s o d iu m l actate in fu sio n s an d p an ic a tta c k s

Sodium Lactate Infusions and Panic Attacks:A Review and Critique

JURGEN MARGRAF, DIPL-PSYCH, ANKE EHLERS, DIPL-PSYCH, ANDWALTON T. ROTH, MD

Response to sodium lactate infusions has been proposed as an experimental model and a biologicmarker for panic attacks. Several authors have claimed that patients suffering from panic attacks,but not normal controls, "panic" in response to lactate. A careful review of methods and resultsof 13 studies, however, reveals serious methodologic problems, lack of specificity and sensi-tivity, and a failure to consider cognitive variables. When baseline differences are ruled out,the responses of patients and controls may not differ. So far, response to lactate cannot beinterpreted as a model and marker for panic attacks and does not provide evidence for theirunderlying biologic distinctness from other types of anxiety. Known biologic mechanisms donot sufficiently explain the effects of lactate. Instead, an interaction of peripheral physiologicchanges, past experience, environmental cues, and their appraisal as threatening or dangerousseems to be a more appropriate model.

In the field of anxiety research muchattention has recently focused on panicdisorder (1-6). New data emphasize theseriousness of the condition. Coryell et al.(7) found significantly lower long-term re-covery rates in patients with panic disor-der than in patients with primary unipolardepression. The same research group, in a40-year retrospective follow-up, found ex-cess mortality in patients with panic at-tacks similar to that of patients with af-fective disorder, with higher suicide ratesand more cardiovascular deaths in malepatients than expected for the general pop-ulation (8).

From the Laboratory of Clinical Psychophysiologyand Psychopharmacology, Veterans AdministrationMedical Center, Palo Alto, CA 94304, and StanfordUniversity Medical Center, Stanford, CA 94305.

Address reprint requests to Dr. Walton T. Roth,Department of Psychiatry (116 A3), V.A. MedicalCenter, 3801 Miranda Ave., Palo Alto, CA 94304 (Dr.Roth)

Received for publication November 13, 1984; finalrevision received June 13, 1985

Several authors see panic disorder asclearly distinct from other anxiety andphobic disorders (1, 2, 9-13). They alsogive panic attacks central importance inthe etiology and course of agoraphobia andpropose to include agoraphobia in the di-agnostic category of Panic Disorder as cur-rently defined in DSM-III (14). Klein (15)argues that panic attacks are primary toagoraphobia and that therefore the diag-nosis should be "panic disorder with orwithout agoraphobia" rather than "agora-phobia with or without panic attacks." Inthe same vein, Sheehan and Sheehan(11-13) divide all anxiety and phobic dis-orders into two groups labeled "endoge-nous" vs. "exogenous" anxiety. The majordefining criterion for "endogenous anxi-ety" is the occurrence of panic attacks(11-13, 16, 17).

This situation is largely responsible forthe recurrence of interest in the effects ofsodium lactate infusions, interest that hadtemporarily vanished after Pitts andMcClure's original explanation for its panic-

Psychosomatic Medicine Vol. 48, No. 1/2 (Jan./Feb. 1986) 23Copyright © 1986 by the American Psychosomatic Society, Inc.Published by Elsevier Science Publishing Co., Inc52 Vanderbilt Avenue, New York, NY 10017

0033-3174/86/S3.50

MARGRAF, A. EHLERS, and W. T. ROTH

inducing effects had been rejected (18-24).Recently, Klein and his colleagues in anumber of publications stated that theyhave confirmed Pitts and McClure's (25)finding that lactate infusions provoke panicattacks in most panic patients1 but in veryfew control subjects (26—36). Currentlyseveral other centers are working in thisarea (37-41). Contemporary researchersfocus more narrowly on Panic Disorder in-stead of considering sodium lactate as thebiochemical substrate of anxiety in gen-eral (42).

Two major applications of lactate in-fusions have been proposed. First, they areseen as an experimental laboratory modelfor evoking and studying panic attackssimilar or even identical to those occur-ring spontaneously. This model could beused to investigate the pathophysiology ofpanic attacks, the efficacy of treatments,and the homogeneity or heterogeneity ofdifferent anxiety disorders. Second, someauthors propose that response to lactateinfusions is a possible biologic marker forpanic attacks, the crucial phenomenon ofPanic Disorder or Agoraphobia with PanicAttacks: "Biological evidence of the dis-tinctness of panic disorders from otheranxiety disorders comes primarily fromlactate challenge tests" (10, p. 4). And Carrand Sheehan (43, cf. 3) conclude that theresults of lactate infusion studies suggest"that panic disorder is a biological dis-ease" (p. 100).

In order to determine whether responseto lactate infusions is suitable for thesepurposes, we evaluate the current statusof the research on the effects of lactate in-

'In this article the term "panic patients" is usedto refer to patients that fulfill DSM-III criteria forPanic Disorder or Agoraphobia with Panic Attacks.

fusions. Specifically, we deal with the fol-lowing questions:

1. To what degree do lactate and placeboinfusions induce panic in patients withanxiety disorders and in controls?2. What are the specific subjective, psy-chophysiologic, and biochemical ef-fects of lactate infusions, and are theredifferences between groups in these ef-fects?3. Are the differences between patientsand controls quantitative or qualitativein nature?4. How similar are the effects of lactateinfusions to naturally occurring panicattacks?5. Do baseline levels of anxiety andarousal affect response to lactate?6. What are the causal or mediatingmechanisms by which lactate inducesthese effects?A careful review of methods and results

of the 13 lactate infusion studies pub-lished so far suggests that the answers tothese questions, although not incompati-ble with a biologic model of Panic Disor-der, do not provide confirmation of it. Sub-stantial methodologic problems, theomission of cognitive variables, and lackof specificity and sensitivity of the re-sponse to lactate infusion limit its inter-pretation as model and marker for panicattacks.

METHODOLOGIC OVERVIEW

Nine of the thirteen published studiesthat we found compared their sample ofpanic patients to a clinical or nonclinicalcontrol group. Four studies did not usecomparison groups. Twelve studies usedone of the two following designs. A com-

24 Psychosomatic Medicine Vol. 48, No. 1/2 (Jan./Feb. 1986)

REVIEW OF LACTATE INFUSIONS

bination of both designs was used by the13th study (39-41):Design A: Different infusions on separate

days. Subjects received several differentinfusions (lactate, saline, lactate pluscalcium, etc.) in separate sessions. Inthese studies, subjects and experimen-ters or observers were generally "blind"to which solution was being given on aspecific day (25, 38, 44-47). Thus, thesestudies generally were double blind.

Design B: Sequential infusions on the sameday. Subjects received placebo infu-sions followed by lactate within one ex-perimental session. In these studies,subjects were not "blind" to which sub-stances they would receive, but only towhen the infusion of lactate would be-gin (26-31, 33-35, 37, 48, 49). However,since experimenters knew when the in-fusions changed, these studies were onlysingle blind with regard to the onset ofthe lactate infusion.The methodologic procedures and qual-

ity of the studies with and without com-parison groups is described in Tables 1and 2 in terms of generally acknowledgedparameters of empirical clinical researchand parameters specific to lactate infu-sions. Any methodologic criticism not ap-parent in these columns is listed in thelast column under "other criticism."

The most important methodologic crit-icisms can be summarized as follows:Many studies fail to report essential in-

formation. Patients, controls, matchingprocedures, settings, instructions, andassessment of dependent variables, es-pecially psychophysiologic variables, arerarely described in sufficient detail. Fur-thermore, results are often reported in-completely and only qualitatively.

Most studies had inadequate criteria forpanic attacks. None used objetive cri-

teria, and several did not explicitlyspecify criteria. This is especially rele-vant in single-blind studies where non-blind observers or the experimentersthemselves determined whether or notpanic attacks occurred.

Many studies used insufficient dependentmeasures, for example, only self-re-ported somatic symptoms or a singleglobal assessment of the number of sub-jects experiencing panic attacks. Moststudies did not present data on subjec-tive anxiety or did not use standard mea-sures of anxiety. Psychophysiologic andbiochemical measures were obtainedrarely, and no behavioral measures werereported. Most studies did not take thetime-course of the events into consid-eration (no frequent or continuous as-sessment).

Control strategies were generally inade-quate. Different infusion rates for con-trol and lactate infusions, and the pres-ence of too many nonblind observersendanger the single blind. Most studiesdid not control sufficiently for demandcharacteristics and expectancy biases.Some even induced different expecta-tions in their experimental groups bygiving them different information beforethe infusions.In spite of these limitations, the results

of these studies contain worthwhile infor-mation about clinical anxiety. Most of thestudies share positive methodologic fea-tures such as the use of a control infusion,testing patients who met the establishedDSM-III criteria for Panic Disorder or Ago-raphobia with Panic Attacks, single- ordouble-blind control strategies, and use ofthe same lactate dose range [with two mi-nor exceptions—Rainey et al. (39—41) andLapierre et al. (38); cf. Table 1]. Convergingevidence from these studies may present

Psychosomatic Medicine Vol. 48, No. 1/2 (Jan./Feb. 1986) 25

j. MARGRAF, A. EHLERS, and W. T. ROTH

Psychosomatic Medicine Vol. 48, No. 1 I2 (Jan./Feb. 1 986)

Desr

gn B:

Sequ

entia

l Infu

sion

s on

the

Sam

e D

ay

Kelly

et

a) 1

0' s

alin

e Si

ngle

-blin

d, o

ne

N =

20,

al

. (48

) (s

low

) (b

lind?

) obs

erve

r eq

uiva

lent

to

b) 2

0' 1

12 s

l pr

esen

t, PD

and

AG

d~

ffere

nt dn

p ra

tes,

no

N =

10,

ad

equa

te

excl

usio

n cr

iteria

Adeq

uate

Sam

e as

Pitt

s an

d M

cClu

re (2

5)

Obs

erve

r rat

ings

and

SR o

f an

xiet

y an

d de

pres

sion

(3' i

nter

vals

), sy

mpt

om

SR li

st,

HR,

FBF

Num

ber o

f su

bjec

ts

repo

rting

onl

y ph

ysio

log~

c pa

nic

sym

ptom

s un

spec

if~ed

in

form

atio

n ab

out

inst

ruct

ions

R

~fki

n et

a) 3

0' D

5W

Sing

le-b

lind,

no

N =

9,

PD

al. (

27)

(slo

w)

info

rmat

ion

b) 2

' D

sW (f

ast)

abou

t obs

erve

rs

C) 2

0' 1

12 s

l (b

l~nd

?)

and

inst

ruct

~ons

Ap

pleb

y a)

30'

DsW

Sm

gle-

bl~n

d, bu

t N

= 2

5, P

D et

al.

(26)

(s

low

) di

ffere

nt~a

l an

d AG

b)

20'

112

s1

expe

ctat

ions

N =

7,

adeq

uate

ex

clus

ion

crite

ria

No

othe

r tha

n sp

ecifl

ed

unde

r cr~

teria

for

panl

c an

xlety

, agi

tatio

n,

restl

essn

ess,

dem

and

to s

top"

? n

o ?

sign.

d~f

f. N

= 1

5,

adeq

uate

ex

clus

ion

criti

er~a

API,

"num

erou

s ra

t~ng

s",

bioc

hem

ical

((n

or)e

pine

phrin

e,

corti

sol,

prol

actm

, te

stos

tero

ne),

resu

lts fo

r ot

her m

easu

res

not

repo

rted

due

to d

iffer

ent

~nst

ruct

ions

for

the

grou

ps,

thre

e no

nbl~

nd

staff

mem

bers

pr

esen

t, d~

ffere

nt dr

ip

rate

s L~

ebow

itz a)

30'

DsW

Si

ngle

-bl~

nd, tw

o N

= 4

3, P

D et

al.

(28,

(s

low

) no

nbl~

nd sta

ff an

d AG

29

, 31

, b)

2'

D5W

(fast

) m

embe

rs

33)

c) 2

0' 1

12 s

l pr

esen

t, sh

ort,

fast

dr~

p of D

5W

no in

form

atio

n ab

out

inst

ruct

tons

N =

20,

ad

equa

te

excl

usio

n cr

iteria

? no

"No

obje

ctiv

e sig

n. d

iff.

cr~t

eria

for

pani

c at

tack

s",

"cl~

nica

l ob

serv

atio

n,

patle

nt s

elf-r

epor

t"

Pani

c at

tack

rat

ing

by

C, h

~ghe

r ratlo

s of

men

in

cont

rol g

roup

pa

rtly

expl

ains

HR

diffe

renc

es

appa

rent

ly n

onbl

ind

staff

mem

ber,

API (

4 x),

HR

, BP

, b~

oche

m~c

al

mea

sure

s (5

x) (

lact

ate,

py

ruva

te, c

alc~

um,

phos

phat

e, p

rola

ctin

, (n

or)e

p~ne

phr~

ne,

corti

sol,

veno

us C

02,

TABL

E 1.

(con

tinue

d)

Con

trol o

f D

eman

d Ch

arac

teris

tics

and

Subj

ects

C

riter

ia fo

r St

udy

Infu

sion

s Ex

pect

ancy

Bias

es

Patie

nts

Con

trols

M

atch

ing

Pani

c At

tack

s D

epen

dent

Mea

sure

s O

ther

Crit

icis

ms

Com

brna

tlon o

f Des

igns

A a

nd 6: Co

mpa

rison

of T

hree

Infu

sions

, Eac

h Pr

eced

ed a

nd F

ollo

wed

by

Plac

ebo

Infu

sion

s Ra

iney

et a)

20'

111

sl

Dou

ble-

blin

d,

N =

1 1,

PD

N =

10

? U

nspe

cifie

d an

xiet

y ST

Al a

nd H

amilt

on a

nxie

ty

B, no

t a1

(39,

b)

20'

DsW

(b

lind?

) sta

ff ad

equa

te

and

RDC

pani

c sc

ales

(4 x)

, pan

ic S

R, co

mpl

etel

y 40

) c)

20'

of 2

0g

atte

ndin

g, n

o ex

clus

ion

sym

ptom

s bl

ood

gase

s an

d ov

erla

ppin

g Fr

eedm

an

isop

rote

reno

l in

form

atio

n cr

iteria

ca

tech

olam

ines

(4 x

), sa

mple

s et

al.

(41)

in

D5W

ab

out

HR,

RR, S

CL,

EMG

, re

porte

d in

Al

l pre

cede

d in

stru

ctio

ns

finge

r tem

pera

ture

di

ffere

nt

and

pape

rs,

follo

wed

by

high

er ra

tio

10' D

5W

of m

en ~

n co

ntro

l gro

up

partl

y ex

plai

ns H

R di

ffere

nces

aAbb

revr

atio

ns:

BP:

Bloo

d pr

essu

re.

- 20

' 112

sl:

Hal

f mol

ar r

acem

ic (D

/L) s

odiu

m la

ctat

e is

give

n at

a

CN

V:

Con

tinge

nt n

egat

ive

varia

tion.

ra

te o

f 10

mllk

g bo

dy w

eigh

t for 2

0 m

in o

r unt

il a p

anic

EE

G:

Elec

troen

ceph

alog

ram

. 3

atta

cks

occu

rs. P

itts

and

McC

lure

(25)

and

Fin

k et

al.

EMG

: El

ectro

myo

gram

. (4

4) a

lway

s co

ntin

ued

for

20 m

ln.

It is

uncl

ear w

hen

FBF:

Fo

rear

m b

lood

flow

. %

Lapi

erre

et a

l. (3

8) st

oppe

d.

HR

: H

eart

rate

. $

20'

111

sl:

Sam

e as

abo

ve,

but

1 m

olar

sod

ium

lact

ate

give

n at

NSF:

N

onsp

ecifi

c sk

in c

ondu

ctan

ce fl

uctu

atio

ns.

.% ra

te o

f 5 m

llkg

body

wei

ght [

Bonn

et a

l. (4

5, 4

6)l o

r 6

RR:

Res

pira

tion

rate

. m

l/kg

body

wei

ght [

Rain

ey et

al.

(39,

40)

, Fre

edm

an et

SC

L: Sk

in c

ondu

ctan

ce le

vel.

P rn

al. (

4l)l

. SR

: Se

lf-ra

ting.

C

alci

um c

hlor

ide.

ST

AI:

F C

aCI2

: St

ate-

Trai

t Anx

lety

Inv

ento

ry [S

p~el

berg

er et a

l., (

5 1 11

. m

D5W

: Fi

ve p

erce

nt de

xtro

se in

wat

er.

EOG

: Ve

rtica

l el

ectro

ocul

ogra

m (

for

blin

ks a

nd e

ye m

ove-

-%

NaC

I: So

dium

chl

orid

e.

men

ts).

QJ

AG :

Patie

nts f

ulfil

l the

DSM

-Ill c

riter

ia fo

r ago

raph

obia

with

a

pani

c at

tack

s.

Met

hodo

logi

c Cr

itrcr

sms:

G

AD:

Patie

nts f

ulfil

l the

DSM

-Ill c

riter

ia fo

r ge

nera

lized

anx

- A:

G

ener

ally

ins

uffic

ient

inf

orm

atio

n ab

out

rele

vant

pa-

ie

ty d

isor

der.

ram

eter

s of

the

stud

y.

?

PD:

Patie

nts f

ulfil

l the

DSM

-Ill c

riter

ia fo

r pa

nic

diso

rder

. B :

N

o co

ntin

uous

mon

itorin

g of

sub

ject

ive

anxi

ety.

rn

AE

P:

Audi

tory

evo

ked

pote

ntia

l. C

: N

o da

ta o

n su

bjec

tive

anxi

ety

(no

stan

dard

mea

sure

of

API:

Acut

e Pa

nic

Inve

ntor

y [c

f. Li

ebow

itz e

t al.

(29,

311

1 an

xiet

y).

3 I

TABL

E 2.

O

verv

iew

of S

tudi

es W

ithou

t Com

pari

son

Gro

ups"

Con

trol o

f Dem

and

Char

acte

ristic

s an

d C

riter

ia fo

r Pan

ic

io

Stud

y In

fusi

ons

Expe

ctan

cy B

~ase

s Pa

t~en

ts

Atta

cks

Dep

ende

nt M

easu

res

Oth

er C

r~t~

c~sr

ns " 5

Desig

n A

Diff

eren

t lnf

usro

ns o

n Se

para

te D

ays

Hasla

rn

a) 2

0' 1

12 s

l D

oubl

e-bl

~nd,

patie

nts

N =

16,

pre

sum

ably

?

Anx~

ety s

elf-r

at~n

g sca

le

A, B

, D,

hete

roge

neou

s 3

(47)

b)

20'

glu

cose

in

were

"aw

are

of

GAD

and

pa

tlent

gro

up

G N

aCl

- na

ture

and

pur

pose

ag

orap

hobi

a r

of tr

ial"

> De

srgn

8:

Sequ

entra

l Inf

usio

ns o

n th

e Sa

me

Day

2

Knot

t et

a) D

5W (t

~rne

?) S~

ngle

-blin

d, pa

tlent

s N

= 6

, PD

and

AG

?

Uns

tand

ardi

zed

patle

nt

A, C

al

. (37

) b)

20'

112

s1

alon

e du

r~ng

(a

ppar

ently

re

ports

leve

r pre

ssin

g,

2 - in

fusi

on, d

~ffe

rent

pa

tient

s' pr

essin

g EE

G an

d AE

P dr

~p ra

tes,

suffi

cien

t le

ver w

hen

(uns

peci

fied

t~rn

e z C

inst

ruct

~ons

pa

nlc

sym

ptom

s sa

mpl

es),

vEO

G, H

R,

C"

occu

rred)

SC

L, NS

F, E

MG

G

orrn

an

a) 3

0 ' D

5W

Sing

le-b

l~nd

, nonb

lind

N =

6,

PD a

nd A

G

? U

nspe

c~fie

d obs

erve

r A,

C

9 Ln et

al.

(slo

w)

obse

rver

s pr

esen

t, ra

tings

, API

(3 x

),

(34)

b)

20'

112

sl

d~ffe

rent

dr~

p rate

s, EE

G, BP

no in

forrn

at~o

n (u

nspe

cifie

d)

abou

t ~ns

truct

lons

G

orm

an

Sam

e as

Gor

rnan

Sa

me

as G

orm

an e

t N

= 1

0, P

D an

d AG

?

Appa

rent

ly o

nly

A, B

, D, o

nly

valid

as

et al

. et

al. (

34)

al (

34)

unsp

ec~f

ied p

atie

nt

stud

y of

lact

ate

(35)

st

atem

ents

and

blo

od

effe

cts

on b

lood

gl

ucos

e le

vels

(3 X

) gl

ucos

e le

vels

"Abb

revr

atio

ns.

EEG:

El

ectro

ence

phalo

gram

. 20

' 1/2

st:

Hal

f mol

ar r

acer

nic

(DIL

) sod

~urn

lact

ate

is gl

ven

at

EMG

: El

ectro

rnyo

grar

n.

rate

of

10 rn

l/kg

body

we~

ght fo

r 20

rni

n or

unt

il a

HR

: H

eart

rate

pa

nic

atta

ck o

ccur

s. H

asla

rn (4

7) a

lway

s co

ntin

ued

NSF:

No

nspe

cific

skin

con

duct

ance

fluc

tuat

ions

. fo

r 20

rnin

. It IS

unc

lear

whe

n Kn

oa et

al.

(37)

stop

ped.

RR

. R

esp~

ratio

n rate

N

aCI:

Sodi

um c

hlor

ide.

SC

L: Sk

in c

ondu

ctan

ce le

vel

D5W

: Fi

ve p

erce

nt d

extro

se in

wat

er.

EOG

: Ve

rtica

l ele

ctro

ocul

ogra

m (f

or b

links

and

eye

rnov

e-

AG:

Patie

nts

fulf~

ll the

DSM

-Ill c

riter

ia f

or a

gora

phob

ia

rnen

ts).

with

pan

ic a

ttack

s.

GAD

: Pa

tlent

s ful

fill th

e D

SM-Il

l crit

eria

for g

ener

aliz

ed an

x-

Met

hodo

logi

c C

ritic

ism

s:

iety

dis

orde

r. A:

G

ener

ally

insu

ffici

ent ~

nfor

rnat

ion a

bout

rele

vant

pa-

PD

: Pa

t~en

ts fulfi

ll th

e D

SM-Il

l cr~

teria

for p

anic

dis

orde

r. ra

rnet

ers o

f the

stu

dy.

B :

No

cont

inuo

us rn

onito

rmg

of s

ubje

ctiv

e an

xiet

y.

AEP.

Au

dito

ry e

voke

d po

tent

~al.

C :

No

data

on

subj

ectiv

e an

xiet

y (n

o st

anda

rd m

easu

re

API:

Acut

e Pa

nic

~nve

ntor

y [cf.

L~eb

owitz

et al

., (2

9, 3

1)].

of a

nxie

ty).

BP:

Bloo

d pr

essu

re.

D:

Mea

sure

s re

str~

cted

to s

elf-r

epor

ts of

sym

ptom

s.

). MARGRAF, A. EHLERS, and W. T. ROTH

important, although not definitive infor-mation, since the convergence may also bedue to shared methodologic inadequacies.

INCIDENCE OF LACTATE- ANDPLACEBO-INDUCED PANIC INPATIENTS AND CONTROLS

The results of the eight comparisons ofpatients and controls are shown in Table3. There were clear differences in the re-sponses of patients and controls to bothlactate and placebo. Across all studies, 56%of the patients (110 of 197) panicked afterroughly 12 min of lactate infusion whereasonly 9% of the nonclinical control subjects(7 of 76) panicked, usually after a longerperiod of time [15-18 min—Kelly et al.(48, 49) and Rainey et al. (39-41)]. Simi-larly, up to 36% of the patients (39-41) ascompared to 0% of the controls panickedon placebo. The greater responsiveness toplacebo in patients is an important find-ing. Nonspecific factors are likely to be in-volved in their response to the lactate in-fusions as well. Thus the basic finding ofpatients responding differently from con-trols may be more true of the response toplacebo than the response to lactate. How-ever, the difference in response to lactateand to placebo clearly indicates an activeeffect of lactate both on patients and, to alesser degree, on controls. In interpretingthese results, we have to take into consid-eration the methodologic shortcomingsdiscussed above. Especially relevant in thecontext of possible placebo effects is theissue of insufficient control of expectancybias and demand characteristics.

A panic rate in controls of up to 30%(39-41) and no significant difference be-tween the panic rates of panic patients andpatients with generalized anxiety disorder

[Lapierre et al. (38)—26.1% vs. 12.5%] in-dicate a lack of specificity of the lactateprocedure that invalidates its clinical use-fulness for discriminating between diag-nostic groups.

The four studies without comparisongroups are not included in the above anal-ysis since they do not give data on controlsubjects and were generally less method-ologically adequate. They may, however,provide useful information on specificquestions, such as a possible contributionof hypoglycemia or the blocking effectsof propanolol. [Their percentages of panicattacks in patients under lactate rangefrom 65% (ref. 47—a total of 16 patients)to 100% (refs. 34, 35, and 37—a total of 22patients).]

Interestingly, all studies yielding 100%panic rates in patients used samples of 10or fewer patients. There is a strong nega-tive correlation of —0.83 [Spearman rankcorrelation, Siegel (50)] between samplesize and percentage of patients panickingunder lactate, meaning that bigger samplesyield fewer panicking patients. This cor-relation could indicate a publication biasin that small samples are only publishedwhen rates are high, or that the experi-menters give more personal attention tosubjects in small studies and select themfor more severe illness or create strongerimplicit demands on them to panic duringinfusion. The only double-blind study re-lying entirely on automatized (noninter-active) self-report of panic symptoms ascriterion for panic attacks found a clearlylower proportion of attacks in patients thanall other studies, namely 2'6% (38). Al-though this lower proportion could alsobe due to the 500-ml limit that Lapierre etal. imposed on their infusion (0.5 molarsodium lactate, 10 ml/kg/20 min), the av-erage panic attack is reported to occur atdoses well below 500 ml of 0.5 molar so-


p

0

05

Panic Patients

L

93

10080'l(>

Controls

P

0

00

L

20

2510

CADPatients

P L

- -

MeanTime

toPanic

1'-2'

8'-1212'


TABLE 3. Proportion of Panic Attacks in Nine Studies with Comparison Groups

Percent Panic AttacksUnder Placebo (P) and Lactate (L)

Number ofPatients/

Study ControlsPitts and 14/10McClure (25)Fink et al. (44) 5/4Kelly etal. 20/10

posttreatment 8 13 25, — — — — ?"less severe":

50Bonn et al 20/9 0 "overt ? ?c — — 14'(45, 46)c panic":

20"would

have":60"

Rifkin et al 9/7 0 100 0 0 — — ?(27)

posttreatment 6 0 0 — — — — —Applebyetal. 25/15 16 64a 0 0 — — 15'(26)a

Liebowitz et al. 43/20 7 72 0 0 — — 12'(28, 31)

posttreatment 27 0 15 _ _ _ _ ?Lapierre et al. 23/16'' 0 26 — — 0 13 ?(38)"Raineyetal. 11/10' 36 91 0 30 — — 1V(39, 40),Freedman et al.(41)'JSome patients panicked after the end of the lactate infusion IKelly et al. (48)—5%, ApplebybAn unspecified number of patients reported only the "physiological concomitants of anxie ,degree of mental fear" (48, p. 133).cAlthough the total number of patients was 24, results are reported for 20 patients only. Results for controls are notreported.

et al (26)—4%l.iety without the usual


J. MARGRAF, A. EHLERS, and W. T. ROTH

dium lactate (average onset time is about12 min; cf. Table 3).

A general problem in all attempts to es-tablish the incidence of panic attacks isthat they show considerable variationacross and within individuals and that thereare no generally accepted objective criteriafor panic attacks. In our opinion, the bestapproach is to record in detail the symp-toms experienced and concomitant phys-iologic changes. This comprehensive ap-proach is the only one that permitscomparisons across studies and mini-mizes the influence of experimenter bias.

SPECIFIC EFFECTS OFLACTATE INFUSIONS

Self-Reported Symptoms andSubjective Anxiety

Table 4 shows the occurrence of self-reported symptoms of lactate infusions inpatients and controls in the five studiesthat provide this information. Significantnumbers of symptoms related to anxietyand distress were described as accompa-nying lactate infusions. The symptoms weresignificantly more frequent and intenseunder lactate than under placebo in all ofthese studies. Similarly, the average ef-fects were stronger in patients than in con-trols in those studies that reported valuesfor both groups. However, the controls stillreported a significant number of symp-toms under lactate, which were qualita-tively comparable to those reported by thepatients. Unfortunately, the symptom listsused were not comparable across all stud-ies and did not contain control scales forresponse styles. Moreover, symptoms wereestablished only by self-report, no behav-ioral measures were taken, and concurrent

validation from psychophysiologic mea-sures was largely missing.

Three studies employed standard anx-iety measures that have been widely usedin other settings: subjective units-of-dis-comfort scales, the Hamilton Anxiety Scale,and the State-Trait Anxiety Inventory(STAI). The results on a 10-point subjec-tive units-of-discomfort scale were 7.9 forpatients and 6 for controls (48,49). Raineyet al. (39-41) found Hamilton Anxiety Scalescores of 30 and 7 as well as STAI scoresof 54 and 38 (state form) for patients andcontrols, respectively (numbers derivedfrom graphs in these reports). Thus, over-all only moderate levels of anxiety werereached. The scores on the psychometricSTAI are within one standard deviation ofthe mean of Spielberger et al.'s (51) generalsample of neuropsychiatric patients (T-scores of 55 and 43, compared to an un-dergraduate sample 66 and 55). Lapierreet al. (38) reported scores of about 5 on the10-point numeric transformation of theirvisual analog anxiety scale for the subgroupof patients who panicked (nonpanickersaveraged 0). Thus, although lactate in-duces a considerable number of self-re-ported symptoms in patients and (to a lesserdegree) in controls, much lower levels ofsubjective anxiety were reached than onewould expect for "panic attacks."

Since the definition of panic attacksclearly specifies sudden onset and limitedduration as criteria (14, pp. 230-231), thetime course of the effects of lactate shouldbe closely monitored. Only Kelly et al.,(48, 49) attempted this. All of the otherstudies we have discussed could be doubtedby a radical critic as ignoring the distin-guishing "attack" property of the anxietyexperience, and instead concentrating onnonspecific sustained components of anx-iety. From a practical point of view, thereis a trade-off between the comprehensive-



Table 4. Self-Reported Symptoms

Symptom

Pitts andMcClure

pb

(25)

Cb

Symptom List by Pitts and McClure (25)Paresthesiasc

Tremorc

Shakinessc

Dizzinessc

Palpitations^GiddinessColdc

NervousnessDyspneac

Chest pain orconstriction0

Blurred visionNervous chillcWeaknessLump in throatHeadacheSmotheringc

SighingFaintness0

IrritabilityNauseaChoking1"

10010010093939379797164

6464575050434336362914

Symptoms not Included in Pitts'DysphoriaVibrationDry mouthTwitchingDifficulty doing jobFearfulnessDifficulty concentratingDifficulty speakingConfusionFear of dyingc

Sweating0

Urgency to urinateDetachment from

body0

Sense of unreality0

Urgency to defecate

1005080405050306030

0

301050105010102010300

Kelly et(48)

P

7590

10045757065956550

3045803560357040804530

al

C

601006010601010405040

20104010300

601020300

and McClure's Original List

Bonn et al.(45)

P C

58 d

75

50

33

92747133

38

Rifkin et al.(27)

P C

100 100100 100

Liebowitz etal. (28, 31)'1

P C

d

58a

66

6750

29

26

76907958534541363620

143

aLiebowitz et al (28, 31) do not give the proportion of subjects experiencing these symptoms. Instead, the averageintensity of symptoms (scale from 0 to 3) is reported. We transformed the results to percent of the maximal intensity.Thus, the percentages listed for Liebowitz et al. are not directly comparable to the other studies.'The percentage of patients (P) and controls (C) experiencing symptoms.CDSM-III symptom.''No information about controls is given by Bonn et al. (45) and Liebowitz et al. (28, 31)



ness of self-reports and how frequently theycan be given. One advantage of most psy-chophysiologic measures is that they canbe monitored continuously.

Psychophysiologic MeasuresIn panic attack research, psychophys-

iologic measures can be chosen to assessthe activity of the different parts of thenervous system or to provide objective re-flections of different symptom groups. Inthe first case, one could choose measuresrepresenting central (CNS), autonomic andsomatic nervous system events. In the sec-ond case, one could choose measures ofcardiac, pulmonary, sweat gland, andmuscle activities. Both strategies have beenfollowed in practice [e.g. Lapierre et al.(38), strategy 1; Freedman et al. (41), strat-egy 2]. Table 5 gives the results on psy-chologic measures reported in eight stud-ies.

In summary, the data show clear andconsistent increases in autonomic (heartrate, blood pressure, skin conductancelevel, forearm blood flow) activity, whereasnonautonomic indicators of somatic activ-ity (electromyogram, respiration rate) failto show consistent changes. Interestingly,the commonly reported pulmonary andmuscular symptoms are not reflected inobjective respiration rate and EMG mea-sures. The CNS changes reported are typ-ical for anxiety patients in general (52) andcan be interpreted as indicators of over-arousal (38, 53).

Biochemical MeasuresTable 6 shows changes in biochemical

measures during lactate infusions. Manyof the effects may be direct reflections ofthe infused lactate, such as hypocalcemiaand mild metabolic alkalosis. Hypogly-

cemia was not observed. In contrast to theresults from psychophysiologic and self-report measures, the biochemical findingsdo not consistently indicate heightenedarousal or stress-related changes in hor-mones. The lack of consistent changes inperipheral catecholamines might be thebiochemical expression of the rather mod-erate levels of subjective anxiety dis-cussed above. Similarly, the decreases incortisol levels argue against a powerfulstressor-effect of lactate infusions. Al-though effects for bicarbonate and pco2were more marked in panicking subjectsthan in nonpanicking subjects (33), thechanges were generally in the same direc-tion in all subjects. At baseline, subse-quent lactate panickers had greater sym-pathetic arousal (33).

Psychophysiologic and biochemicalchanges occurred in most subjects regard-less of diagnostic category and of observerdetermination of panic attacks. There wasno psychophysiologic, biochemical, or self-report measure that reliably and consis-tently differentiated panic attacks fromnonattack periods, or lactate-induced fromisoproterenol or placebo-induced attacks.No single variable has been shown to be anecessary or sufficient condition for panicattacks. Thus, the psychophysiologic andbiochemical findings fail to provide objec-tive and reliable criteria for panic attacksand to distinguish reliably between pa-tients and controls.

Quantitative or Qualitative DifferencesBetween Patients and Controls?In the preceding sections, we have de-

scribed differences between patients andcontrols in response to lactate. Are thesedifferences qualitative or quantitative?Significant qualitative differences wouldexist if core symptoms occurred exclu-


TABL

E 5.

Ps

ycho

phys

iolo

gic

Mea

sure

so

Gor

man

Ra

iney

et a

l et

al.

(39,

40)

Li

ebow

~tz e

t R

Kelly

et

Bonn

et a

l. 19

83

Free

dman

et

al.

(28,

31,

La

p~er

re et a

l '

Mea

sure

F

~nk et

al.

(44)

al

. (4

8)

(45,

46)

Kn

ott e

t al.

(37)

(3

4)

al.

(41)

33

) (3

8Ib

2 ~n

crea

sed

incr

ease

d in

crea

sed

mcr

ease

d ~n

crea

sed

incr

ease

dc

~ncr

ease

d"

(2 He

art r

ate

Bloo

d pr

essu

re

Fore

arm

blo

od

flow

Fo

rear

m

elec

trom

yogr

am

Res

pira

t~on

rate

El

ectro

- en

ceph

alog

ram

Aud

~tor

y evo

ked

pote

nt~a

ls

Cont

inge

nt

nega

tlve

varia

t~on

Ve

rtica

l ele

ctro

- oc

ulog

ram

Sk

in c

ondu

ctan

ce

leve

l N

onsp

ec~f

~c

fluct

uat~

ons

Skm

tem

pera

ture

incr

ease

d

incr

ease

d be

ta,

decr

ease

d al

pha

for

patie

nts

mcr

ease

d sy

stol

ic

incr

ease

d in

crea

sed

no ch

ange

no c

hang

e in

crea

sed

beta

, de

crea

sed

alph

a m

arke

d in

crea

se

In d

elta

de

crea

sed

P2

and

N2

ampl

~tud

es

incr

ease

d bl

ink

rate

in

crea

sed'

incr

ease

d ov

er

neck

, de

crea

sed

over

ha

nd

mcr

ease

d sy

stol

icd

no c

hang

e

no c

hang

e

no c

hang

e

~ncr

ease

d bl

mk

rate

b no

cha

nge

no c

hang

e

no c

hang

e Fi

nger

te

mpe

ratu

re

"Mar

ked

incr

ease

s/de

crea

ses o

ccur

red

In a

ll su

bjec

ts u

nles

s ot

herw

ise

spec

~fie

d. N

o ch

ange

mea

ns th

at n

o s~

gnifi

cant

spec

ific

chan

ges

due

to la

ctat

e w

ere

repo

rted.

bL

apie

rre e

t al.

(38)

repo

rt si

gnifi

cant

cha

nges

onl

y In

pan

icki

ng p

atie

nts,

not

in th

e ot

her

subj

ects

. Thu

s th

ese

chan

ges

refe

r onl

y to

the

pani

cker

s.

'Gre

ater

inc

reas

es In

pan

~cke

rs than

in n

onpa

nick

ers.

dS

ysto

lic b

lood

pre

ssur

e in

crea

sed

in m

ost s

ubje

cts,

dia

stol

ic o

nly

In 5

0% o

f the

pan

~cke

rs.

eSkin

cond

ucta

nce

leve

l and

non

spec

ific

fluct

uat~

ons in

crea

sed

cons

tant

ly o

ver

the

sess

ions

, re

gard

less

of w

heth

er la

ctat

e or

pla

cebo

was

glv

en.

'Non

spec

ific f

luct

uatio

ns i

n th

is st

udy

incr

ease

d m

ore

unde

r the

pla

cebo

con

d~tio

n than

und

er th

e la

ctat

e co

nditi

on.


Table 6. Biochemical Measures During Lactate Infusion"

Measure

LactatePyruvateBlood glucoseVenous p HPCO2Ionized calc iumPhosphateProlactinCortisolTestosterone

Epinephrine

NorepinephrineBicarbonate

Bonn etal. (45,

46)

increased

decreaseddecreased

increased

Applebyet al. (26)

increasedno changedecreasedin malesincreasedwi th panicno change

Gorman etal. (35)

no change

Liebowitz et a l .(28, 29, 3 1 ,

33)

increasedincreased

increaseddecreased6

decreaseddecreasedincreaseddecreased0

no change

no change11

increased

^Increases/decreases occurred in patients and controls unless specified otherwise. "No change" means that nosignificant changes were observed.Signi f icant ly greater changes for panickers than for nonpanickers.cSmaller decreases in panickers than in nonpanickers at 10 min of lactate only (not at 20 min)''At 5 min of lactate (not at 10, 15, or 20 min) panickers had higher levels than nonpanickers.

sively in patients, or if clearly differentpatterns of symptoms were observed. Ta-ble 4 shows that all symptoms with theexception of choking and smothering havebeen found in both patients and controls.We concluded above that no psychophys-iologic or biochemical measure reliably andconsistently discriminated between groups.The response profiles in both groups arecharacterized by paresthesias, tremor andshakiness, dizziness, palpitations, giddi-ness, dyspnea, and nervousness as well asincreased autonomic arousal, hypocal-cemia, and mild alkalosis. The lack ofqualitative differences between patients andcontrols in anxiety research in general hasled Lader to the conclusion that "patho-logical anxiety seems to differ only in de-gree and not in quality from normal anx-iety" (54, p. 559; cf. 52, 55-57). Moreover,there appears to be no qualitative differ-ence between the responsiveness of the av-

erage patient and the average control formeasures of anxiety and heart rate. Al-though patients reach higher levels of sub-jective anxiety and heart rate during lac-tate infusions, the actual increase frombaseline to lactate levels is consistentlysimilar for controls and patients (28-31,33, 39-41,48,49). Together, these findingssuggest that lactate has no specific actionon panic patients.

SIMILARITY OF LACTATE-INDUCEDAND NATURALLYOCCURRING PANIC

One approach to the question of simi-larity is to compare the symptoms of bothphenomena. Though comprehensive re-search on the phenomenology of naturalpanic attacks is largely missing, we cancompare lactate-induced symptoms with



the symptoms of panic attacks listed inDSM-III. A look at Table 4 shows that thereis considerable overlap. All 12 symptomgroups listed in DSM-III were registered inat least one study, 9 in at least two studies,and 7 in three or more studies of lactateinfusions. The percentages of patients ex-periencing these symptoms varied from14% to 100% (controls: 0%-100%). How-ever, this approach does not tell us whetherindividuals experience their personal con-figuration of symptoms for natural and lac-tate-inducing panic to be similar.

A second approach is to compare stan-dardized similarity ratings of natural andlactate-induced attacks. So far, only twostudies report direct evaluations of simi-larity. Rainey et al. (40) directly asked theirsubjects for a similarity rating. Of the 12panic attacks recorded under lactate, 3 wererated as somewhat or moderately similar,7 as very much so, and 2 as identical. Theratings for isoproterenol were similar. Ofthe six placebo-induced panic attacks, onewas rated not at all identical and five assomewhat or moderately similar to natu-rally occurring panic. Liebowitz et al. (31)compared psychologist ratings of patientreports of natural attacks with ratings oflactate-induced panic using a 17-item"acute panic inventory." They found sig-nificant differences for the items fear ofdying, confusion, sense of unreality, dif-ficulty with concentration, and sweating,which were higher in usual panic. Lac-tate panics were accompanied by greaterurinary urgency and twitching, whichwere considered direct effects of theinfused volume and lactate-inducedhypocalcemia.

Further information about similarity canbe inferred from two other studies. Kellyet al. report that an unspecified number ofpatients experienced only "the physiolog-ical concomitants of anxiety without the

usual degree of mental fear" (48, p. 133)when infused with lactate. Bonn et al. (45,46) reported that of 20 patients only 4 (20%)experienced overt panic, whereas 12 (60%)"would have panicked but for your pres-ence, doctor," 3 (15%) experienced "prel-ude" to panic, and 1 (5%) experienced no"mood change." No patients thought thatlactate resulted in an "exact reproduction"of their natural attacks. These results strik-ingly resemble Maranon's (58) finding thatepinephrine injections resulted in so-calledcold or as if emotions. Five other studiesdid not report data on subjective anxietyduring their "panic attacks" (criticism "C"in Tables 1 and 2), making it impossibleto judge whether the "intense apprehen-sion, fear, or terror" required as part ofpanic attacks by DSM-III (14, p. 230) waspresent.

A third approach is comparison of phys-iologic data. However, for natural panicattacks these data are still sparse. Laderand Mathews (59) recorded heart rate in-creases of 40-51 bpm in three sponta-neous attacks occurring in their labora-tory. Taylor et al. (60, 61) measuredambulatory heart rate and observed in-creases disproportionate to physical activ-ity levels in up to 58% of all self-reportedpanic attacks. Mean increases were 38.6bpm. Although heart rate increases withlactate, the increases are considerably lower[average 21 bpm, calculated from sevenstudies (33-35, 37, 38, 41, 45, 46)]. Theyare in the range of the 19 bpm recorded innormal students before examinations (62),but much less than the 145 bpm reachedby inexperienced parachutists beforejumping (63).

It is important to note that lactate re-searchers have restricted their assess-ments to a single emotion—anxiety. Thusit is impossible to judge whether lactatespecifically increases anxiety or whether



a more general discomfort is induced, ofwhich anxiety may be only a part. Al-though anxiety may be similar in naturalpanic attacks, other feelings may be quitedifferent. The only study to evaluate de-pressed mood did not give informationabout changes over time or baselines butdid find significantly greater peak valuesfor patients than for controls (48).

Thus, the question of similarity is stillopen. Although there are unquestionablesimilarities in symptoms and physiologicchanges, there are not enough direct andcomprehensive investigations of this is-sue. Both subjective anxiety and heart ratesaccompanying lactate infusions are rela-tively moderate, and comparable data onnatural panic attacks are lacking.

INFLUENCE OF BASELINE LEVELSOF ANXIETY AND AROUSAL

In the preceding section we have shownthat diagnostic category predicts the levelof anxiety and autonomic arousal that sub-jects reach under lactate. In addition, thebaseline (prelactate) values of anxiety andautonomic arousal seem to be a strong pre-dictor of panic response to lactate. The evi-dence for this is twofold. First, patients asa group are more likely to panic, and as agroup they have higher baseline values thando controls for anxiety (28-31, 33, 39-41,48,49), heart rate, systolic blood pressure,and forearm blood flow (31, 34, 48). Bi-carbonate and pco2 levels were lower (33,45, 46). Second, among patients, those withhigher fearfulness, diastolic blood pres-sure, and heart rates at baseline are morelikely to go on to panic (28-31, 33).

That baseline state can influence the ef-fects of arousing drugs had been reportedas early as 1924. Maranon (58) found thatwhether a subject responded to an epi-

nephrine injection with more pronouncedand genuine emotions or with weak and"as if" emotions depended on whether thesubject was excited or calm before theinjection.

The baseline differences between groupsmay reflect acute anticipatory anxiety ratherthan chronic differences in level. For ex-ample, Liebowitz et al. (33) report that heartrate differences between groups were lessmarked on a prior testing day on whichsubjects knew they would not receive lac-tate. Lactate may simply add to the ele-vated baseline arousal associated with an-ticipatory anxiety, and push more highlyaroused subjects across a tolerance thresh-old.

In our own laboratory we recently com-pleted a study that suggests the reactivityof patients and controls to lactate infu-sions may be the same (64). Subjects withthe diagnosis of Panic Disorder or Agora-phobia with Panic Attacks had higherpreinfusion subjective anxiety and heartrates than a control group, whereas bothgroups had equal increases in these mea-sures during infusion. In other words, thegroups differed in level but not in reactiv-ity.

POSSIBLE MEDIATORS OFLACTATE EFFECTS

There are several ways by which a causalchain between lactate infusion and panicmight be investigated. The studies re-ported above looked for psychologic, bio-chemical, or physiologic correlates of lac-tate infusions and attempted to establishwhich ones were most consistently asso-ciated with panic. Another approach is todirectly manipulate components of thelactate response to discover which are mostessential for its panicogenic effect. A third



approach is to find other agents that in-duce panic and to look for effects they havein common with lactate that might explaintheir panic-inducing property.

Blocking of Response to LactatePanic rates of panic patients to lactate

infusions are much lower after medium-term treatment (4-17 weeks) with tricyclicantidepressants, MAO inhibitors, and insome cases clonidine and mianserin, thanbefore treatment (27-31, 33, 48, 49). Pro-panolol, naloxone, and calcium chloridehave been tested as acute blockers of lac-tate effects. Although propanolol loweredtonic levels of heart rate and systolic bloodpressure, it failed to alter phasic responseto lactate in panic patients (34) and normalsubjects (65, 66). Similarly, naloxone didnot alter response to lactate in panic pa-tients (32). However, the addition of 20mM calcium chloride significantly atten-uated the effects of lactate infusions (25,44), although in both studies "the responseto lactate-calcium was similar to that oflactate alone, but clearly less intense andof shorter duration . . ." (44, p. 1429).Blockers are not restricted to active phar-macologic agents. The presence of medicalpersonnel during the infusions has beennoted to have panic-blocking effects (45,48, 49).

Unfortunately, except for the calciumchloride studies, blocking studies have notbeen double blind and have confoundedtreatment effects with sequence effects, inthat the blocker was always given afterprevious infusions. The importance of se-quence effects is underlined by a study ofBonn et al. (45, 46), who gave lactate in-fusions to 33 patients for 3 weeks twiceweekly as a "flooding" procedure. Scoreson an anxiety self-rating scale significantly

and greatly decreased over time, and thesedecreases persisted at a 6-week follow-up.

Alternative Challenge TechniquesDirect comparisons with lactate have

been undertaken for isoproterenol (39-41;cf. 67), bicarbonate (21), CO2-inhalation andhyperventilation (36; cf. 68), and placebo.Other reported agents for inducing panicattacks in the laboratory are yohimbine(69-72) and caffeine (72, 73).

While an infusion of 1 |j,g/min of iso-proterenol, a beta agonist, in 6 ml/kg dex-trose in water over 20 min (39-41) and theinhalation of a mixture of 5% CO2 with95% room air over 20 min produced al-most the same rate of panic attacks as lac-tate, hyperventilation was far less effective(36). In addition, Grosz and Farmer (21)were able to produce symptoms similar tothose of lactate by giving 500 mM of so-dium bicarbonate (8 ml/kg, 30 min) to tennormal subjects. Placebo infusion can alsoproduce effects similar to lactate in somepatients: panic response rates from 0% to36% have been reported (cf. Tables 3 and7).

Although not directly compared withlactate, yohimbine, an alpha-2 antagonist,and caffeine have been shown to inducesubjective anxiety and autonomic arousalin panic patients and controls (69-72), andeven to induce panic attacks in patients(yohimbine, 71, 72) and controls (caffeine,72, 73). The effects of yohimbine werecompletely blocked in normals by 10 mgdiazepam or 5 (xg/kg clonidine.

Surprisingly, psychologic manipula-tions for inducing or blocking panic havenot been explicitly investigated in the con-text of lactate infusions, although there isevidence that such manipulations couldbe effective. Van den Hout and Griez (74)were able to manipulate normal subjects'



TABLE 7. Direct Comparisons of Lactate with other Agents"

Study Lactate Isoproterenol CO2 Hyperventilation PlaceboRainey et al.(40)Freedman et al.(41)(N = 11)Gorman et al.(36)(N =12)

73 36

67 58 25

aThe percentage of patients that reported to have had panic attacks is presented. A dash indicates that this conditionwas not part of the study concerned.

responses to short inhalations of a 35:65CO2-air mixture in the direction of eithertension/unpleasant or relaxation/pleasantby different instructions.

Proposed Biologic Mechanisms

Pitts and McClure (25, 42, 75) originallyproposed a causal link between elevatedserum lactate and pathologic anxiety.However, several methodologic criticismsof the evidence and conflicting empiricalfindings made it clear that elevated serumlactate was neither a necessary nor a suf-ficient condition for pathologic anxiety(18-24). Similarly Pitts's (76, 77} recentproposal of a beta-adrenergic mechanismhas been refuted by the failure of propan-olol to block the effects of lactate infusions(34, 65, 66).

A number of biologic mechanisms arecurrently being discussed as explanationsfor the effects of lactate infusions (20, 21, 33,35, 36, 43, 78, 79). Some of these are basedon peripheral physiologic changes like theJames-Lange theory of emotion and, as such,are subject to its criticisms (cf. 52, 80-82),whereas others are more central. In eithercase, it has been impossible to show thatsingle mechanisms are necessary or suffi-

cient for panic, Lactate-induced panic canoccur without peripheral catecholaminesurges, hyperventilation, or hypoglyce-mia; thus, these mechanisms are not nec-essary causes. Hypocalcemia and alkalosismay occur in people who do not panic; thus,these mechanisms are not sufficient causes(cf. Tables 5 and 6). For one recent theorythat postulates a shift in the ratio of NAD +to NADH, crucial data are still missing: theeffects of D- and L-lactate need to be com-pared since the former does not lead to a re-doxshift (33,43, 79).

Carr and Sheehan (43) hypothesize thatpanic patients have central chemoreceptorhypersensitivity. They assume that "pH orCO2 changes that would have little or noeffect on normals would produce signifi-cant excitatory effects on brain stem chem-oreceptors in panic patients, with second-ary excitation of central sympatheticneurons." (33) This implies that lactateshould have little or no effect on normalsbut significant effects on patients. Carr andSheehan (43) explicitly claim that normalsdo not complain about "noxious effects oflactate" and that patients do not panic un-der placebo. However, the studies re-viewed above do not support this claim.

Finally, the similarity of common phys-



iologic changes during lactate infusions tothe results of central sympathetic activa-tion, such as heart rate and blood pressureincreases, has led several authors to ex-plain lactate-induced panic as a dysfunc-tion of the structures and neurotransmit-ters subserving this activation (33, 36, 79).This would be consistent with the anxiety-inducing effects of other noradrenergic andadrenergic agents presented above. Thespecific brain structure advanced most oftenin this context is the locus ceruleus in thedorsolateral tegmentum of the pons (33,36, 71, 79, 83, 84). This nucleus containsmore than half of the cerebral noradren-ergic neurons. The locus ceruleus modelof noradrenergic discharge is in keepingwith the panic suppressing effects of clon-idine, an alpha-2 agonist (31, 69, 85, 86),the tricyclics (2), and diazepam (87), sinceall inhibit locus ceruleus firing (88-90).Increased firing of the noradrenergic neu-rons of the locus ceruleus also offers a pos-sible common pathway for the panico-genic effects of lactate and CO2 (36).Elevated cerebral CO2 has been shown inanimals to increase the firing rate of itsnoradrenergic neurons (91). CO2, a meta-bolic product of L-lactate, is able to crossthe brain-blood barrier freely and thusmight transiently build up cerebrally inspite of a peripheral decrease in pco2 (33).Thus, there is considerable reason to arguefor an involvement of noradrenergic dis-charge in the locus ceruleus in the effectsof lactate infusions.

However, there are many problems withthis model. Not even the most frequentsympathomimetic concomitants of lac-tate-induced panic are present in all at-tacks, and the same changes appear in asubstantial group of subjects that do notpanic. Similarly, the evidence from thestudies with propanolol and clonidine is

equivocal. Propanolol neither blocks lac-tate-induced panic (34, 65) nor is signifi-cantly better than placebo in the treatmentof natural panic (87). The anxiolytic effectof clonidine wears off within weeks andit may even worsen anxiety (85, 92). Fur-thermore, clonidine may act on nonadren-ergic systems (93-96). With regard to thelocus ceruleus, animal studies show thatit responds to a variety of nonanxiety stim-uli (97), and other brain areas respond toanxiety stimuli as well. Pharmacologicallyspecific lesions of noradrenergic systemsof the locus ceruleus in rats do not haveanxiolytic effects (94). The locus ceruleusseemsto be involved in a more global nor-adrenergic "alarm" system, whereas "anx-iety" may be more specifically related tobenzodiazepine/GABA-systems (91, 94,98-101).

More generally, purely biologic theoriesof lactate effects make the assumption of"identity" (102): they imply a one-to-onerelationship between a pattern of physio-logic or biochemical processes and spe-cific behaviors or psychologic states. How-ever, significant proportions of subjectsshow no or very little response to lactatein both patient and control groups, andrepeated lactate infusions have been ef-fectively used as a treatment. The responseto lactate is modulated by cognitive vari-ables as expressed in Bonn's and Kelly'sfindings of physiologic symptoms withoutsubjective anxiety, the placebo respon-siveness of patients, and the relevance ofanticipation shown in the predictive powerof infusion day baseline values. No centralor peripheral physiologic change investi-gated to date is a sufficient or necessarycondition for lactate-induced panic. Ingeneral, research on emotions has long re-jected the assumption of identity (52, 55,82, 103-106).



A Cognitive PsychophysiologicFormulation

Panic is extreme anxiety and, as such,an emotional state (52, 57,107,108). Emo-tions are generally regarded as complexorganized states with several components(103, 106, 109-115). Although differentviews about the classification of differentemotions and the theoretical formulationof cognitive variables exist, modern re-search has established an unequivocal ex-perimental basis for the role of cognitiveand physiologic variables in emotions ingeneral and in anxiety in particular (52,55, 82, 103, 105, 106, 111-114, 116-123).However, both experimental research onlactate infusions and the theoretical ex-planations of its effects have neglectedcognitive variables.

Experimentally identified cognitive pa-rameters of great relevance for anxiety in-duction studies include past experience(133, 134), expectancy and anticipation(109, 124, 125), appraisal of external andinternal cues (109, 114, 126), helplessness(126), uncertainty and unpredictability(109,124, 128,129), and the perception ofthreat/harm (109,124, 130, 131), responseunavailability (124), control (129-131),situational cues (102, 132, 134), and bod-ily feelings (correct or incorrect; 117, 118,121, 135-138). The preceding excitatorystate of the organism also has been shownto influence emotional responses (124).Furthermore, the concept that organismsare genetically prepared to learn phobicresponses to certain specific stimuli (139)must be taken into consideration.

The importance of cognitive variableshas been demonstrated in the body of lit-erature on epinephrine challenges andanxiety, a topic with striking parallels tothat of lactate infusion and panic. Some ofthese parallels are exemplified by Basow-

itz et al. (133). They infused epinephrinein normal volunteers, using a design al-most identical to that of Rainey et al.(39-41). The pattern of epinephrine- orplacebo-induced symptoms was best pre-dicted by the individual's own prior anx-iety experiences. In addition, subjects de-termined to be more emotion-prone in apreceding interview responded with moregenuine anxiety. Basowitz et al. also notedthat the "anxiety" often had a "cold" qual-ity and was generally milder than naturalanxiety. Breggin (134) concluded on thebasis of an extensive review of the litera-ture on epinephrine challenges that ap-parent inconsistencies in those resultscould be eliminated by taking into accountthe presence of two variables:

1. Previously learned association ofsympathomimetic symptoms and acuteanxiety2. Anxiety-related cues in the experi-mental environment

When these two variables are not presentto high degrees, the emotions producedhave a cold or "as if" quality, as in thepreviously quoted experiments of Mara-non (58), Basowitz et al. (133), Bonn et al.(45, 46), and Kelly et al. (48,49). This find-ing was noted both in the pioneering stud-ies of Tompkins et al. (140), Wearn andSturgis (141), Maranon (58), and Basowitzet al. (133), and in recent studies (52, 77,81, 135).

Only one of the theories put forward toexplain the effects of lactate takes into ac-count biologic and cognitive variables.Ackerman and Sachar (24) proposed aconditioned phobic response to singlesymptoms or patterns of symptoms of anx-iety as the panic-inducing mechanisms inlactate infusions. This hypothesis can ex-plain the differences between patients andcontrols as being due to a learned phobicresponse to bodily sensations that can be

42 Psychosomatic Medicine Vol. 48, No. 1/2 Qan./Feb. 1986)


mimicked by lactate. It also can explainthe apparent therapeutic success of re-peated lactate administrations (and CO2inhalations, 47, 68) as extinction. It iscongruent with the anxiety-provokingeffect of falsely elevated heart rate feedback(117, 118, 137), and the greater treat-ment success of beta-blocking agentsin somatic rather than psychic anxiety(101, 135, 142).

Although Ackerman and Sachar stressthe relevance of cognitive factors in mod-ulating the phobic response to somaticsymptoms, they are vague on how thismodulation takes place. For this reasonAckerman and Sachar have been misun-derstood as advancing a nonspecific stresshypothesis (e.g., 33, 79). Their hypothesisis nonspecific in the sense that they do notassume a single specific biologic "stressor,"but specific in the sense that it postulatesindividual-specific learned associations ofbodily symptoms with mental states. Thus,the fact that other stress tests such as cold-pressor or mental arithmetic do not pro-voke panic attacks in panic patients (79)is not a valid argument against Ackermanand Sachar's hypothesis, since the patternof symptoms produced by these tests mightnot have been previously associated withpanic. The symptoms of hypoglycemia maybe more like panic symptoms, but the onestudy inducing hypoglycemia in panic pa-tients (143) induced it gradually over 3-5hr and thus failed to mimic the abrupt andrapid onset of symptoms typical for panicattacks. This might explain why no panicattacks were precipitated.

However, the explanatory power ofAckerman and Sachar's original formula-tion can be considerably enhanced by ex-plicitly taking into account cognitive vari-ables and their interactions withphysiologic variables. The data from lac-tate studies may be best explained by a

cognitive psychophysiologic approach fo-cusing on the association of perceivedbodily symptoms with past panic attacksin the following way:

The subject has learned to associate cer-tain bodily sensations with acute anxietyby a process of repeated interoceptive con-ditioning and subsequent cognitive elab-oration. Phobic (anxiety-relevant) stimuliand especially interoceptive stimuli arelearned faster and are more resistant to ex-tinction than other stimuli (144-146). Thepattern of sensations may differ betweenpeople or within an individual at differenttimes, depending on new learning expe-riences and changes in the internal phys-iologic "environment." However, the pat-tern of sensations constitutes a complexanxiety stimulus specific to each individ-ual and derived from past experience. Notall symptoms will be associated equallyeasily with anxiety, since genetic prepar-edness makes some more easily learned(139). The fact that panic patients developindividually highly characteristic and sta-ble descriptions of the symptoms associ-ated with their panic attacks points to therole of individual response stereotypy inthese attacks. The existence of individ-ually specific physiologic response pat-terns is well documented (147-149).

Lactate infusions induce anxiety-rele-vant sensation patterns in a significantproportion of subjects. The response to thisstimulus pattern depends on the percep-tion of the bodily changes and on the ap-praisal of environmental and internal cuesin terms of perceived uncertainty, threat/potential harm, and availability of re-sponses or coping strategies. Therefore, in-structions and other cues in the experi-mental environment are crucial variablesin anxiety-induction studies. The ap-praisal process is influenced by both traitvariables (individual differences due to


]. MARCRAF, A. EHLERS, and W. T. ROTH

learning history and genetic endowmentof the individuals) and state variables (e.g.,the preceding excitatory state of the or-ganism or situational determinants). Thisprocess is dynamic in the sense that itsoutcome may lead to changes in emotionalstate, physiology, general behavior, andenvironment, which in turn constitute newstimuli and trigger a new cycle of ap-praisal, etc. This dynamic process can pro-duce a positive feedback loop where theappraisal of the lactate anxiety as beinggenuine results in an ascending spiral ofanxiety and arousal.

This formulation explains 1) the higherpanic rate during lactate in patients withpanic attacks or Generalized Anxiety Dis-order in terms of more numerous or strongerlearned associations and higher priorarousal, 2) the higher response to placeboinfusions in patients in terms of higherprior arousal and negative expectanciespartially related to past anxiety experi-ences, 3) the higher rate of anxiety re-sponses to lactate than to other agents interms of closer resemblance of lactate's ef-fects to learned concomitants of anxiety,4) the effects of baseline levels in terms ofprior arousal, anxious cognitions, and neg-ative expectancy, and 5) the anxiety/panicattenuating effect of the presence of med-ical personnel in terms of reduced per-ceived threat and increased available cop-ing strategies. In this framework, theefficacy of methods for blocking lactate-induced anxiety depends on changing priorarousal or changing the anxiety-relatedsymptoms or cognitions elicited by lac-tate. The failure of propranolol to blocklactate effects can be related to its failureto block the rise in heart rate produced bylactate and to block the symptoms asso-ciated with hypocalcemia.

Our model closely follows Arnold's (126)and Lazarus's (114) theories of emotion and

is compatible with other major theories ofemotion and anxiety (e.g., 52, 82,103,104,107). Although we derive it from lactateinfusion data, it may be applicable to theeffects of CO2 inhalation, hyperventila-tion, caffeine ingestion, and so on. In fact,a version of it may apply to naturally oc-curring panic attacks in that positive feed-back loops between physiologic changesand appraisal processes (52) may operatehere as well. An "exacerbation circle" (130)or a "spiral" (134) of anxious cognitionsand physiologic arousal could produce theintense, sudden peaks typical for panic.Each new occurrence of such a spiral wouldlead to further enhancement of the asso-ciation of subjective anxiety and the in-dividually specific patterns of bodilysymptoms.

CONCLUSIONS AND SUMMARY

The response to sodium lactate infusionhas been proposed as an experimentalmodel for panic attacks and as a possiblebiologic marker of the panic attacks typi-cal for Panic Disorder and Agoraphobiawith Panic Attacks. We have reviewed theresults of 13 published studies that sup-posedly support a specific panicogenic ef-fect of lactate on patients but not on con-trols. As we have discussed, however, anyinterpretations drawn from this literaturemust be regarded as tentative since sig-nificant methodologic problems are pre-sent in most of these studies, including therecent ones. Already in 1972, Levitt, com-menting on "psychiatric breakthrough" re-search, criticized lactate research for its"primitive" psychologic and behavioralmeasurements and lack of "routine pre-cautions against the encroachment of ex-perimenter bias" (23, p. 233). In addition,Levitt emphasized that placebo effects are

44 Psychosomatic Medicine Vol. 48, No. 1/2 Qan./Feb. 1986)


ubiquitous, and warned that "the experi-ment which fails to turn up a single pla-cebo reaction might be suspect" (23, p. 233).Nine of our thirteen studies reported noplacebo-induced panic in patients. In gen-eral, studies rarely considered cognitivevariables and ignored relevant psycho-logic and physiologic literature. Given thesemethodologic shortcomings, what can weconclude from these studies?

First, lactate infusions are an effectivelaboratory anxiety induction technique,producing anxiety that resembJes natu-rally occurring panic. Thus, the results oflactate studies may bear implications forthe theory of Panic Disorder and anxietydisorders in general. However, one cannotregard lactate-induced anxiety as identica]to natural panic, and we do not know howvalid a laboratory model for panic it pro-vides. Among other problems, there are nodata to demonstrate that lactate producesthe explosive onset of anxiety regarded ascharacteristic for panic attacks rather thana gradual dose-related increase. The anx-iety is generally of only moderate inten-sity, and for that reason perhaps does notdeserve to be called "panic." Therefore, itis premature to use lactate infusion as asubstitute for standard clinical methods forevaluating treatments for panic attacks.

Second, response to lactate infusioncannot be regarded as a biologic marker ordiagnostic test for Panic Disorder or Ago-raphobia with Panic Attacks. A biologicmarker should be sensitive, specific, andindependent of cognitive and emotionalstates. However, results summarized aboveindicate a lack of sensitivity of the pro-cedure in that among studies with com-parison groups only 56% of panic patientsreact to lactate with panic (see Table 3).As for specificity, the one study comparingpanic patients to another clinical groupfound no significant differences (38). Fi-

nally, there is a strong influence of cog-nitive and emotional states on the likeli-hood that lactate will induce panic (28-31,33, 39-41, 45, 46, 48, 49, 64). Baseline dif-ferences expressing anticipatory anxietyclearly predict the results of infusion.Therefore, lactate infusion data do notconfirm the biologic distinctness of panicdisorder claimed by several authors (1,2,9,10-13). The responses of panic patients,controls, and patients with GeneralizedAnxiety Disorder differ quantitativelyrather than qualitatively, which is con-sistent with findings of anxiety research ingeneral (52, 54-57).

It is interesting to note that a second lineof argument for the biologic distinctnessof panic, the drug-specificity argument, hasalso been somewhat shaken by recent evi-dence. Klein (1,2,9) claimed that tricyclicantidepressants and MAO inhibitors sup-press panic but not anticipatory anxiety,whereas benzodiazepines suppress antic-ipatory anxiety but not panic. However, anew benzodiazepine, alprazolam, has beenshown to be effective for Agoraphobia withPanic Attacks and Panic Disorder (10, 17).And Noyes et al. (87) only recently showedin a double-blind placebo-controlled de-sign that diazepam, the standard benzo-diazepine anxiolytic, effectively and spe-cifically treats panic attacks. On the otherhand, controlled studies comparing the ef-fects of tricyclic antidepressants and stan-dard benzodiazepines on anticipatoryanxiety are still lacking.

The results of the lactate infusion stud-ies together with the recent drug treatmentfindings suggest that the interaction of bi-ologic and psychologic mechanisms inanxiety disorders may well be quite dif-ferent from Klein's model or the simplemetabolic disease model of Carr and Shee-han (43). At least for lactate infusions, itis more reasonable to conceptualize the



results in terms of an extension of the Preparation of this review has been sup-learned phobic response theory of Ack- ported by the Veterans Administration, theerman and Sachar (24). Known lactate ef- German National Scholarship Founda-fects could be entirely explained by the tion, and the German Academic Exchangeinteraction of perceived physiologic Service of the Federal Republic of Ger-changes, past experience, environmental many. We wish to thank Margaret Rosen-cues, and their appraisal as threatening or bloom, Kristin McCJenahan, and Garydangerous. Marshall for helpful comments.

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