Mania

Compared Kenneth

Andrew

I. Shulman,

Satlin,

Objective:

The

goal

of this

study

to a private

in Old

Tohen, M.D., Dr.P.H., Douglas Kalunian,

and

Age

M.D.

to clarify the meaning and importance of mania in a retrospective study ofSO elderly patients consecu-

was

conducted mental

Depression

S.M., Mauricio Mallya, M.D.,

M.D.,

The authors

admitted

Unipolar

Gopmath

M.D.,

old age. Method: tively

With

hospital

with

an index

episode

ofmania.

As a comparison

group, they used 50 age- and sex-matched patients with unipolar depression. They reviewed the charts of the I 00 patients for family history, clinical course, and neurological disorders. Outcome was determined by contacting patients, families, physicians, institutional settings, and vital statistics records. Survival analysis compared mortality rates. Results: The manic patients

had

a greater

familial

predisposition

to affective

disorder

and

were

younger

at first

psychiatric hospitalization. For the 20 manic patients whose sion, an average of 1 5 years elapsed before mania became patients, compared with only four of the depressed patients, manic patients had a significantly higher mortality rate than

first affective episode was depresmanifest. Eighteen of the manic had neurological disorders. The the depressed patients; by the end

of the follow-up,

1 0 of the depressed

25

of the

manic

patients,

compared

with

patients,

had

died. Conclusions: Mania appears to have a poorer prognosis and to be a more severe form ofaffective illness than unipolar depression. The 1 8 manic patients with neurologi cal disorders seemed to have “secondary mania. Subtle cerebral changes due to aging may have been responsible for the conversion to mania in the 20 patients who experienced a long latency from “

f irst

depression

to onset

highlights the need (Am J Psychiatry

T

ofmania.

he incidence of first admissions increase with advancing age

ing and clear.

importance

of mania

In contrast,

the community adults to 0.4% many

elderly

as long

the

in old

age remains

of bipolar

manic

patients, separates

frequency

a latency the

from

first

un-

disorder

with age from 1.4% older than 65 years

as 17 years

low

for mania tends to (1, 2), yet the mean-

prevalence

decreases in those

The

to differentiate early1992; 149:341-345)

period episode

in

in young (3). For

Even

a manic

among

young

Akiskal

et al.

episode

within

patients

(7)

found

a 6-year

with

that

follow-up.

Department

of Psychiatry,

Sunnybrook

Health

de-

experienced

Therefore,

Science

Cen-

tre, 2075 Bayview Ave., Toronto, Ont. M4N 3MS, Canada. Supported in part by a grant from the Ontario Mental Health Foundation (Dr. Shulman) and by grant AG-00236 from the National Institute on Aging (Dr. Satlin). Copyright C) 1992 American

Am

J

Psychiatry

149:3,

Psychiatric

March

Association.

1992

the concept of a unipolar-bipolar dichotomy of affective disorder (8) has been challenged by spectrum and threshold theories that consider mania a more severe form of affective disorder (9, 10). The average age at onset of affective disorder has been reported to be in the late 40s or SOs in elderly manic pahave suffered from mania before the age of 30 (5). Age at onset may distinguish subgroups of manic patients with different clinical and biological features (11). In both mania and depression in old age, a good deal of attention has been directed at the role of cerebral-organic factors. Retrospective studies have found an association between coarse brain disorders and mania in old age (4, 5, 12). In a recent prospective study, Broadhead and Jacoby (6) used CT scans to study elderly as well as young patients with mania. They concluded that “organic factors may play an important role in the genesis of affective disorder in old age.” Based in part on the earlier findings of Shulman and Post (4), we hypothesized that, compared with depression in old age, mania in old age 1) is a more severe form of affective disorder, 2) is associated with a preponderance of neurological disorders, and 3) has a poorer prognosis. Usually, depression in old age has

Presented at the 144th annual meeting of the American Psychiatric Association, New Orleans, May 1 1-16, 1991. Received Jan. 25, 1991; revision received July 22, 1991; accepted Aug. 29, 1991. From McLean Hospital, Belmont, Mass., and the Department of Psychiatry, Harvard Medical School, and the Department of Epidemiology, Haryard School of Public Health, Boston. Address reprint requests to Dr. Shulman,

group

tients.

unipolar

20%

in this study

averaging

and the onset of mania (4-6). Furthermore, numerous depressive episodes often occur during the latency pression,

mania

mania.

of depres-

sion

period.

ofearly-onset

late-onset

Indeed,

few

elderly

subjects

with

bipolar

disorder

341

MANIA

AND

DEPRESSION

been studied knowledge, elderly tients

IN

separately this is the

OLD

AGE

from mania first reported

manic patients with agewith unipolar depression.

and

(13, 14). To our study comparing

RESULTS

sex-matched

Comparison

pa-

Each

Using

medical

record

data,

we

conducted

discharged

from

a chart

a private

re-

view

of all patients

hospital missions

in 1 980-1 987 to identify SO consecutive adof patients 65 years old or older who met DSMcriteria for a manic episode. Since the outcome

mental

were recorded in 1 990, the minimum follow-up 3 years and the maximum was 10 years. Subjects medical problems or cerebral-organic disorders not excluded. For each year’s group of manic pa-

tients, tients

a comparison group who met DSM-III-R

were

selected.

nia and included

of age-

sex-matched

pa-

criteria for major depression SO elderly patients with ma-

In this way,

SO elderly patients in the study. To

and

with select

major depression a homogeneous

were group

of depressed patients, patients suffering from bipolar depression at index episode were excluded. Information was recorded regarding demographic data, family history of affective disorder, and previous psychiatric and neurological tients at the hospital were

rologist.

We

recorded

history. routinely

the

All geriatric paassessed by a neu-

presence

of a neurological

disorder only when the evidence was clearly documented by the clinical consultation note or by a radiologic report. When there was any uncertainty as to the presence or absence of a neurological disorder, consensus was reached by the two raters (K.I.S. and G.M.).

To assess the reliability of the information from medical records regarding family history disorder,

type

of index

episode,

and

collected of affec-

presence

of pre-

existing neurological disorder, we compared the ratings of 12 randomly selected patients with blind ratings of the same patients made by one of us (M.T.). For all three variables there was full agreement on the 12 patients. The number and type of subsequent psychiatric hospitalizations

relatives, tings. tion,

were

determined

physicians,

The dates or death

and

of any occurring

by contacting

appropriate

hospitalization, during the

were recorded. Institutionalization placement in a supervised residential rest homes, homes for the aged, chronic trolled

care settings. Treatment in this naturalistic study.

To estimate the effects logistic regression models

patients,

institutional

set-

institutionalizafollow-up period

was defined as any setting, including nursing homes, or issues

were

not

con-

of risk factors simultaneously, (15) and the computerized Statistical Analysis System (SAS) (16) were used. We obtained adjusted odds ratios with 95% confidence intervals. Survivalcurves based on the Kaplan-Meier method (17) were used to estimate time to psychiatric rehospitalization, institutionalization, or death. We obtained adjusted hazard ratios (1 8) and their 95% confidence intervals, controlling for other variables, by using the SAS (19).

342

was

men.

women

METHOD

tive

group

(30%)

15

III-R data was with were

of Patients

The mean

mean

mania

range=65-83); pression group

Mania

composed

The

in the

With

Depression

of 35 (70%) age at index

group

was

the mean age was also 70

age at index

and

women

and

admission

70 years

of the

(SD=4.S,

of the women in the (SD=4.1, range=65-79).

admission

of the men

de-

in the ma-

nia group was 74 years (SD=7.0, range=65-85); the mean age of the men in the depression group was 72 (SD=4.7, range=66-79). No significant differences existed between the subgroups of manic and depressed patients. There was no significant difference in length of follow-up between the mania and depression groups.

The mean range=3-10). ity

was

follow-up Outcome

obtained

period was information

for

all

100

5.6 years regarding

patients

(SD=2.S, mortal-

either

by

direct

contact with patients and families or by referring to the official vital statistics records. Eighteen (36%) of the manic patients had evidence of neurological disorders, compared with four (8%) of

the depressed

patients.

The

difference

was

statistically

significant after adjusting for age, sex, and previous episodes (adjusted odds ratio=8.0, 95% confidence interval=2.3-27.4, p=O.OO1 ). Table 1 lists the type of neurological disorders evidenced by the 1 8 manic patients. Because of the retrospective nature of the study we did not attempt to establish an exact temporal relationship between first episode of mania and cerebral-organic disease.

The

manic

patients

tality rate than ratio=2.4, 95% after controlling

had

a significantly

higher

mor-

the depressed patients (adjusted hazard confidence interval=1.1-1 1.8, p=O.O2) for age, sex, previous episodes, and

neurological disorder. At the end of the follow-up, (50%) of the manic patients were dead compared 10 (20%) ofthe depressed patients. Figure 1 shows the

probability

low-up was polar major nia.

of remaining

approximately depression

By 10 years

alive

after

90% and 65%

S years

for patients for patients

25 with that of fol-

with with

unima-

probability of remaining alive for and 30%, respectively. With the use of survival curves we can estimate the probability of remaining alive for 10 years after being alive for S years; for manic patients this probability was 54% (0.35 divided by 0.65) and for depressed patients it was 82% (0.70 divided by 0.85). Only one death by suicide

each

group

was

reported-that

sion-in

the

was

75%

of a patient

the entire

study

with

unipolar

depres-

group.

The depressed patients had a shorter time to institutionalization (adjusted hazard ratio=3.6, 95% confidence

interval=1.1-S.4,

p=O.O2)

after

age, sex, previous episodes, and At follow-up, 18 (37%) of the were institutionalized compared manic

patients.

(Patients

who

died

ized were included in this analysis.) Twenty-six (52%) of the manic

AmJ

controlling

for

neurological disorder. 49 depressed patients with 13 (30%) of 44

Psychiatry

while

patients

149:3,

institutional-

compared

March

1992

SHULMAN,

TABLE

1. Demographic

and Clinical

Data for 18 Elderly Patients Age at Onset

Family

History

Patient

Sex

of Affective Disorder

With Mania and Neurological

TOHEN,

SATLIN,

at Index Hospitalization

Disorders

Age at First

of Affective

Manic

Disorder (years)

Episode (years)

Neurological

1

M

Negative

82

82

Chronic

2 3 4

F F F

Positive Negative Negative

20 SO 67

20 SO 67

Frontal Chronic Chronic

S

M

Negative

6

M

Negative

69 68

70 68

Chronic Cerebral

7

F

8

F

Positive Negative

41 39

46 43

Parkinson’s disease Right cerebral infarct

alcoholism,

peripheral

lobotomy, alcoholism, alcoholism,

Disorder

neuropathy

bilateral encephalomalacia dementia seizures/delirium

alcoholism, contusions

blackouts/delirium

9

F

Negative

83

83

Multiple

10 11

F M

Negative Negative

43 58

58 58

Encephalopathy/neuroleptic Closed head injury

12

M

13

F

Negative Positive

80 71

80 71

Recurrent cerebral contusions (boxing), lacunar infarct Left cerebral hemorrhage 20 years before onset of affective

14

F

15 16 17 I8

M M F F

Positive Positive

39 84

39 85

Cerebral Dementia

Negative Negative Positive

76 19 68

76 19 68

Embolic cerebral infarct, mild dementia Right capsular necrosis, cerebral vasculitis Parkinson’s disease

with

16 (32%)

of the depressed

patients

had

a positive

family history of affective disorder in a first-degree relative (odds ratio=2.3, 95% confidence interval=1.015.2, p=O.O4).

The

manic

patients

were

significantly

ET AL.

younger

cerebral

infarcts malignant

syndrome

disorder

infarct

(rheumatoid)

FIGURE 1. Cumulative Probability of Death for 50 Elderly Patients With Mania and 50 Elderly Patients With Unipolar Depression at Index Hospital Admission

at first

psychiatric hospitalization than the depressed patients (two-tailed t test=2.3, df=98, p=O.O2). The mean age at first psychiatric hospitalization of the depressed patients was 62.7 years (SD=1 1 .0, range=34-79). For the manic patients the mean age at first psychiatric hospitalization was 55.5 years (SD=18.8, range=19-84). Manic

Patients 0

Twenty-three

pitalized

(46%)

in a psychiatric

low-up

period.

ofthe

index

chiatric

Having

admission

interval=1.1-19.2,

logical justed

(odds

p=O.O3)

episodes.

after

Twelve

tutionalized Unlike

during Shulman

differences

tients tion,

adjusting

(24%)

the fol-

50 50

at the time

-46--

for

sex,

episode.

Twenty

(40%)

of the manic

previous were

insti-

and

no significant

depressed

pa-

disorders. In addi55 years predicted a

p=O.O4). The clinical

course

before

the index

admission.

logical disorder, and the 1 8 neurologically

Depressed

Am

J

Psychiatry

(x2=4.6,df=1,

1 49:3,

March

patients

of six manic

episodes

patients

episodes. manic

Six (33%) of patients had a

disorder in first-dewith 26 (52%) of all p=O.O3).

1992

10

8 4

2 1

experienced

but

not

de-

at a mean age of The mean latency

in these 20 patients There was a sig-

nificant difference in mean age at first men (mean=S8.7, SD=16.6, range=19-83) (mean=68.7, SD=1 3.2, range=42-85)

by manic

positive family history of affective gree relatives (table 1 ), compared

9

of

affective episode range=19-84).

terized

previous impaired

8

age,

Neuro-

period.

manic

7

24 18 Numb.r

from first depression to first mania was 14.9 years (SD=S.1, range=1-48).

patients

with respect to neurological an age at onset of more than

manic

6

-37-----31

-42

shorter time in remission until first psychiatric rehospitalization (adjusted hazard ratio=3.9, 95% confidence interval=1 .2-13.5) after controlling for age, sex, neuro-

so

5 VEAIATSK

for age, sex, and

(4), we found

the

4

pression as their first 47.5 years (SD=18.3,

the follow-up

between

3

2

institutionalization (adconfidence interval=1.2-

of the manic

and Post

during

adjusting

and age at first manic predicted 95%

1

rehos-

of subsequent psy95% confidence

ratio=4.6, after

were

disorder

was a predictor

disorder also odds ratio=7.7,

48.1,

unit at least once

p=O.OS)

episodes,

patients

a neurological

hospitalization

previous

sex

of the manic

mania between and women (t=2.0S, df=47,

patients depressive

was

characepisodes

Patients

Not surprisingly, in the depressed

older patients

95%

interval=1.0-1.4,

confidence

age predicted (adjusted

higher hazard

p=O.O2)

mortality ratio=1.2,

after

con-

343

AND

MANIA

trolling

DEPRESSION

IN OLD

for sex, previous

AGE

episodes,

and neurological

dis-

Genetic

loading

order. Also, depressed patients who had been institutionalized before the index episode had a higher mor-

manic though

tality

a less prominent associated with

(adjusted

odds

interval=1.0-287.7,

ratio=17.2, p=O.OS)

95%

after

confidence

controlling

for

age

and sex. In addition,

nonmarried status predicted institutionalization for the depressed patients (adjusted odds ratio=4.7, 95% confidence interval=1.2-1 8.6, p= 0.02) after controlling for age and sex.

patients genetic

history higher family

be more

of a factor

in elderly

role in old age (22), mania has been a higher prevalence of positive family

than has unipolar depression (23). We found a proportion of manic patients with a positive history of affective disorder (52%) than has been

reported in other studies plied the same assessment comparison tive family

DISCUSSION

may

than in elderly depressed patients. Alfactors are generally considered to play

group history.

(5, 6, 12). measures

However, we apto the depression

and found that only The manic patients

32% had a posihad an earlier

particular,

the

prevalence

of cerebral-organic

disorder

age at onset of first psychiatric hospitalization than the depressed patients. An earlier age at onset is associated with a positive family history (5, 6). Even in old age, manic patients appear to be genetically predisposed to

was

to be significantly

higher

patients

affective

This study supports ings of earlier studies found

a number of elderly

of hypotheses manic patients

and find(4-6). In

in manic

(36%) than depressed patients (8%). Neurological ders were heterogeneous in nature and nonspecific regard

to brain

location.

As in previous

lence of Alzheimer-type expected

related

proportion

disorders

neurological brovascular

dementia in the

studies,

with

the preva-

was no higher

general

disor-

than

population.

the

Alcohol-

accounted

impairment disease

was

for four of the 1 8 cases of in the manic patients, and cereevident in six of the 1 8 patients.

Despite the uncertain relationship der to the onset of mania, a unique

of neurological

disor-

disorder

but perhaps

less so than

ies of old age

(4, 5). The

found in other studies was 29 years only three of our SO elderly manic

tients

had suffered

average

from

than 30. A study compared elderly

age at onset

mania

when

they

were

close temporally

a high mortality rate? This raises questions damental differences between early-onset

category

of

patients

with

They

“secondary

seemed mania”

to fit the described

by Krauthammer and Klerman (20), associated with a relatively lower rate of genetic predisposition to affective disorder. This is in marked contrast to the long latency from first depression to manic episode for many of the elderly manic patients who did not have evidence of neurological disorder. Manic patients experienced a poor outcome, suffering a significantly higher mortality rate. Half of the manic patients were dead after almost 6 years of followup, compared with 20% of the depressed patients. This high mortality rate has not been reported in follow-up studies of patients with early-onset mania (21). The higher mortality rate among manic patients may account for the relatively shorter time to institutionalization for depressed patients. For elderly manic patients whose first psychiatric hospitalization was for depression, an average of 15 years elapsed before mania became manifest. This is suggestive

of a “conversion”

that

may

be due

to factors

different from those operating in patients with obvious neurological disorders. It should be emphasized that this retrospective study used coarse measures of cerebral-organic disorder. Therefore, we may have underestimated the true role of cerebral dysfunction, especially subtle cerebrovascular pathology. With newer imaging

techniques

such

as magnetic

ing, positron emission tomography, emission computed tomography,

ied more accurately.

344

resonance

imag-

and single photon this issue can be stud-

and

younger

found

a higher

prevalence

patients-7.3%

patient

with

of “early-

(23, pa-

younger

of university clinic outpatients patients with young depressed

tients

patients.

manic

onset” mania 24). Indeed,

pattern appears to be evident in these 1 8 patients. The age at first mania and age at onset of affective disorder were the same or very in these

young

patients (23). Overall, age at onset of mania was late in life (mean= 55.5 years), a finding that is consistent with other stud-

versus

bipolar

disorder

(25) pa-

of mania

1.4%. burn

Does

out

in the

the young

(26)

or is there

about funand late-on-

set mania.

Our

data

Akiskal

( 1 0), which tive disorder. nia,

are consistent

(9)

and

the

with

the spectrum

threshold

theory

theory

of Tsuang

consider mania a more severe form Controlled studies of the treatment

particularly

with

lithium

carbonate,

are

of et al.

of affecof maneeded

to

explore the hypothesis that mania in old age represents a manifestation of greater CNS vulnerability (27). As a group, the SO elderly manic patients in this study had a genetic predisposition to affective disorder that became manifest relatively late in life. This applies especially

to the manic

orders.

With

growing

greater

numbers

patients

interest

of patients

without

coarse

in elderly will

brain

manic

be available

dis-

patients, for study.

Furthermore, the advent of new technologies (28, 29) and advances in our conceptualization of affective disorders should help to clarify the special meaning and importance of mania in old age. We have highlighted two distinct subgroups of patients with mania in old age: 1) patients whose first episode of affective disorder is depression

and

who

have

a long

latency

period

before

they experience their first episode of mania and 2) those suffering from secondary mania associated with neurological disorders, whose mania is often their first affective

episode

or follows

closely

depression. Further studies should focus on its distinct pression

that

begins

and

its

early

after

their

first episode

of

of mania in the elderly nature compared with de-

fundamental

difference

from

mania

in life.

Am

J

Psychiatry

149:3,

March

1992

SHULMAN,

User’s Guide, Version Institute, 1986

REFERENCES I . Spicer

CC, Hare

depressive

EH, Slater

illness:

evidence

plc. Br J Psychiatry 2. Eagles JM, Whalley first onset Psychiatry

E: Neurotic from

and psychotic

age-incidence

I 973; 123:535-541 U: Ageing and affective

of affective disorders 1985; 147:180-187

forms

in a national

disorders:

in Scotland,

of

I 969-1978.

Br

J

1980;

Int

J

Geriatr

1990;

disorders:

is there

evidence

supporting

the disPsychiatry

tinction between unipolar and bipolar disorders? Br J 1985; 146:268-271 1 1 . Shulman K: The influence of age and ageing on manic disorder. IntJ Geriatr Psychiatry 1989; 4:63-65 12. Glasser M, Rabins P: Mania in the elderly. Age Ageing 1984; 13: 13.

210-213 Murphy

E: The

prognosis

ofdepression

in old

try 1983; 142:111-119 14. Baldwin RC, Jolley DJ: The prognosis BrJ Psychiatry 1986; 149:574-583 15. Rothman KJ: Modern Epidemiology.

age.

BrJ

of depression

20.

22.

Boston,

Little,

Brown,

Am

J

FE: The logist

Psychiatry

1 49:3,

procedure,

March

in SUGI

1992

User’s

Guide,

Supplemental

Library

The

life tables.

ET AL.

NC,

SAS

of Failure

I 980 J R Stat Soc Series B

in SUGI

5. Edited

Cary,

Analysis

& Sons,

procedure,

Version

RP.

Statistical

and

analysis. Arch Gen Psychiatry Mendlewicz 5, Fieve R, Rainer

by Hastings

Supplemental RP. Cary,

LiNC,

1 990;

47:1106-1111

J, Fleiss JL: Manic depressive illness: a comparative study of patients with and without a family history. Br J Psychiatry 1972; 120:523-530 Winokur G: Mania and depression: family studies and genetics in relation

to treatment,

in Psychopharmacology:

of Progress. Edited by Lipton York, Raven Press, I 978 24.

by Hastings

Wiley

models

SATLIN,

SAS Institute, 1986 Krauthammer C, Klerman GL: Secondary mania: manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry 1978; 35:1333-1339 Tohen M, Waternaux CM, Tsuang MT: Outcome in mania: a four year prospective follow-up of 75 patients utilizing survival

Goodwin

FK, Jamison

KR:

A Generation

MA, DiMascio

A, Killam

Manic-Depressive

Illness.

KF. New New

York,

Oxford University Press, I 990 25. Muserti L, Perugi G, Soriani A, Rossi VM, Cassano GB, Akiskal HS: Depression before and after age 65: a re-examination. Br J Psychiatry

26.

Winokur

27.

depressive Himmelhoch

1989;

28.

JM,Neil

and

1980; 137:941-945 SchwartzJM, Baxter LRJr, MazziottaJC, The differential diagnosis ofdepression:

O’Connell computed diagnosis

studies dichotomy.

tomography

Gerner RH, Philps MC: relevance ofpositron emis-

of cerebral glucose metabolism JAMA 1987; 258:1368-1374

RA, Van Heertum H,

and course

in manic 1975; 16:125-13 1 May SJ, Fuchs CZ, Licata SM: Age, lithium response. Am J Psychiatry

JF,

dyskinesias,

sion tomography polar-unipolar

29.

155:330-336

G: The Iowa 500: heterogeneity illness (bipolar). Compr Psychiatry

dementia,

tial

Harrell

John

Regression

A, Notardonato

1986 16.

23.

Psychia-

in old age.

RL:

York,

19.

5:215-222

Akiskal H, Walker P, Puzantian VR, King D, Rosenthal TL, Dranon M: Bipolar outcome in the course of depressive illness. J Affective Disord 1983; 5:115-128 8. Leonhard K, Korffl, Schulz H: Die Temperamente in den Familien der monopolaren und bipolaren phasischen Psychosen. Psychiatr Neurol 1962; 143:416-443 9. Akiskal H: Diagnosis and classification of affective disorders: new insights from clinical and laboratory approaches. Psychiatr Developments 1983; 2:123-160 10. Tsuang MT, Faraone SV, Fleming JA: Familial transmission of affective

DR:

Prentice

1972; 34:187-220 Harrell FE: The PHGLM

7.

major

New

Data.

Cox

21.

136:26-32

Psychiatry

JD,

Time

brary

S. Stone K: Mania in the elderly. Br J Psychiatry 1989; 155:220224 6. Broadhead J, Jacoby R: Mania in old age: a first prospective study.

Kalbfleisch

I 8.

the age at

3. Weissman MM, Leaf PJ, Tischler GL, Blazer DG, Karno M, Bruce ML, Florio LP: Affective disorders in five United States communities. Psychol Med 1988; 18:141-153 4. Shulman K, Post F: Bipolar affective disorder in old age. Br J Psychiatry

17.

sam-

5. Edited

TOHEN,

Luck

RL, Billick

D, King

(SPECT)

of psychiatric

LN:

with

disorders.

SB, Holt AR, Gonzalez Single

[123I]IMP

J

to the bi-

photon

emission

in the differen-

Neuropsychiatry

I 989;

1:145-153

345