateral

FCT (Squire and Slater, 1978; Sa&eimet al, 1986). Recent studies have raised the

intriguing possibility that for efficacious unilateral ECT, electrical stimulus in-

tensity needs to be quite high--in fact, above what is needed for inducing a grand

ma1 seizure (Sackeim et al, 1991). Such a relationship has not been postulated with

bilateral. placement of electrodes. Based on many of the above-listed factors, bi-

lateral ECT remains the widely used form of treatment.

The other parameter considered as a possible modifier of cognitive deficits with

ECTcegnitive effects altered ph~cologic~~ 863

XT is the electrical waveform (sine wave vs. brief pulse). Proponents of brief

pulse stimulus such as Abrams (1988) stated that 'I... the brief pulse square wave

stimulus is the only appropriate one for modern ECI as the older sine wave stimulus

is excessively toxic, providing substantial sub-threshold energy that contributes

significantly to the confusion and memory loss, but none to the therapeutic effect".

However, much of the literature regarding m@nory effects of XT consists of findings

frcm patients who received sine waveform of EXZP stimulus. With the sine waveform of

stimulus, learning and memory functions are markedly affected after a few treatments

but can take quite a variable course for each patient. Clinically, scme patients

forget simple facts during the day they received M;T, such as what they had for

breakfast or whether their spouse visited. On formal testing such as paired-associate

learning, they perform about 60% to 80% below the performance of matched controls

(Squire, 1986). Such profound effects start to inmediately diminish at the end of

the ECT course. The general consensus is that those patients with anterograde mime-

sia seem to have recovered six months after treatment. There is no good evidence

that their learning ability is still deficient at this time (Weeks et al, 1980;

Squire and Chase, 1975; Weiner, 1984; Weiner et al, 1986), although one of the re-

viewers suggested that the average time for return to baseline function is 72 days

(Weeks et al, 1980). In addition to such learning deficits, patients appear to have

retrograde amnesia after MST. Both recall of public events and autobiographic recall

appear to be affected. However, the magnitude of these effects varied among patients

and were not detectable when tested seven mnths after ECT (Squire, 1986). A signif-

icant number of patients complained of poor memory after ECT. Freeman and Kendell

(1980) noted that 303& of their patients reported their mgnory did not return to nor-

mal after ECT. Squire and colleagues (Squire et al, 1979; Squire and Slater, 1983)

noted the complexities in evaluating manory complaints in depressed patients. They

found that the quality of memory canplaints seven months after ELX suggested that

patients were interpreting their memory abilities just as they had experienced them

scan after ECT. That is, they had continuing doubts that memory had fully recovered

and a tendency to blanX? even normal failure of memory on the ECT. They also noted

that these patients, when asked prior to IXX', had difficulties remembering for the

previous five months. Pettinati and Nilsen (1985) best delineated the cognitive

effects of bilateral brief pulse stimulation in a series of patients they studied.

After five ECT sessions, they noted the following cognitive effects: an approximate

1) 15% decline in learning paired unords, 2) 3% decline in learning a short story,

3) 30% decline in recall of a number of objects, 4) 7% decline in the recall of a

short story, and 5) 5@$ decline in the recall of a figure test (Column #l, Table 4,

p. 1090, Horne et al, 1985). It thus appears that brief pulse stimulation, although

more sparing than sine wave stimulus, still results in significant cognitive defi-

cits. Most of the ECT performed in the USA used brief pulse stimulus.

It is clinically highly unlikely that technical changes alone can completely miti-

864 A.Khan etal

gate EcT's cognitive effects. Several researchers have therefore tried other alter-

natives. The primary focus of this non-mechanical approach has been the use of drugs

to mitigate EXIT-induced cognitive deficits. This report primarily focuses on pub-

lished studies evaluating pharmacotherapy for m-induced cognitive effects. The aim

is to compare and evaluate the diverse studies and, based on our analysis, to suggest

future directions for research in this area.

2. Methodology

After a detailed review of the literature, which included a Medline search, the

authors decided to include for review in this paper those studies meeting the follow-

ing criteria: The studies should 1) be written in English, 2) not be single case

reports, 3) have a control group, 4) use standardized measures of neurocognitive

functions, and 5) explain the rationale for use of the chosen drug. The authors

found 12 studies, dating from 1966 to 1991, encompassing these criteria, and reviewed

each one in the following categories: 1) demographic features such as age and sex

distribution, 2) nature of matched sample, 3) psychiatric diagnosis, 4) study design,

5) electrode placement, 6) clinical effectiveness of agent, 7) type of cognitive

tests given and times used, and 8) study design deficits noted by investigators re-

porting the studies. The following section reports the analysis of these studies.

3. Results ~

3.1. General Remarks

The authors found no simple ways to cluster these 12 studies for a ccmnon thread to

assist our analysis. The drugs used included stimulants, peptides, hormones,

nootropic agents, opioid antagonists and ergot alkaloids--a wide range of pharmaco-

logical agents (see Tables 1, 2 and 3). A majority of the investigators of these

studies felt that they had either used too low a dose of the drug, or that a single

dose strategy was inadequate to fully evaluate the potential of the tested drug.

The demographic and diagnostic features of the patients also varied among the

studies. All of the studies included patients with non-psychotic depressive disorder.

Many studies used a multiplicity of criteria. Other investigators, such as %a11 et

al (1968) and Levin et al (1987), included a more heterogeneous group of patients

consisting of patients with depression and schizophrenia. Ezzat et al (1985) included

patients with schizophrenia, mania and a puerperal psychosis. The number of patients

in each study ranged frcxn 9 to 44, including patients assigned to the control group.

Electrode placement and current characteristics also varied, or were not mentioned

in the studies. Eight studies used bilateral stimulus (Small et al, 1968; &all et

al, 1977; Mindus et al, 1975; Lerer et al, 1983; Nasrallah et al, 1986; Levin et al,

1987; Mattes et al, 1989; Stern et al, 1991). One study (D'Elia et al, 1978) used

unilateral stimulus. Sachs et al (1988) reported that 6 of their 10 patients were

ECTcognitive effectsaltered pharmacologically 865

switched frcm bilateral to unilateral JXl' because of mild confusion. Scme studies

(Small et al, 1968; &all et al, 1977; Bagadia et al, 1980) reported the use of a

sine wave current. Mattes et al (1969) use brief pulse, while other studies did not

mention current type.

A majority of the investigators (Small et al, 1968; Bagadia et al, 1980; Ierer et

al, 1983; Ezzat et al, 1985; Mattes et al, 1989) used the Weschler Memory Scale for

detecting cognitive improvement. The other studies used similar tests such as the

memory tests developed by Sackheim, by Dronholrn and Ottosson and the Kohs block test.

Of all the investigators, only Stern et al (1991) did not include a visual test to

measure cognitive functions.

The most logical and coherent model to group these 12 diverse studies was to ascer-

tain the nature of individual studies, i.e., whether they were design& primarily to

be preventive or therapeutic. We classified these 12 studies into three subgroups:

Type I, a preventive model, consists of giving a drug prior to and throughout the

course of ECT to prevent the patients from developing cognitive deficits (Table 1).

Type II, a treatment model, consists of giving a drug inmediately after ECI to miti-

gate post-ictal cognitive deficits (Table 2). Type III, a treatment model, consists

of giving a drug after m-induced cognitive deficits are established (Table 3).

3.1.1. Type I Study Design. This design appears to have attracted the frost atten-

tion, with six independent studies using this tie1 with various drugs. Three re-

ported positive results. Ezzat et al (1985) did not mention using non-blind raters.

Table 1

Type I Studies: Preventive Model

Author/year/drug/dose Design Response Ccnments 1. &all et al, 1968 parallel groups/ +1 Preliminary Study

penoline 50 ng F0 qD non-blind 2. D'Elia et al, 1978 L- parallel groups/ -1 Found dysnnesic effects

tryptophan 6 mg W qD double-blind 3. Ezzat et al, 1985 parallel groups/ +2 Patients not matched for

Piracetam 5 g IV qEcf non-blind severity of cognitive effects 4. Sachs et al, 1988 parallel groups/ +I Switched fraa bilateral to

Ergot Mes. 2 mg PO TID double-blind unilateral ECI, small sample 5. Mattes et al, 1989 parallel 0 Data set not available for

Vasopressin 4 units &ID, groups/double- review/re analysis intranasally blind

6. Stern et al, 1991 parallel groups/ +2 T3 patients had a mean of 8 T3 50 micrograms PO qD double-blind EC& ccmpared to 12 for

controls -l=negative effects O=no clear effects +l=positive effects with +2=positive effects with statistically

non-significant trends significant results

Sachs et al (1988) suggested the possibility that the results were skewed by the

effect of switching patients fmm bilateral to unilateral XX'. However, they did not

866 A. Khan et&.

note improvements in the memory scores of those patients switched to unilateral ECP.

Stern et al f1991) noted that their &ug-treat& (T3) patients needed fewer XT

treatments and considered this to be the most parsimonious explanation.

3.1.2. Type II Study Design. Three studies using the Type II study design reported

no clear effects, while one did show positive trends. These investigators were most

concerned about factors such as underdosage and techniques pertaining to patient

management before and during XT, e.g., the armunt of oxygen administered.

Table2

Type II Studies: Imnediate Treatment of Post-I&al Deficits Rode1

~uthor/ye~/~~J~e Design ResPonse Ccements 1. Mindus et al, 1975 crossover/ 0 Underdosage and poor

Piracetam 4.8 g qD double-blind oxygenation 2. Lerer et al, 1983 crossover/ 0 Underdosage

Vasopressin 25 micrograms double-blind intranasally

3. Levin et al, 1987 crossoverJ +1 Physostigmine 0.5 ring, IV double-blind

+l=positive effects with non-significant trends *no clear effects

3.1.3, Type III Study Design. One of the three studies using the TVpe III study

design reported positive results. Rowever, the results of the study rePorted by

Ragadia et al (1980) are worth further scrutiny. patients given the drug (Pirwemn)

appear&d to have higher performance scores on the Wesehler Mary Scale @MS) com-

pared to those given placebo. The placebo-treated patients had a baseline scose of

Table 3

Typo III: Treatment of Established Deficits Rode1

AuthorJyearJdrugJdose Design Response Ccements la. Small et al, 3977 first study- +1 Used single EKT

ACTRl5-3Omgsc ~ub~~bli~dJ~ro~ver lb. Srall et al, 1977 second studv- 0 Underdosase and

ALTH3omgsc parallel g~u~J~uble- timing of &itive blind. tests-

2. Ragadia et al, 1980 parallel groups 0 Data analysis not PGacetam 2.4 g qD clarified

3. Nasrallab et al, 1986 parallel groups/ 0 Underdosage Naloxone 0.1 mg/kg IV double-blind

+l=positive effects with non-significant trends S=no clear effects

31.8 and then had weekly scares of 32.0, 38.1 ztnd 36.8. The corresponding m scores

for the piracetam group were 24.5 (baseline), 35.5, 41.8 and 46.8, respectively.

Bagadia et al (1980) reported that statistical differences in the psychometric eval-

uation scores did not exist between drug-treated and placebo-treated patients.

ECT cognitive effects altered pharmacologically 867

However, they did not provide any information on statistical tests used, nor data

such as the standard deviation or the standard error of the mean which would allow us

to reexamine their data. They also noted that after two weeks of treatment, 80?& of

drug-treated patients had recovered their cognitive functions compared to 50& of

placebo-treated patients. All of these factors lead us to suggest that Bagadia et al

(1980) minimized the results of their study.

4. Discussion

4.1. General Remarks

Our review of the 12 published studies evaluating phannacotherapy for ECl'-induced

cognitive deficits indicated only a modest effect for the tested drugs. However, it

is our impression that the potential for effective phmcotherapy to prevent, re-

store and/or treat cognitive deficits induced by ECT has not yet been fully explored.

We base this conclusion on our critical review of these 12 studies. Two of the 12

studies reported a positive and statistically significant effect for the drug tested

(Ezzat et al (1985) using piracetam and Stern et al (1991) using T3). A cautionary

note for each of these studies is indicated. First, Ezzat et al (1985) did not state

that they used blind raters. They also had a non-homogeneous sample of patients in

their study. Second, Stern et al (1991) reported that their T3 treated patients had

an average of 8 EC& compared to 12 EKTs for those in the control group. This sug-

gests that a sparing effect on cognitive functions in this study may be related to

the fewer treatments in the T3 treated group of patients. Three of the 12 studies

reported a positive trend for those receiving the drug compared to placebo. six of

the 12 studies found no differences between drug and placebo treated patients. In

one of the 12 studies placebo was superior to the drug (D'Elia et al, 1978).

4.2. Pitfalls in Study Design.

Several factors make evaluation of drug treatment for MTT-induced cognitive defi-

cits difficult:

1) Considerable individual variation exists arrpng patients, both quantitatively

and qualitatively, as to their vulnerability to lXX"s effect on their cognitive

functions. There are no obvious factors predisposing an individual patient to ECT-

induced effects. Scane potential factors include age and sex of patients, their sei-

zure threshold and their ability to recover quickly after each FXT session (post-

ictal state) based on the findings of several investigators (Fraser et al, 1978;

Heshe et al, 1978; Sackheim et al, 1986).

2) Unlike other psychopathological states such as psychosis or depression, which

have accepted standards for diagnostic measurements (DSM-III-R) and for measures of

severity and change (Brief Psychiatric Rating Scale, Hamilton Depression Rating

Scale), no "gold standard" exists for measuring cognitive functions to delineate a

868 A.KhanetaL

psychopathological cognitive state. The general cognitive scales, such as the

Weschler Adult Intelligence Scale (or its subscales), are not easily used as either

diagnostic tools or to measure changes. Sclaes such as the Bushke Selective Bemind-

ing Test or Benton Visual Retention Test are thought to measure change, but are not

easy to use, including ccmplexity in their scoring criteria. Valid use includes

testing under controlled conditions such as a laboratory, and evaluation of the over-

all functioning of the patients in his or her environment is not possible. Another

major drawback in using these scales is the presence of the practice effect which can

confound any results.

3) In patients, KT elicits three phenomena: first, a significant improvement in

mood; second, a related improvement in mental functioning due to the first factor;

and third, an individualized deterioration in selective cognitive functions. The

combination of these factors has seriously hampered investigators evaluating phartna-

cotherapy for ECT-induced cognitive effects. Cylert is a stimulant and may have aug-

mented the effects of ECT in the study of Small et al (1968). Both Sachs et al

(1988) and Stern et al (1991) found that the drugs they used (ergot mesylate and T3,

respectively) might have had a sparing effect for patients' cognition secondarily,

since these drugs appeared to enhance ECT's mcod altering effects. Although critical,

it is hard to establish whether a drug has primary effect on mood, enhances ECI"s

effect, or selectively improves cognitive functions.

4) Mechanical factors such as type and amount of electricity delivered, quality of

physical care during recovery from XT (oxygenation and other basic life support

system), and dose and type of medications used for modifying ECI (anesthetics, muscle

relaxants, and anticholinergic agents) can be related to cognitive deficits seen with

EXT. These factors vary frcm site to site as well as change over time. Such factors

should therefore be carefully evaluated when conducting clinical trials to assess the

effectiveness of drugs for ECT-induced cognitive deficits. We hope that burgeoning

research in Alzheimer's Disease (AD) may help resolve many of the methodological

questions discussed. Alternatively, it is possible that m-induced cognitive state

may offer a distinct and unique model to study alterations in human cognition and may

further our advances in research in AD and other CNS disorders.

The authors wish to address certain specific factors of the 12 studies reviewed,

and later suggest scme directions for future research. So far, most effort has gone

towards using drugs to prevent patients from developing ECI-induced cognitive defi-

cits, i.e., Type I design (6 of 12 studies). We have scme reservations about the

feasibility of this model. It suggests that a single drug can scmehow alter both the

cascade of events occurring after each JKT session and those taking place after a

series of IXT. The second design, consisting of altering acute post-ictal recovery

phasepharmac ologically, was used by three groups of investigators with negative re-

sults for the tested drugs. This type of study is comparatively easy to execute and

can provide a reasonably quick answer to the question of overall efficacy of a

ECTcognitive effects~te~dph~aco~ogic~ly 869

potential drug. However, it is not clear that an alteration in acute recovery may

prevent the patient from developing ECT-induced cognitive deficits at the end of a

series of ECT. Furthermore, such a study may not be able to evaluate the cnmulative

therapeutic (as well as the toxic effects) of a drug. For example, this type of

study would never have led to the discovery of antidepressants or neuroleptics which

work only after multiple doses are given. The third study design, using a cognitive

enhancer once the IKT-induced cognitive deficits are present, lends itself well to

other well established concepts about clinical trials in pathological states. How-

ever, its major drawback is the lack of consensus for defining the inclusion criteria

and dependent measures in evaluating cognitive functions.

4.3 Future Directions for Research.

Our major conclusion from this review is that many investigators have tested a

series of drugs in the hope of making a serendipitous discovery, but have not re-

ceiveil a satisfactory answer. We reccnrnend an alternative direction: namely, reach-

ing an understanding of ECl"s neural mechanism in inducing cognitive deficits. We

feel this direction is mrth considering and should be the major focus of research in

this field.

A few leads do exist in this area. For example, Fink (1966) in his review paper

noted that increases in intercellular free acetylcholine seen after ECT resemble

those seen after head trauma. This increase in acetylcholine or increased cboliner-

gic receptivity may be associated with changes in the electroencephalogram, such as

the presence of high voltage slow wave activity. Following the report of Dansieff

et al (1982) and using an animal model, Lerer et al (1986) hypothesized that XX-

induced manory impairment may be related to a reduction in the cortical cholinergic

receptor concentration. They noted a 15% to 30% decrease in (3H)-quinuclidinyl

benzilate binding for muscarinic receptors in the rat brain with electroconvulsive

shock (FLS). Furthermore, Stanley and Lerer (1985) showed that pilocarpine-induced

catalepsy is blunted after EKS. This suggests a decrease in the function of choli-

nergic system. Clinically supporting this suggestion is the finding that higher

serum anticholinergic levels were related to greater post-XT confusion (Bondtire

et al, 1983). Other cholinergic measures, such as high-affinity choline uptake

(&KU) (Atterwill, 1980) and choline acetyltransferase (ChAT) activity (Longoni et

al, 1976; Atterwill, 1980), are not significantly changed following either single

or repeated EXJS. However, Atterwill (1980) used brain tissue slices instead of syn-

aptoscme preparation for measuring of HACU, and measured HACU at only one time point

after repeated ECS treatment. Furthen-sore, significant changes in ChAT and HACU may

indicate structural disruption of the cholinergic neurons, which may not occur with

5 to 10 ECS in a period of 1 to 2 weeks. It thus appears that a mild decline in

muscarinic receptors coupled with decline in pilocarpine-induced catalepsy are the

major demonstrable effects of MTT on the cholinergic system.

870 AKhanetaL

The breakdown of the blood-brain-barrier (EBS) after ED. may be another significant

thread to follow. The change in the HHH may be related to the efficacy of ECT (Bol-

wig, 1988), although other investigators (Nitsch and Klatzo, 1983) have suggested

that the HEX3 breakdown seen with pharmacologically-induced seizures may be related to

neuronal damage. The transient disruption of HHH with EYES may be linked to three

factors: hypertensive effects, non-specific seizure effects such as massive depolari-

zation of neurons and glial cells, and passage of electricity. We note that not all

animals have EBH disruption with MIS and it is interesting to speculate that this

phenomenon may parallel the individual variability seen with XT-induced cognitive

deficits in humans. Other relevant and interesting factors are as follows. Abolition

of hypertensive effects of ECS may block disruption of EBH (Holwig et al, 1977). Al-

ternatively, drugs such as methantheline, a cholinergic antagonist, may minimize HHH

disruption with drug-induced seizures (Iorenzo et al, 1972). The loss of HHH with

ECS may decrease some of the chemical and electrical activity in the CNS secondary

to changes in electrolyte concentrations and presence of large molecules such as

plasma proteins. It is possible that this disruption may further decrease the func-

tional capacity of the cholinergic system.

A third relevant area of research is the role of excitatory amino acid transmitters

and their receptors. Lglutamate is the principal mediator of excitatory synaptic

transmission in the mammalian CNS. In fact, glutamate excites virtually all central

neurons and is present in nerve terminals at millimolar levels (Curtis and Johnston,

1974). However, sustained exposure to high levels of glutamate can destroy neurons.

This may well occur in such states as stroke and head injury. Antagonists for the

N&DA-receptor (a glutamate receptor subtype) not only have anticonvulsant properties

(Nevins and Arnolde, 1989), but also have detrimental effects on visuo-spatial

learning (Morris et al, 1986). This latter effect may be related to blockage of

long-term potentiation (LTP) in the hippocampus. These factors lead us to speculate

that a specific dysfunction in the glutamate transnission system may be related to

M;T-induced cognitive deficits. Studies evaluating behavior and LTP in relation to

localized (e.g., hippocampus versus cortical system) glutamate receptor subtypes

(NMDA, quisqualate and kainate) may provide us with sane leads in the future.

5. Conclusions

The authors believe that the potential for effective pharmacotherapy to prevent or

restore XT-induced cognitive deficits has not yet been fully explored. Two major

factors lead us to this conclusion: 1) a series of inconclusive clinical trials

(n=12) associated with ccmplex methodological problems in evaluating m-induced

cognitive deficits, and 2) a lack of a coherent model to understand the neural

mechanisns related to ECT-induced cognitive deficits.

ECTcogniUve effec~~teredph~acolog~~~~

Ackmwledgments

871

The authors would like to thank Dr. Henry Lai for reviewing the manuscript. Par-

tial support was provided for this by the Washington Institute for Mental Illness

Research and Training.

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Inquiries and reprint requests should be addressed to:

Dr. Arifulla Khan Department of Psychiatry, RP-10 University of Washington Seattle, WA 98195 U.S.A.