Journal of Affective Disorders, 5 (1983) 115 128

Elsevier Science Publishers

115

Bipolar Outcome in the Course of Depressive Illness

Phenomenologic, Familial, and Pharmacologic Predictors

H a g o p S. Akiskal 1,2 Parks Walker 2 Vahe R. Puzantian 1,, D o u g

King 1'**, Ted L. Rosenthal i and M a r t h a D r a n o n 2
I Affective Disorders Program, Department of Psychiatry, Universi(v of Tennessee College of Medicine, and
2 Northeast Men tal Health Center, Memphis, TN (U.S.A.
(Received 5 May, 1982)
(Accepted 20 August, 1982)

Summa~
Twenty percent of a cohort of 206 outpatient depressives with no past bipolar
history switched during prospective observation. These 41 probands developed
manic periods on the average of 6.4 years (median 4, range 1 25) after their first
depressive episode. The change in polarity occurred throughout the life span, but
was most common in adolescence and early adulthood. The following variables were
found useful in predicting this outcome: onset < 25 years, bipolar family history,
loaded pedigrees, precipitation by childbirth, hypersomnic-retarded phenomenology,
and pharmacologically-mobilized hypomania. Although the respective sensitivities of
these findings were relatively low (32-71%), their specificities ranged from 69% to
100% for bipolar outcome; the diagnostic specificity of any 3 of these variables when
combined was 98%. When compared with nonbipolar depression, bipolar disorder
was seldom chronologically secondary to nonaffective psychiatric disorders. These
findings suggest that many young depressives with lethargy and oversleeping are not
manifesting a "neurotic" disorder, but rather a precursor of primary bipolar
affective disorder. Finally, a psychotically depressed adolescent or young adult with
Preliminary data from this study were presented at the 6th World Congress of Psychiatry, 27
August 3 September, 1977, Honolulu, Hawaii.
The writing of this paper was in part supported by the Tennessee Department of Mental Health and
Mental Retardation, Nashville, and USPH MH-06147 and MH-05931 from the National Institute of
Mental Health, Rockville, MD.
Correspondence to: Dr. H.S. Akiskak Suite 633, U T Department of Psychiatry, 66 North Pauline
Street, Memphis, TN 38163, U.S.A.
* Deceased, 3 April, 1982.
** Currently with Department of Psychiatry, University of Michigan, A n n Arbor, MI, U.S.A.
0165-0327/83/0000 0000/$03.00 ) 1983 Elsevier Science Publishers

116
positive bipolar family history should be observed for eventual bipolar outcome,
especially when the clinical presentation is that of stupor.
Key words: Bipolar

illness
Familial predictors
Follow-up
course
Hypersomnic-lethargic depression - P h a r m a c o l o g i c h y p o m a n i a

Introduction

The criteria for major depression, especially in their current broadened version in
D S M - I I I (1980), select a heterogeneous group of conditions, some of which fall
outside the domain of primary affective disorders. By contrast, bipolar illness (as
defined in DSM-III) is a relatively distinct psychopathological entity. As depressive
manifestations often precede manic symptoms by many years (Perris 1969; Angst
1974), the question arises whether the clinician can predict which clinically depressed
individual will eventually develop this illness. The transformation to mania occurs in
4-33% of depressives (reviewed in Clayton 1981), higher rates being found in
recurrent depressions (Akiskal et al. 1979), endogenous depressive psychoses (Rao
and N a m m a l v a r 1977), and in long follow-up studies (Winokur et al. 1982). Dunner
et al. (1976) have reported that most switches occur within 18 months from the first
depressive episode. However, bipolar transformations one or more decades after first
depressive episodes are not uncommon (Rao and N a m m a l v a r 1977; Shulman and
Post 1980).
The purpose of this study is to identify factors that would prospectively predict
the development of a manic episode in the course of a depressive disorder. Such
prediction is important from theoretical and nosologic standpoints, and may be
useful for treatment planning.
In previous prospective research, we have shown that the future occurrence of
spontaneous manic episodes in depressed patients could be successfully predicted
from a cyclothymic premorbid temperament (Akiskal et al. 1977), or the development of brief hypomanic responses to antidepressants (Akiskal et al. 1979). We
suggested that bipolar outcome was also related to family history for bipolar illness,
especially in a "loaded" multigenerational pattern of transmission. This suggestion
was based on the finding that these familial parameters were associated with a
primary depressive outcome in 40 of 100 neurotic depressives; the number of bipolar
transformations was too small to test whether those familial parameters were specific
for all primary depressions, or for the primary bipolar subgroup alone. The present
investigation addresses that question with a larger number of depressives who
developed manic symptoms during prospective follow-up.

Methods
Patients and controls

From a total of 206 consecutive depressed outpatients with no past history for

117
manic and hypomanic symptoms or cyclothymic disorder prior to entry into our
clinic - 41 developed mania during an average prospective follow-up period of 3
years (range 1-9). They will be henceforth referred to as the "bipolar group". Their
mean age at index depressive episode was 31.4 years (range 14-67). Ninety percent
of these patients were in their first, second, or third episode of depression, and the
remaining 10% had had up to 6 episodes.
The 41 control subjects were selected by taking every fourth of the remaining 165
depressives who failed to convert to bipolar illness during an equivalent period of
prospective follow-up. Accordingly, they were designated as "nonbipolar controls".
Their mean age at index episode was 41.4 years (range 18-78). Most were in their
first or second depressive episodes.
About 50% of each group had been hospitalized for depression on at least one
previous occasion. One-third of each group was black, and social class was about
equally distributed among the Hollingshead-Redlich classes I I - I V .

Procedures and diagnostic criteria

The clinical procedures adhered to in our mood clinic program have been
previously described in great detail (Akiskal et al. 1978) and will be briefly
mentioned here. Private and nonprivate patients with affective disorder receive
comprehensive psychiatric evaluation, usually in a semistructured format, and are
routinely followed up on a prospective basis as warranted by their clinical condition.
The diagnostic criteria are largely based on the Washington University approach
(Feighner et al. 1972). One modification we have introduced is to ignore the presence
of alcohol and drug dependence in making the primary-secondary distinction in
depression if full-fledged depression develops outside the time frame of a detoxification period; this is in accordance with recent recommendations by Feighner (oral
communication, October, 1980), based on the observation that substance abuse may
complicate the early course of affective disorders. A second modification is to
consider a duration of 1 week sufficient for the diagnosis of mania (DSM-III 1980).
Finally, we define "pharmacologic-hypomania" (Bunney 1978), not specifically
identified in the Feighner system, as an affective state (1) meeting the criteria for
mania or probable mania, (2) lasting for as few as 2 days, and (3) when occurring
not later than 4 weeks after initiation of antidepressant treatment (Akiskal et al.
1979).
Variables examined
Depressions were categorized as hypersomnic-retarded if they exhibited both
hypersomnia and psychomotor retardation (anergic depressions with oversleeping),
psychotic if delusions or hallucinations were present, chronic if duration was longer
than 2 years, and postpartum if they occurred within 3 months of childbirth.
Onset of illness was the age at first depressive manifestation requiring clinical
attention; this age did not necessarily coincide with the age at index episode. The
duration of years until mania was the latency from age of onset to the age of first
manic episode at prospective follow-up (Fig. 1). We excluded probands who had
experienced manic symptoms prior to the period of prospective follow-up. This was

118

to ensure that data on phenomenologic, familial-genetic, and pharmacologic factors

- hypothesized as potential predictors of bipolar outcome - were collected before
the occurrence of mania. To exclude past history of mania and cyclothymia,
available past records were carefully examined, and both patients and significant
others were interviewed. First periods of depression were experienced on the
average, a few years before the index episode. This was easily verified; in the few
patients whose onset of illness occurred 10 or more years prior to index episode, two
of us (HSA and PW) - having trained, taught, and practiced in Memphis during that
period of time - had the advantage of knowing them from previous hospitalizations
or outpatient visits before our clinic was established.
In one-third of the sample, family history for affective disorders was obtained by
the guidelines developed in the Research Diagnostic Criteria - Family History
version (Andreasen et al. 1979). In another third, affected relatives were patients
under our care; the remaining third were specifically interviewed for diagnostic
evaluation by the Feighner criteria (1972). In other words, evidence for familial
psychopathology was gathered through a combination of family interview (two-thirds)
and family history (one-third) methods.
Pedigrees were examined for: (1) the presence of bipolar illness: (2)
consecutive-generation (or multigenerational) transmission, i.e., when members in
probands' offspring or parental and grandparental generation were affected without
skipping a generation; and (3) "loaded" patterns, i.e., when at least 3 family members
beyond the proband were affectively ill. As shown in Fig. 2, a pedigree can be

;:0

First Episode
of Depression

l
_

Index Episode
of Depression

,4

TT[

3
O

o0
"o
o

Mania

No Mania

BIPOLAR
GROUP

NONBIPOLAR
CONTROLS

Fig. 1. Design of study.

Fig. 2. Consecutive-generation (top) and loaded (bottom) pedigrees.

119

multigenerational without being loaded, but virtually all loaded pedigrees are
multigenerational. Our approach to patterns of pedigree analysis has been fully
described elsewhere (Akiskal et al. 1979).

Hypotheses
The data on clinical and familial correlates - explored in this study as potential
predictors of bipolar outcome - were collected at index episode, i.e., prior to the
development of mania. The hypotheses tested, based on previous work by our group
(Akiskal et al. 1979) and on literature reviews on unipolar-bipolar differences (Fieve
and Dunner 1975; Depue and Monroe 1978) predicted that bipolar outcome in
depressive illness would be positively correlated with:
(1) Onset in young adulthood (_< 25 years);
(2) Hypersomnic-retarded depressive phenomenology;
(3) Psychotic depression;
(4) Postpartum depressive episode;
(5) Bipolar family history;
(6) Loaded pedigrees;
(7) Consecutive-generation pedigrees;
(8) Pharmacologic-hypomania in the course of antidepressant treatment.
We also predicted that two factors would be negatively associated with bipolar
outcome:
(1) Chronicity of depression;
(2) Depression chronologically following a nonaffective psychiatric disorder.

Statistical techniques
The 2-group continuous data were analyzed by Z-tests (since each group N was
> 30). Categorical data were analyzed by chi-square (1 df) when all assumptions of
the technique could be met; all other categorical data analyses used Fisher's exact
test (McNemar 1962). Although the direction of virtually all differences was correctly predicted in advance, we conservatively used two-tailed statistics.
The diagnostic performance of the variables explored for their association with
bipolar outcome was analyzed according to Vecchio's approach (1966):
(1) Sensitivity refers to the percentage of bipolars who exhibit the variable; it
measures the true positive rate in the bipolar population.
(2) Specificity is the percentage of nonbipolars who do not exhibit the variable; it
identifies the proportion of accurately diagnosed nonbipolars (true negatives). Thus,
the smaller the false positive rate, the more specific the test.
(3) The diagnostic confidence refers to the certainty with which a bipolar diagnosis
can be entertained in the presence of a given variable. It is computed by dividing the
number of bipolars with the variable by the total number of subjects (bipolar and
nonbipolar) exhibiting the variable, and expressing the result as a percentage.

120

Results
Age of onset and switch
Forty-one of the 206 depressives (20%) developed mania during the period of
prospective observation. As shown in Fig. 3, patients who eventually switched to
bipolar illness were significantly younger at onset than those who did not, by the
critical ratio test ( Z = 3.00, P = 0.003). This was largely contributed by the fact that
71% of onsets in the bipolar group were before age 25, as compared with 32% in the
nonbipolar group.
The age at bipolar transformation ranged from 14 to 73 years, with a mean of
32.3. As shown in Fig. 4, it occurred on the average 6.4 years (median 4 years) after
onset of first depression (range 1-25). Only in 7 patients was the shift a direct
extension of the first episode. The greatest number of depressive episodes before
mania was 8. Most patients developed mania after 2 4 depressive episodes. In
general, the higher the episode frequency, the shorter was the time from onset to
bipolar transformation. For instance, the 3 patients who did not develop mania until
23-25 years after first depressive attack had suffered 3 - 4 depressive episodes.

80

70

60

"

5O
e-"

12)
'4-"
0
Q)

40

30

.21==

05

20

0 0ii0 0

"

Mean _+SO
26.1 -+ 13.3

Mean :t SO
3 5 . 5 15.'3

I0

Bipolar Nonbipolor
Fig. 3. Distribution, median (transverse lines) and mean age of onset of depression in bipolar and
nonbipolar groups.

121

t/)

I0

12

14

16

le

20

22

24

26

Interval (in years) Between First Depression

and Onset of Mania
Fig. 4. Distribution of cases according to interval from first depression to first mania.

Clinical features
T h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e i n s e x r a t i o b e t w e e n t h e t w o g r o u p s ( T a b l e 1).
As expected from epidemiologic considerations, women outnumbered men in both
groups - especially in the nonbipolar group; the ratio of women to men was
s o m e w h a t s m a l l e r in t h e b i p o l a r g r o u p .
Hypersomnic-retarded
phenomenology,
psychotic depression, and postpartum
episodes were significantly more common
i n t h e b i p o l a r g r o u p ( T a b l e 1). B y
contrast, nonbipolar depression was significantly more likely to develop in the
setting of a nonaffective disorder (most typically an anxiety disorder) and to follow

TABLE 1
COMPARISON OF BIPOLAR A N D NONBIPOLAR GROUPS
Variable

Female sex
Hypersornnic-retarded
depression
Psychotic depression
Postpartum episode
(history) a
Chronic depression
Depression superimposed on
nonaffective disorder
Pharmacologic hypomania
Bipolar family history
Loaded pedigree
Consecutive-generation
affective family history

Bipolar group
(N = 41)

Nonbipolar group
( N = 41)

Statistics

25

61

29

71

X 2 = 0.87

NS

24
17

59
42

5
6

12
15

X 2 = 19.26
X 2 = 7.31

< 0.001
< 0.01

7 (7/12) a
4

58
10

1 (1/16) "
15

6
37

Fisher's
Fisher's

< 0.01
< 0.01

2
18
17
13

5
32
56
32

11
0
1
2

27
0
2
5

Fisher's
Fisher's
Fisher's
Fisher's

<
<
<
<

16

39

17

X 2 = 6.21

< 0.02

0.01
0.001
0.001
0.002

a The denominator for postpartum episodes was not 41, because it is based on the number of women in
each group who had childbirth.

122
an intermittent course; one-third of the nonbipolar group was "secondary" in this
sense. Interestingly, 3 of the 4 patients in the bipolar group designated as "chronic",
had developed mania superimposed on a dysthymic-type illness of adolescent onset.
The other chronic patient had suffered from a phasic obsessive-compulsive disorder
with chronic secondary depression and switched at the age of 45; the manic episode
occurred after 12 weeks of treatment with 60 r a g / d a y of phenelzine and did not
respond to phenelzine discontinuation, necessitating the use of lithium carbonate.
One other bipolar patient had a chronologically antecedent nonaffective psychiatric
disorder - mental retardation (IQ = 55).

Pharmacologic hypomania
Hypomanic responses to antidepressant drugs were considered pharmacologically-occasioned if they occurred within 4 weeks of drug treatment. Indeed, most
occurred in 7-12 days, were not behaviorally disruptive, and tended to subside upon
downward adjustment of antidepressant dosage. This response was exclusively
limited to 32% of the group that eventually developed mania during prospective
follow-up (Table 1).

Family pedigrees
Bipolar family history had a highly significant association with bipolar outcome,
followed by loaded pedigrees, and consecutive generation family pedigrees (Table 1).

Sensitivity, specificity, and predictive strength

Table 2 summarizes the diagnostic performance of those parameters that were
shown to distinguish the bipolar and nonbipolar groups in the above statistical
comparisons. The four most sensitive indices are onset in young adulthood (71%),
hypersomnic-retarded features (59%), postpartum episodes (58%), and bipolar family
history (56%). However, of these, only bipolar family history seems to have a very
TABLE 2
SENSITIVITY, SPECIFICITY AND PREDICTIVE VALUE OF VARIABLES SIGNIFICANTLY
ASSOCIATEDWITH BIPOLAROUTCOME
Variable

Sensitivity (%)

Specificity (%)

Predictive
value (%)

Onset _<25 years

Hypersomnic-retarded
depression
Psychotic depression
Postpartum onset
Pharmacologic hypomania
Bipolar family historyLoaded pedigrees
Consecutive-generation
affective family
history

71

68

69

59
42
58
32
56
32

88
85
84
100
98
95

83
74
88
100
94
87

39

83

72

123
high degree of specificity (98%) for predicting a bipolar outcome. Pharmacologic-hypomania and loaded pedigrees, although low in sensitivity (32%), emerge as parameters with very high specificity (95-100%). The diagnostic confidence of these
parameters ranged from 69% to 100%. In combination, when any 3 of these
parameters listed in Table 2 were present, sensitivity went down to 24%, specificity
reached 98%, and diagnostic confidence was 91%.

Discussion

One out of 5 depressives developed mania during prospective observation. This

relatively high rate (20%) of switches from depression to bipolar illness is in line with
previous reports (Rao and Nammalvar 1977; Akiskal et al. 1 9 7 8 ) a n d recent
evidence regarding higher than the conventionally low bipolar-unipolar ratio when
systematic search for elevated periods is made (Egeland 1982).

lnterval from depressive onset to first manic episode

Although change from depression to mania most commonly occurred in young
adulthood, the phenomenon was not restricted to that age group and was distributed
throughout the life span. As a result, the mean interval of 6.4 years from depression
to mania (with a median of 4 years) is longer than that reported in other studies, but
in accord with Shulman and Post (1980). This is partly due to the fact that we
considered the age of first depression requiring clinical attention - w h e t h e r endogenous or not, primary or secondary, hospitalized or not - as the onset of the illness;
in other studies onset was based on endogenous (Rao and Nammalvar 1977),
primary (Dunner et al. 1976), and hospitalized episodes (Winokur et al. 1982).
Since the longest period of prospective observation was 9 years, it is possible to
argue that retrospective anamnesis missed hypomanic or mild manic episodes in
those cases where the interval from depression to mania was longer. This is unlikely
in view of the fact that other systematic studies in three countries on different
continents, by Winokur et al. (1982) in the U.S., Shulman and Post (1980) in Great
Britain, and Rao and Nammalvar (1977) in India, have reported similar findings.
It has been suggested that the development of mania in old age is possibly due to
organic cerebral pathology (Spicer et al. 1973; Shulman and Post 1980). This is a
plausible explanation for late onset "pure" manic states that occur in the absence of
depression and are considered secondary to medical illness (Krauthammer and
Klerman 1978), or "unipolar" manias (Abrams and Taylor 1974; Taylor and
Abrams 1982). It is also possible to argue that in some patients with recurrent
depressions, such a "secondary" or "organic" manic state can be by chance
superimposed on the course of their illness in old age. However, concurrent medical
disorders known to precipitate mania were not observed in this cohort. In our
experience, manic states in old age (1) are, in general, phenomenologically indistinguishable from early onset manias, (2) the specificity of the contribution of
organic cerebral factors to their etiology is difficult to establish, and (3) response to
treatment and prognosis need not be unfavorable. Wertham (1929) and Roth (1955),

124

on the other hand, have reported a relatively poor prognosis for late onset manic
states; this may have been due to the unavailability of potent antimanic agents for
general clinical use when these studies were conducted.

External validating criteria for bipolar disorder

The results of the present study may help in defining a depressive profile which is
most likely to convert to bipolar illness during prospective follow-up. Our data
support the literature on unipolar-bipolar differences based on retrospective studies
(Fieve and Dunner 1975; Depue and Monroe 1978). They do not necessarily prove
that unipolar and bipolar disorder are separate entities; they suggest, however, that
within the universe of depressed patients there exists a subgroup with lowered
threshold for experiencing manic episodes. We propose to define this diathesis by
familial bipolar illness and multigenerational loaded pedigrees (Winokur et al. 1969),
expressing itself throughout life, but most typically before age 25, and possibly
activated by childbirth (Reich and Winokur 1970; Brockington et al. 1981) or
antidepressant drug challenge (Bunney 1978).
In previous work (Akiskal et al. 1979), we have found that pharmacologic-hypomania, bipolar family history, loaded pedigrees, and consecutive-generation family
history are associated with primary depression. Table 3 compares the diagnostic
performances of these variables for primary depression with that for bipolar depression. As expected, these variables generally appear to be more sensitive indicators of
bipolar than primary outcome, with relatively little loss of specificity and predictive
strength. However, consecutive generation family history appears less specific, and
does not predict bipolar outcome as well as it does primary outcome. This finding
suggests that consecutive-generation family history better discriminates primary
from secondary than bipolar from nonbipolar depression.
From a familial-genetic standpoint, these findings suggest that primary affective
disorders form a spectrum (Gershon et al. 1975; Smeraldi et al. 1977; Taylor and
Abrams 1980) characterized by multigenerational occurrence in a loaded pattern and
that a special threshold for the bipolar diathesis
which may be activated by

TABLE 3
COMPARISON OF DIAGNOSTIC PERFORMANCE OF PHARMACOLOGIC AND FAMILIAL
VARIABLES FOR PRIMARY VERSUS BIPOLAR DEPRESSION
Predictor

Sensitivity (%)

Specificity (%)

Primary

Primary

Bipolar

Predictive
strength (%)

Bipolar
Primary

Bipolar

Pharmacologic hypornania

25

32

100

100

100

100

Family history:
bipolar illness
loaded pedigrees
consecutive-generation

20
38
20

56
32
39

98
97
98

98
95
83

89
88
89

94
87
72

125

pharmacologic challenge (Bunney 1978) - is clinically manifested by full-fledged

manic episodes during the longitudinal course of the illness.

Onset of bipolar illness with hypersomnic-retarded depression in adolescents and young

adults
Our data confirm that depressive onsets are common in bipolar illness (Perris
1969) and that adolescence and early adulthood are high risk periods for this illness
(Carlson and Strober 1978; Loranger and Levine 1978; Coryell and Norten 1980).
Clinically it is important to identify potential bipolar depressives among juvenile
and young patients (Hassanyeh and Davison 1980) because this form of affective
disorder can lead to serious personal, marital, and vocational incapacitation, has a
high suicide potential and, most importantly, exhibits a relatively specific pharmacologic response profile (Dunner 1980). There is a clinical stereotype which equates
anergic, inhibited, lethargic, and hypersomnic depressions with "neurotic" illness
(Hartmann 1980). Our data, in line with suggestions made by the Pittsburgh group
(Kupfer et al. 1975), provide evidence for considering these patients as "latent"
bipolars. Indeed, pharmacologic challenge to elicit brief switches to hypomania can
be used as a "provocative test" (Akiskal 1978, 1980) to ascertain whether these are
in the spectrum of bipolar disorders (Klerman 1981) considered "atypical" in
DSM-III (1980) and bipolar II by Fieve and Dunner (1975). The subsequent
development of a spontaneous manic episode leaves little doubt about the bipolar
nature of this disorder. In more severe cases, hypersomnic-retarded features may
present as stupor, which is often misdiagnosed as "catatonic schizophrenia".
Pharmacologic mobilization of hypomania
The 32% rate of bipolar switches on antidepressants is higher than that reported
in the literature based on retrospective chart review (Bunney 1978; Nasrallah et al.
1982). Our observations (Akiskal et al. 1977, 1979, 1980) based on prospective
follow-up have suggested the importance of considering mild hypomanic states of
durations as short as 2 days.
It is legitimate, however, to argue whether the production of hypomania during
antidepressant treatment represents pharmacologic induction or a behavioral response that would occur in the natural course of the disorder (Prien and Coffey
1977; Lewis and Winokur 1982). The early occurrence of this phenomenon during
antidepressant treatment and the subsequent disappearance with reduction of drug
dosage support a direct relationship between the pharmacologic challenge and the
behavioral response. Nevertheless, the presence of bipolar family history in almost
all of these patients, the virtual absence of the phenomenon in nonbipolar patients,
and the subsequent development of spontaneous mania, suggest that the introduction of pharmacotherapy is merely activating or mobilizing a latent biologic potential and not producing a phenomenon de novo. Therefore, "pharmacologically-mobilized" would be a more precise designation than what is sanctioned in the literature
as "pharmacologically induced" hypomania (Murphy et al. 1971).
Does "'secondary'" bipolar disorder exist?
The conversion of 3 teenage onset dysthymic patients to bipolar illness is in

126
accord with previous reports by our group (Akiskal et al. 1980; Rosenthal et al.
1981) about the relationship between a special subgroup of dysthymic disorders and
bipolar illness. By contrast, most chronic depressions
occurring largely in the
setting of nonaffective disorders such as anxiety disorders
display no bipolar
tendencies (Akiskal et al. 1981).
The two exceptions to the nonconversion of such secondary depressions to
bipolar illness in our series deserve further comment. The occurrence of bipolar
illness in mental retardates has been previously observed (Reid 1972; Carlson 1979)
and is best considered to be a chance association; the coexistence of the two
disorders is noteworthy because the presence of mental retardation creates difficulties in recognizing a concurrent primary mood disorder (Akiskal and Puzantian
1979). Although the occurrence of bipolar illness in the setting of an obsessional
illness can also be ascribed to chance, there are some grounds for considering phasic
obsessional disorders as bipolar affective equivalents (Slater and Roth 1969).
The above considerations suggest that bipolar illness rarely arises in the setting of
a validated nonaffective disorder. Although " p u r e " mania can be secondary to a
variety of medical conditions (Krauthammer and Klerman 1978), mania as part of
bipolar illness is almost always a primary affective disorder (Goodwin and Guze
1980). In brief, if alcohol and drug abuse - as frequent early manifestations or
complications of bipolar illness are excluded from consideration when making the
primary-secondary distinction, there probably is no such entity as "secondary
bipolar illness".

Conclusion
Transformation of depression to bipolar disorder is not an uncommon outcome,
but it tends to be limited to certain predisposed individuals with primary affective
disorder. Various clinical, familial-genetic, and pharmacologic parameters we have
studied can be used to predict such an outcome with confidence levels ranging from
69% to 100%. Our data concur with those of a recent study by Strober and Carlson
(1982) on juvenile bipolar illness.
Depressed young adults experiencing lethargy and oversleeping (often considered
to be "neurotically" depressed) or a retarded psychotic depression (often misdiagnosed as catatonic schizophrenia) should be clinically observed for the eventuality
of bipolar outcome when family history is positive for bipolar illness or is affectively-loaded. By contrast, depressions without psychotic features, chronic in course,
or chronologically superimposed on nonaffective psychiatric disorders, are least
likely to convert to bipolar disorder. Our results suggest that descriptive variables
can serve as objective clinical markers for predicting diagnostic outcome in psychiatry.

Acknowledgements
Jan Amberson provided assistance with data analyses, and Christy Wright
provided editorial assistance.

127

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