Volume 44, Issue 2, Pages 102-109 (March 2003)

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Is there a link between atypical and early-onset “unipolar” depression and bipolar II disorder?☆☆☆

Abstract

The aim of the present study was to determine whether there is a link between “unipolar” depression with atypical features and early onset, and bipolar II disorder, using atypical features and early onset as markers of bipolarity. A total of 158 consecutive unipolar and 234 bipolar II major depressive episode (MDE) outpatients were interviewed using the Structured Clinical Interview for DSM-IV (SCID). Patients were divided into those with and without atypical features, and into those with and without early onset. Comparisons were made on variables reported to distinguish bipolar from unipolar: age of onset, recurrences, atypical features, depressive mixed state (MDE plus three or more concurrent hypomanic symptoms [DMX3]), and bipolar II family history. Compared to bipolar II patients, patients with atypical unipolar were not significantly different regarding age of onset, DMX3, recurrences, and bipolar II family history. Compared to non-atypical unipolar patients, atypical unipolar patients had a significantly different age of onset. Nonatypical unipolar patients, versus bipolar II patients, were significantly different regarding age of onset, recurrences, DMX3, and bipolar II family history. Early onset unipolar, versus bipolar II, were not significantly different regarding atypical features, recurrences, DMX3, and bipolar II family history. Later onset unipolar patients, versus bipolar II patients, were significantly different regarding atypical features, recurrences, DMX3, and bipolar II family history. These results support a link of atypical and early-onset “unipolar” depression with bipolar II disorder, and support Pages and Dunner's suggestion to combine bipolar II and recurrent unipolar into a single group. Copyright 2003, Elsevier Science (USA). All rights reserved.

Article Outline

• Abstract

• Methods

• Statistics

• Results

• Discussion

• Limitations

• References

• Copyright

In the DSM-IV Text Revision1 mood disorders are classified in two categories, bipolar disorders and (unipolar) depressive disorders, whereas Kraepelin classified bipolar and recurrent depressions under a single disorder, manic-depressive illness.2 Kraepelin's unitary view of mood disorders underwent a rebirth during the last 20 years.2 Pages and Dunner3 suggested that bipolar II and recurrent unipolar depression should be combined into a single group. Goodwin and Jamison's review4 supported the bipolar spectrum. They stated that “a substantial number of unipolar patients are very closely related to bipolar patients and may represent an intermediate place on a polarity spectrum” (p 80). Goodwin and Jamison found that the features supporting the inclusion of recurrent depressions in the bipolar spectrum were bipolar family history, atypical features of depression, early onset, many recurrences, antidepressant-induced hypomania, and lithium response.4 This conclusion was based on the analysis of different studies. Kupfer et al.5 reported on a subgroup of unipolar with symptoms similar to bipolar, like atypical features. Winokur,6, 7 Winokur and Clayton,8 and Mendels9 reported on subgroups of unipolar showing bipolar features, such as early age of onset, many recurrences, and bipolar family history. Dunner et al.10, 11 and Endicott et al.12 reported similarities between bipolar II and unipolar. Early onset, atypical features, many recurrences, and bipolar family history were reported to be the typical features distinguishing bipolar from unipolar.13, 14, 15 Because age of onset is not normally distributed, comparing the mean age of onset is misleading.4 The median is used for data not normally distributed, but comparison of the age of onset distribution seems to be the best method.16 By comparing the age of onset distribution, bipolar II showed a significantly lower age of onset than unipolar.16

Differences in age of onset are important because they support the subtyping of mood disorders and are useful for genetic studies.1, 4, 13, 17 Early-onset mood disorders are often reported to have a stronger family history of mood disorder than later-onset mood disorders, which are often reported to have more neurological disorders.1, 4, 14, 16, 17 The bipolar spectrum described by Akiskal13, 18, 19 included a “substantial proportion of apparently ”unipolar“ patients whose depressions show bipolar affinity” (p 37).19 Akiskal's bipolar spectrum included, apart from bipolar I and bipolar II, bipolar III (recurrent depression and antidepressant-associated hypomania), and bipolar IV (depression with hyperthymic temperament, bipolar family history, atypical depression, and depressive mixed states). Mixed states were included by Kraepelin in the manic-depressive illness.2 Recent studies20, 21, 22, 23 showed that depressive mixed states (major depressive episode [MDE] plus three or more DSM-IV hypomanic symptoms [DMX3]) were common among bipolar II and unipolar MDE outpatients, and that DMX3 had a high specificity for predicting the diagnosis of bipolar II.

Frequency of bipolar II (30% to 60% of depressed outpatients),24, 25, 26, 27, 28, 29, 30, 31 possible negative effects of antidepressants,32, 33, 34, 35, 36 high suicide risk,37 high anxiety disorders and substance abuse (related to the setting) comorbidity,38, 39 and high frequency of persistent residual depressive symptoms40 support the clinical importance of bipolar II. Strong diagnostic stability,41 different family history,4, 42, 43 and linkage studies44 support the bipolar II/bipolar I distinction and the independent study of bipolar II.

Following Akiskal's bipolar spectrum concept, and Pages and Dunner's suggestion to combine bipolar II and recurrent unipolar into a single disorder, the aim of the present study was to determine whether there is a link between “unipolar” depression with atypical features and early onset, and bipolar II disorder, using atypical features and early onset as markers of bipolarity. The study aim was twofold: to test the link with bipolar II disorder, and to test the inclusion in the bipolar spectrum of this group of “unipolar” depressions.

Methods

The study was conducted by a senior clinical and mood disorder research psychiatrist in his outpatient psychiatry private center. A private setting was chosen because more representative of mood disorder patients spontaneously seeking psychiatric treatment in Italy (and United States).45 In Italy, private practice is the first (or the second, after family doctors) line of treatment of mood disorders. Mood disorder patients in tertiary care academic centers are thought not to be representative of the population usually treated in clinical practice.18, 36, 46, 47

A total of 158 consecutive unipolar (major depressive disorder [MDD], and MDD superimposed on dysthymic disorder) and 234 consecutive bipolar II outpatients, presenting spontaneously for treatment of MDE, were included in the last 3 years. Patients participated voluntarily after informed consent was obtained. MDD and MDD superimposed on dysthymic disorder were combined into one group, following reports suggesting that unipolar MDD is a clinically homogeneous illness.48, 49 Included patients had not received psychopharmacotherapy for the index MDE before evaluation in order to avoid the inclusion of patients with antidepressant-induced mixed states18 and neuroleptic-induced akathisia. However, some patients on low-dose benzodiazepines (no more than 0.75 mg/d of alprazolam or equivalents) were included in both groups. Patients with current substance abuse and severe personality disorder were not included, as these conditions may confound the diagnosis of bipolar II and mixed states.24 In this setting, the prevalence of bipolar II and unipolar patients with severe personality disorder was found to be very low.50 Patients with clinically significant general medical illness or dementia were not included.

Patients were interviewed by the author during the first visit (cross-sectional assessment) with the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version, Mood Disorder module (SCID-CV) (reliability kappas 0.70 to 1.00),51 and the Global Assessment of Functioning (GAF) scale.52 The SCID-CV is partly semistructured and based on clinical evaluation. Clinicians trained on bipolar II diagnosis using a semistructured interview made more correct diagnoses than interviewers using strict structured interviews.53 Patients were systematically interviewed for history of manic/hypomanic episodes, changing the wording of the sentences when unclear to the patient or when the interviewer was in doubt about its understanding by the patient (as suggested by the SCID-CV manual guidelines). Patients were systematically probed for all DSM-IV hypomanic symptoms during the index MDE. Hypomanic symptoms had to last at least 1 week, appear during the MDE, and be present at the time of the interview. The SCID-CV structured question on racing thoughts was supplemented by Koukopoulos and Koukopoulos' definition34 of crowded thoughts (head continuously full of ideas that the patient is unable to stop). The SCID-CV skip-out instruction of the question about past periods of manic/hypomanic mood was not followed, as a negative answer would not allow the assessment of the other past hypomanic symptoms. It has been shown27, 53 that systematic assessment of all past hypomanic symptoms increases the frequency of bipolar II diagnoses, as hypomanic behavior is easier to remember (by patient and family members/close friends) than hypomanic mood. However, diagnosis of past hypomania required hypomanic mood, easier to remember after having remembered past hypomanic behavior, even when past hypomanic mood had been reported not to be present at the first stem question. History of mania/hypomania was always investigated soon after having made the diagnosis of MDE, and before the assessment of other variables, in order to avoid a possible bias related to the knowledge of indicators of bipolarity.4, 15, 16, 24 Most of the bipolar II patients in the present study had had more than one hypomania (increasing reliability of bipolar II diagnosis).24 Often, family members or close friends supplemented clinical information during the interview (increasing reliability of the diagnosis, as bipolar II patients often do not see hypomania as a disorder, and may not easily remember positive events [as hypomanias often are] due to the negative cognitive bias of depression).24 The DSM-IV 4-day minimum duration of hypomania for bipolar II diagnosis (a cut-off not based on data54) was not followed. Instead, at least 2 days of hypomania were required for bipolar II diagnosis, on the basis of previous studies.13, 24, 29, 41, 55, 56, 57 The study variables (Table 1) were taken from studies comparing bipolar and unipolar.23, 41, 58 Family history of bipolar disorder was investigated using the Family History Screen,59 a fully structured questionnaire for collecting lifetime psychiatric history on first-degree relatives (median sensitivity, 67.6%; specificity, 87.6%).

Table 1.

Sample Features: Bipolar II Versus Unipolar MDE Patients


Variable	Bipolar II (N = 234)	Unipolar (N = 158)	t/z	df	P
Female gender	66.6%	60.7%	1.1		.2320
Age (yr)	41.7 (14.1)	47.1 (15.6)	−3.5	390	.0004
Age of onset first MDE (yr)	22.9 (10.9)	32.3 (14.7)	−7.2	390	.0000
Duration of illness (yr)	18.9 (13.4)	14.7 (12.5)	3.1	390	.0019
GAF score	50.3 (8.9)	50.7 (9.2)	−0.4	390	.6670
MDE symptoms for >2 yr	41.0%	29.7%	2.2		.0226
Axis I comorbidity	55.9%	46.8%	1.7		.0768
>4 MDEs	81.6%	60.1%	4.7		.0000
Psychotic features	8.5%	8.2%	0.1		.9163
Melancholic features	14.1%	18.9%	−1.2		.2039
Atypical features	52.9%	24.0%	5.7		.0000
DMX3	58.9%	24.6%	6.6		.0000
Bipolar II family history	51.9%	16.1%	7.1		.0000

NOTE. Values are % or mean (SD)

In order to test study aim (inclusion in the bipolar spectrum, and the link with bipolar II disorder of “unipolar” depressions with DSM-IV atypical features specifier and early onset), unipolar and bipolar II patients were divided into four groups: those with and without atypical features, and those with and without early onset. Early onset was defined as onset of the first MDE before 21 years, as the median age of onset of the bipolar II sample was 20 years. This cut-off for defining early onset was in line with previous reports about age of onset of bipolar disorders, and with previous definition of early onset in mixed-age bipolar samples, where the median age of onset was often used to split patients into early and late onset.4, 14, 16, 28, 60 Comparisons were made on the variables typically reported to distinguish bipolar from unipolar4, 14, 15, 16, 18, 23, 26: age of onset of the first MDE, many MDE recurrences (>4 MDEs), DSM-IV atypical features specifier during the index MDE, depressive mixed state (DMX3), and bipolar II family history. Bipolar II family history, and not bipolar I + II family history, was tested, because different studies reported more bipolar II than bipolar I among first-degree relatives of bipolar II probands,4, 42, 43 on the basis of a linkage study supporting the genetic autonomy of bipolar II versus bipolar I.44 The first MDE onset was found to be a highly reliable onset definition of mood disorders.16 Age of onset was among the Robins and Guze's criteria61 for establishing diagnostic validity, including family history. Recurrences were divided into more than four MDEs, and four or fewer MDEs, because unipolar MDD and bipolar patients with more than four MDEs were found to have a very high probability of MDE recurrence.1, 62, 63 Depressive mixed state was defined as a MDE plus three or more (DMX3) concurrent superimposed DSM-IV hypomanic symptoms, following Benazzi and Akiskal23 and previous mixed states definitions (which required at least two opposite mood symptoms during a major mood episode).18, 24, 64, 65, 66 Atypical features specifier was defined according to DSM-IV criteria.

Statistics

Means were compared using t test, and with one-way analysis of variance (ANOVA) with Bonferroni's multiple comparison test. As a frequency can be reported as a mean (SD), and follows a normal distribution if the sample is large and the frequency is not too small or too big, frequencies were included in the ANOVA.67 Proportions were compared with the two-sample test of proportion. Logistic regression was used to study associations. STATA Statistical Software, Release 7, was used (Stata Corp, College Station, TX). P values were two-tailed, and a conservative probability level of P < .01 was chosen to further reduce type I error related to many comparisons.68, 69

Results

Sample features (bipolar II v unipolar) are presented in Table 1. Bipolar II patients had significantly lower age, lower age of onset, longer duration of illness, more recurrences, atypical features, DMX3, and bipolar II family history. Comparisons among atypical and non-atypical bipolar II, and atypical and non-atypical unipolar are presented in Table 2.

Table 2.

Comparisons Among Atypical Bipolar II, Non-atypical Bipolar II, Atypical Unipolar, and Non-atypical Unipolar MDE Patients


Variable	BPII-Aty (A = 124)	BPII-NAty (B = 110)	UP-Aty (C = 38)	UP-NAty (D = 120)
Age of onset first MDE	21.0 (9.4)	25.0 (12.0)	26.1 (13.0)	34.3 (14.7)
> 4 MDEs	0.822 (0.38)	0.809 (0.39)	0.631 (0.48)	0.591 (0.49)
DMX3	0.685 (0.46)	0.481 (0.50)	0.394 (0.49)	0.200 (0.40)
Bipolar II family history	0.575 (0.49)	0.446 (0.50)	0.185 (0.39)	0.151 (0.36)

Results of One-Way ANOVA With Bonferroni's Multiple Comparison test
	Onset	>4 MDEs	DMX3	BPII Family History
A v B	P > .05	P > .05	P < .01	P > .05
A v C	P > .05	P > .05	P < .01	P < .001
A v D	P < .001	P < .001	P < .001	P < .001
B v C	P > .05	P > .05	P > .05	P < .05
B v D	P < .001	P < .001	P < .001	P < .001
C v D	P < .01	P > .05	P > .05	P > .05

NOTE. Values are mean (SD).

Abbreviations: BPII-Aty, atypical bipolar II; BPII-NAty, non-atypical bipolar II; UP-Aty, atypical unipolar; UP-NAty, non-atypical unipolar.

The atypical unipolar group, versus the atypical and non-atypical bipolar II groups, was not significantly different in terms of age of onset, recurrences, DMX3 (only v non-atypical bipolar II), and bipolar II family history (only v non-atypical bipolar II) (6/8 similarities). Atypical unipolar patients, versus non-atypical unipolar patients, were significantly different as regards age of onset, but were not significantly different for recurrences, DMX3, and bipolar II family history (3/4 similarities). Compared to atypical and non-atypical bipolar II patients, non-atypical unipolar patients were significantly different regarding age of onset, recurrences, DMX3, and bipolar II family history (0/8 similarities).

Comparisons among early- and later-onset bipolar II, and early- and later-onset unipolar are presented in Table 3.

Table 3.

Comparisons Among Early-onset (<21 years) Bipolar II, Later-onset (>20 years) Bipolar II, Early-Onset (<21 years) Unipolar (UP-EO), and Later-Onset (>20 years) Unipolar (UP-LO) MDE Patients


Variable	BPII-EO (A = 128)	BPII-LO (B = 106)	UP-EO (C = 39)	UP-LO (D = 119)
Atypical features	0.617 (0.48)	0.424 (0.49)	0.435 (0.50)	0.176 (0.38)
>4 MDEs	0.882 (0.32)	0.735 (0.44)	0.846 (0.36)	0.521 (0.50)
DMX3	0.640 (0.48)	0.528 (0.50)	0.307 (0.46)	0.226 (0.42)
Bipolar II family history	0.545 (0.50)	0.480 (0.50)	0.291 (0.46)	0.115 (0.32)

Results of One-Way ANOVA With Bonferroni's Multiple Comparison Test
	Atypical	>4 MDEs	DMX3	BPII Family History
A v B	P < .01	P < .05	P > .05	P > .05
A v C	P > .05	P > .05	P < .001	P < .05
A v D	P < .001	P < .001	P < .001	P < .001
B v C	P > .05	P > .05	P > .05	P > .05
B v D	P < .001	P < .001	P < .001	P < .001
C v D	P < .05	P < .001	P > .05	P > .05

NOTE. Values are mean (SD).

Abbreviations: BPII, bipolar II; EO, early onset; LO, later onset; UP, unipolar.

The early-onset unipolar group, versus the early- and later-onset bipolar II groups, was not significantly different in terms of atypical features, recurrences, DMX3 (only v later-onset bipolar II), and bipolar II family history (7/8 similarities). Early-onset unipolar patients, versus later-onset unipolar patients, were significantly different regarding recurrences, but not atypical features, DMX3, and bipolar II family history (3/4 similarities). Later-onset unipolar patients, versus early- and later-onset bipolar II patients, were significantly different in terms of atypical features, recurrences, DMX3, and bipolar II family history (0/8 similarities).

To determine the relationship among early-onset, atypical features, and bipolar II, a series of logistic regressions was performed. Logistic regression of atypical features (dependent variable) versus age of onset in the whole sample (bipolar II and unipolar) found an odds ratio of 0.9, z = −5.2, P = .000. Logistic regression of MDE recurrences (dependent variable) versus age of onset in the whole sample found an odds ratio of 0.9, z = −6.2, P = .000. Logistic regression of DMX3 (dependent variable) and age of onset in the whole sample found an odds ratio of 0.9, z = −4.8, P = .000. Logistic regression of bipolar II family history (dependent variable) versus age of onset in the whole sample found an odds ratio of 0.9, z = −3.5, P = .000. Logistic regression of bipolar II diagnosis (dependent variable) versus age of onset, atypical features, MDE recurrences, DMX3, and bipolar II family history in the whole sample found (respectively): odds ratio = 0.9, z = −6.3, P = .000; odds ratio = 3.5, z = 5.5, P = .000; odds ratio = 2.9, z = 4.6, P = .000; odds ratio = 4.3, z = 6.5, P = .000; odds ratio = 5.6, z = 5.1, P = .000.

Discussion

The high frequency of bipolar II disorder in the sample (234/392, 59.6%) is not unusual, as many studies have recently shown that the frequency of bipolar II in MDE outpatients is much higher (up to 60%) than previously reported.24, 25, 26, 27, 28, 29, 30, 31 The results showed that bipolar II versus unipolar MDE patients had a significantly lower age, a lower age of onset, and a longer duration of illness, as well as more recurrences, atypical features, DMX3, and bipolar II family history. Logistic regression replicated these findings, which are in line with previous reports on bipolar II features24, 28, 29, 30 and suggest that a typical bipolar II sample was studied. The results suggest that atypical unipolar, and early-onset unipolar, may have an intermediate place between bipolar II and non-atypical and later-onset unipolar. The atypical unipolar group, versus the atypical and non-atypical bipolar II groups, was not significantly different on six of the eight comparisons. Non-atypical unipolar patients, versus atypical and non-atypical bipolar II patients, were significantly different on all comparisons. Atypical unipolar patients, versus non-atypical unipolar patients, had a significantly different age of onset, which supports a distinction between the two.16 The early-onset unipolar group, versus the early- and later-onset bipolar II groups, was not significantly different on seven of the eight comparisons. Later-onset unipolar patients, versus early- and later-onset bipolar II patients, were significantly different on all comparisons. The frequency of these unipolar subtypes was not small. Atypical unipolar was present in 24.0%, and early-onset unipolar was present in 24.6% of unipolar patients. Unipolar with atypical features and early onset was present in 37.9%. These findings are in line with previous statements that many unipolar cases may be closely related to bipolar, and may have an intermediate place in the polarity spectrum.4, 18 The results not only support the inclusion of atypical unipolar and early-onset unipolar in the bipolar spectrum, but also support Pages and Dunner's suggestion3 that recurrent unipolar and bipolar II could be combined into a single group. We had previously shown that also highly recurrent unipolar was related to bipolar II.70

Early onset was found to be the common background from which bipolar II, atypical unipolar, and early-onset unipolar came. Bipolar II and atypical features were reported to have an early onset (1,4,16,26,42,55). Early onset was found, by logistic regression, to be associated with all the typical variables distinguishing bipolar from unipolar, in line with studies placing early onset among the features of bipolarity.4, 14, 15, 16, 18, 23, 26 While misclassification of atypical and early-onset unipolar may have been possible (related to a recall error of past hypomanic episodes by patient and family members/close friends), the methods of the study should have greatly reduced this possibility.

Limitations

The use of a single interviewer and cross-sectional assessment limit the validity of these findings. Bipolar II and unipolar sample features of the present study were in line with typical features distinguishing bipolar from unipolar,4, 14, 15, 16 supporting the validity of the interview. History of mania/hypomania was always investigated soon after having made the diagnosis of MDE, and before the assessment of other variables, in order to avoid a possible bias related to the knowledge of indicators of bipolarity. Age of onset of the first MDE, number of recurrences, and family history may be subject to recall bias. However, the sample had the typical features distinguishing bipolar from unipolar, suggesting that a skillful interview during a MDE (when the MDE is not too severe, as in patients of the present patients whose median GAF was 50) may still give valid clinical information. The interview was conducted by a clinician studying and treating mood disorders for a long time, using validated structured interviews and information from family members/close friends, and systematically interviewing about past hypomania; all of these features reduce study limitations.1, 4, 14, 24 The partly semistructured SCID-CV, based on clinical evaluation, increased the probability of making correct bipolar II diagnoses.53, 71, 72 The Family History Screen59 might not have high specificity for the diagnosis of bipolar II in relatives (meaning more false positives), but, if this were the case, it would have led to a nondifferential misclassification bias between bipolar II and unipolar, thus reducing the problem.69 As this screen is fully structured, an interviewer's bias was reduced.

Advantages of the study were inclusion of only outpatients, no concurrent psychopharmacotherapy, no substance abuse disorders, inclusion of a large sample of bipolar II, and a non-academic setting.

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Outpatient Psychiatry Center, a University of California San Diego (San Diego, CA) Collaborating Center, Ravenna and Forlì; Department of Psychology, University of Bologna, Bologna; and the Department of Psychiatry National Health Service of Forlì, Forlì, Italy

☆ Address reprint requests to Franco Benazzi, M.D., Via Pozzetto 17, 48015 Castiglione di Cervia RA, Italy.

☆☆ 0010-440X/03/4402-0001$30.00/0

PII: S0010-440X(03)00035-X

doi:10.1053/comp.2003.50015

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