Symptoms of depression as possible markers of bipolar II disorder

Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 471 – 477 www.elsevier.com/locate/pnpbp

Symptoms of depression as possible markers of bipolar II disorder Franco Benazzi * Hecker Psychiatry Research Center, Forli, Italy University of California at San Diego (USA) Collaborating Center, United States Department of Psychiatry, University of Szeged, Szeged, Hungary Department of Psychiatry, National Health Service, Forli, Italy Accepted 23 November 2005 Available online 19 January 2006

Abstract Underdiagnosis and misdiagnosis of bipolar-II disorder (BP-II) as a major depressive disorder (MDD) are frequently reported. The study aim was to find which symptoms of depression could be possible cross-sectional markers of BP-II, in order to reduce underdiagnosing BP-II. Methods: Consecutive 379 BP-II and 271 MDD major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide, and the Family History Screen, by a senior psychiatrist in a private practice. Inside-MDE hypomanic symptoms (elevated mood and increased self-esteem always absent by definition) were systematically assessed. Mixed depression was defined as an MDE plus 3 or more inside-MDE hypomanic symptoms, a definition validated by Akiskal and Benazzi. Results: The MDE symptoms significantly more common in BP-II versus MDD were weight gain, increased eating, hypersomnia, psychomotor agitation, worthlessness, and diminished ability to concentrate. The inside-MDE hypomanic symptoms significantly more common in BP-II were distractibility, racing/crowded thoughts, irritability, psychomotor agitation, more talkativeness, increased risky and goal-directed activities. Multiple logistic regression showed that hypersomnia, racing/crowded thoughts, irritability, and psychomotor agitation were independent predictors of BP-II. Irritability had the most balanced combination of sensitivity and specificity predicting BP-II. Psychomotor agitation had the highest specificity but the lowest sensitivity. Racing/crowded thoughts had the highest sensitivity but the lowest specificity. These symptoms had a similar positive predictive value (PPV) for BP-II, which was around 70% (PPV is more clinically useful than sensitivity and specificity), which in turn was similar to the PPV of mixed depression and atypical depression (two diagnostic clinical markers of BP-II). All possible combinations of these symptoms had a PPV similar to that of the individual symptoms. The validity as BP-II markers of these symptoms was supported by a significant association with bipolar family history. Conclusions: Hypersomnia, racing/crowded thoughts, irritability, and psychomotor agitation may be useful, cross-sectional markers of BP-II. Finding these symptoms in depression should lead the clinician to careful probing for history of hypomania, which should reduce the BP-II misdiagnosed as MDD. Results may also have treatment impacts, as antidepressants used alone (i.e., no concurrent mood stabilising agent) in BPII depression misdiagnosed as MDD may increase cycling. D 2005 Elsevier Inc. All rights reserved. Keywords: Bipolar II disorder; Depressive mixed state; Mixed depression; Hypersomnia; Irritability; Psychomotor agitation

1. Introduction Abbreviations: BP-II, bipolar II disorder; CI, confidence interval; df, degrees of freedom; DSM-IV, diagnostic and statistical manual of mental disorders, fourth edition; DSM-IV-TR, diagnostic and statistical manual of mental disorders, fourth edition, text revised; GAF, global assessment of functioning scale; MDD, major depressive disorder; MDE, major depressive episode; NPV, negative predictive value; OR, odds ratio; SCID-CV, structured clinical interview for DSM-IV axis I disorders, clinician version; SE, sensitivity; SP, specificity; PPV, positive predictive value. * Via Pozzetto 17, 48010 Castiglione di Cervia RA, Italy. Tel.: +39 335 6191 852; fax: +39 054 330 069. E-mail address: [email protected]. 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.11.016

Bipolar-II disorder (BP-II) is frequently misdiagnosed as major depressive disorder (MDD) (Dunner, 2003; Howard et al., 2003; Hirschfeld et al., 2003). Instead, in recent community and clinical samples studies, the BP-II to MDD ratio was found to be near one by improving the probing for history of hypomania (Hantouche et al., 1998; Akiskal and Pinto, 1999; Manning et al., 1999; Benazzi, 2003a,b; Angst et al., 2003; Benazzi, 2004; Rybakowski et al., 2005; Smith et al., 2005).

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In clinical practice, cross-sectional clinical markers (i.e., current features directly observed by the clinician, and not retrospective features) suggesting that what seems to be MDD may actually be BP-II would be very useful. Clinical markers of BP-II should then induce a careful probing for history of hypomania. Two cross-sectional features of the major depressive episode (MDE) were found to be useful clinical markers of BP-II: atypical depression and atypical depression symptoms (Angst et al., 2002, 2003; Akiskal, 1996; Perugi et al., 2003; Agosti and Stewart, 2001; Benazzi, 2002a), and mixed depression (depressive mixed state, defined as an MDE mixed with hypomanic symptoms) (Akiskal and Pinto, 1999; Benazzi, 2002b; Koukopoulos, 2003; Akiskal and Benazzi, 2003; Sato et al., 2003; Ducrey et al., 2004; Mantere et al., 2004; Benazzi, 2005). The present report focuses on the search for symptoms of depression (MDE symptoms and inside-MDE hypomanic symptoms) which could be useful cross-sectional markers of BP-II. A clinical marker has similarities with a screening test and it could share similar statistics. The most common statistics in diagnostic testing are sensitivity, specificity, positive predictive value, and negative predictive value (Altman et al., 2000; Dawson and Trapp, 2001; Armitage et al., 2002; Zimmerman et al., 2004). Among these, the positive predictive value is more important in clinical practice because it is the probability that a person who is identified as ill by the marker actually has the illness. Study aim was to test the positive predictive value for BPII of MDE symptoms and of inside-MDE hypomanic symptoms. 2. Methods More details on study methods can be found in previous reports (Akiskal and Benazzi, 2003; Benazzi and Akiskal, 2003; Benazzi, 2003c). 2.1. Study setting An outpatient psychiatry private practice in EmiliaRomagna region, northern Italy. This setting is more representative of the mood disorders usually seen in psychiatric clinical practice in this area (apart from the psychotic ones) because (1) it is the first or second (after general practitioners) line of treatment of mood disorders, (2) the most severe and socially disadvantaged individuals are usually seen in tertiary-care centers (i.e., national health services and academic centers), (3) mood disorder patients do not like to be treated in the national health services for fear of stigma, and 4) most individuals can afford a private psychiatrist (fee-for-service) in this area, reducing a possible income bias. 2.2. Interviewer A senior clinical and mood disorder research psychiatrist.

2.3. Patient Population Consecutive 379 BP-II and 271 MDD outpatients, presenting voluntarily (i.e., self-referred) for the treatment of a major depressive episode (MDE), were included in the last 6 years. Substance-related and borderline personality disorders were excluded because may confound the diagnosis of BP-II, due to the high background mood instability present in these disorders (Akiskal and Pinto, 1999). Anyway, these disorders are rare in the study setting (Benazzi, 2000). Clinically significant general medical illnesses and cognitive disorders were also excluded. Patients had to present off psychoactive drugs for at least 2 weeks (apart from a few individuals on small doses of benzodiazepines) in order not to include patients with druginduced or drug-suppressed hypomanic symptoms. 2.4. Assessment instruments During the first visit, the following instruments were used: (1) the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (First et al., 1997) (SCID-CV, reported inter-rater reliability k = 0.70 – 1.0), as modified by Benazzi and Akiskal (2003) to improve the detection of BP-II; the question on racing thoughts was supplemented by the Koukopoulos and Koukopoulos’ (1999) definition of crowded thoughts (i.e., mind continuously full of non-stop thoughts), following Kraepelin’s description of the grading of the thought disorders of hypomania (1921); (2) the Global Assessment of Functioning scale (GAF, in the SCID-CV) for assessing MDE severity; (3) the Hypomania Interview Guide (Williams et al., 1994) (reported inter-rater reliability k = 0.88) to assess insideMDE hypomanic symptoms; (4) the structured Family History Screen (Weissman et al., 2000) (reported inter-rater reliability k = 0.85) for assessing bipolar disorders (type I and II) family history in probands’ first-degree relatives. Often, family members or close friends supplemented clinical information during the interview, increasing the validity of the diagnosis of BP-II and of the family history (Akiskal et al., 2000; American Psychiatric Association, 2000). The interviewer’s inter-rater reliability k for the diagnosis of BP-II was 0.73 (Benazzi, 2003c). Ratings were cross-sectional: for the MDE, the time frame was the last 2 weeks before the interview, for the insideMDE hypomanic symptoms, it was the last week before the interview. 2.5. Interview methods Systematic interviews about history of hypomanic and manic episodes were always conducted soon after the diagnosis of MDE and before the assessment of study variables, in order to avoid a possible bias related to knowledge of bipolar signs (Ghaemi et al., 2002). The SCID-CV is partly semi-structured and based on clinical evaluation (not on simple yes/no answers to structured questions). Wording of the sentences can be changed to improve and to check the understanding by the interviewee. This is an important advantage versus fully structured interviews because this interview method has been

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shown to reduce the false negative mood disorders, especially BP-II (Dunner and Tay, 1993; Brugha et al., 2001; Aalto-Setala et al., 2002; Simpson et al., 2002; Benazzi, 2003b). The skip out instruction of the stem question on history of mood changes (elevated/irritable mood) was not followed, in order to assess all past hypomanic symptoms, especially overactivity (increased goal-directed activity). This method followed previous reports showing its usefulness to improve the detection of BPII (Dunner and Tay, 1993; Simpson et al., 2002; Angst et al., 2003; Benazzi, 2003b; Benazzi and Akiskal, 2003). Overactivity is an observable behavior easier to remember than mood changes (Angst et al., 2003; Benazzi and Akiskal, 2003). Mood changes were always required for the diagnosis of BP-II according to DSM-IV-TR (American Psychiatric Association, 2000), and were more easily remembered after remembering overactivity. A minimum duration of hypomania of 2 days was required (instead, DSM-IV-TR requires a minimum duration of 4 days), on the basis of data supporting this cut-off (Benazzi, 2001; Judd et al., 2003; Angst et al., 2003; Benazzi and Akiskal, in press a), while DSM-IV-TR cut-off is not databased (Dunner, 2003). Among the present study BP-II, around 30% met the 2-day cut-off for hypomania, while all the others met DSM-IV-TR cut-off. Therefore, the frequency of DSM-IVTR BP-II in the present sample was around 40%, a frequency very close to that found in outpatient sample studies (Dunner and Tay, 1993; Hantouche et al., 1998; Manning et al., 1999; Rybakowski et al., 2005; Smith et al., 2005). 2.6. Diagnostic definitions Mixed depression was defined as an MDE mixed with 3 or more hypomanic symptoms (elevated mood and increased selfesteem were always absent by definition), according to a definition validated by Akiskal and Benazzi (2003), and by Benazzi (2005). Hypomanic symptoms had to appear during the MDE (i.e., a hypomanic symptom-free interval of at least one month before the MDE was required), to last at least 1 week, and to be present at the time of the interview (to increase validity). 2.7. Validator Bipolar family history was used as an external validator (Kraepelin, 1921; Robins and Guze, 1970; Kendler, 1990). 2.8. Data analysis The following statistics were used. Sensitivity is how well a test identifies individuals with the illness. Sensitivity is high when the false negatives are few. Specificity is how well a test identifies individuals without the illness. Specificity is high when the false positives are few. The positive predictive value is the probability that a person who is identified as ill by a test actually has the illness. The negative predictive value is the probability that a person who is identified as not ill by a test actually is not ill. The positive and negative predictive values are related not only to sensitivity and specificity but also to the

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prevalence of a disorder. A disorder with a high prevalence will have a higher positive predictive value than a low prevalence disorder. For population screening, sensitivity is usually more important than specificity. In clinical practice instead, clinical markers (not screening tests) are more useful, and the positive predictive value is more important than sensitivity. Clinicians need to know which disorder a person has, so a high positive predictive value is important in clinical practice. Univariate and multivariate logistic regression were used to study associations and to control for confounding (Hosmer and Lemeshow, 2000). Odds ratios for continuous variables were calculated, as suggested by Hosmer and Lemeshow (2000), by dividing age and age at onset by 10-year intervals, and GAF by 5-point intervals. STATA Statistical Software, Release 8.2, was used (Stata Corporation, College Station, TX, USA, 2003). P values were two-tailed, and alpha level was set at 0.05, given the exploratory nature of the study. 3. Results Sample features are presented in Table 1. BP-II, versus MDD, had significantly lower age at onset, more MDE recurrences, more atypical and mixed depressions, and more bipolar family history. Comparisons of MDE symptoms and of inside-MDE hypomanic symptoms between BP-II and MDD are presented in Table 2. The following symptoms were significantly more common in BP-II: weight gain, increased eating, hypersomnia, psychomotor agitation, worthlessness (including also excessive or inappropriate guilt), and diminished ability to concentrate (including also indecisiveness), among the MDE symptoms; distractibility, racing/crowded thoughts, irritable mood, psychomotor agitation, more talkativeness, risky activities, and increased goal-directed activity, among the inside-MDE hypoTable 1 Sample features. Bipolar-II disorder versus major depressive disorder (by univariate logistic regression) Variables: mean (SD); % Index age, years Age at onset first MDE, years Index GAF Female gender > =5 MDEs Index MDE symptoms >2 years Axis I comorbidity Index psychotic features Index melancholic features Index atypical features Index mixed depression (MDE plus > =3 hypomanic symptoms) Bipolar (type I + II) family history

BP-II n = 379

MDD n = 271

OR

95%CI

41.3(13.0) 22.8(10.7)

46.6(14.6) 31.7(13.7)

0.7 0.5

0.6 – 0.8** 0.4 – 0.6**

50.3(9.2) 67.2 80.2 37.7

50.7(9.6) 61.6 57.1 34.6

0.9 1.2 3.0 1.1

0.8 – 1.0 0.9 – 1.7 2.1 – 4.3** 0.8 – 1.5

54.0 7.6 11.8 53.0 63.5

47.9 8.4 13.2 29.1 34.6

1.2 0.8 0.8 2.7 3.2

0.9 – 1.7 0.5 – 1.5 0.5 – 1.4 1.9 – 3.8** 2.3 – 4.5**

45.2

16.0

4.3

2.7 – 6.7**

(BP-II = bipolar-II disorder; MDD = major depressive disorder; MDE = major depressive episode; GAF = Global Assessment of Functioning scale; OR = odds ratio; 95% CI = 95% confidence interval; nc = not calculable; *P < 0.05; **P < 0.01).

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Table 2 Major depressive episode and inside-depression hypomanic symptoms in bipolar-II disorder versus major depressive disorder (by univariate logistic regression) Variables, % MDE symptoms Depressed mood Diminished interest Weight loss Weight gain Decreased eating Increased eating Insomnia Hypersomnia Psychomotor agitation Psychomotor retardation Fatigue Worthlessness Diminished ability to think or concentrate Thoughts of death

BP-II n = 379

MDD n = 271

OR

95%CI

96.5 95.7 34.5 22.1 47.5 27.1 79.6 36.9 34.3 3.4 86.2 65.9 86.8

97.0 97.0 40.2 10.3 56.4 14.0 81.9 22.8 20.6 5.5 88.5 55.3 77.4

0.8 0.6 0.7 2.4 0.7 2.2 0.8 1.9 2.0 0.6 0.8 1.5 1.9

0.3 – 2.0 0.2 – 1.6 0.5 – 1.0 1.5 – 3.9** 0.5 – 0.9* 1.5 – 3.4** 0.5 – 1.3 1.3 – 2.8** 1.3 – 2.8** 0.2 – 1.2 0.5 – 1.3 1.1 – 2.1** 1.2 – 2.8**

52.5

45.0

1.3

0.9 – 1.8

67.1 56.4 37.2 20.6 10.7 8.1 1.4

1.7 2.4 2.5 2.0 2.6 2.6 5.3

1.2 – 2.5** 1.7 – 3.3** 1.8 – 3.5** 1.3 – 2.8** 1.7 – 4.1** 1.5 – 4.3** 1.8 – 15.3**

0.0 0.0 0.0

nc nc nc

nc nc nc

Inside-MDE hypomanic symptoms Distractibility 78.3 Racing/crowded thoughts 75.2 Irritable mood 60.6 Psychomotor agitation 34.3 More talkativeness 24.2 Increased risky activities 18.7 Increased goal-directed 7.3 activity Reduced need for sleep 1.5 Increased self-esteem 0.0 Elevated mood 0.0

(BP-II = bipolar-II disorder; MDD = major depressive disorder; MDE = major depressive episode; OR = odds ratio; 95% CI = 95% confidence interval; nc = not calculable; *P < 0.05; **P < 0.01).

manic symptoms. As there was a statistically significant age difference between BP-II and MDD, and as age may impact the clinical picture of depression, the statistically significant symptom differences found in Table 2 were tested by logistic regression controlled for age. It resulted that all the tested symptom differences were still highly statistically significant. Table 3 Multiple logistic regression of bipolar-II disorder versus major depressive episode and inside-depression hypomanic symptoms (with frequency greater than 20% in both samples, similar symptoms included only once) Variables

OR

95%CI

Depressed mood Diminished interest Weight loss Decreased eating Insomnia Hypersomnia Fatigue Worthlessness Thoughts of death Distractibility Racing/crowded thoughts Irritable mood Psychomotor agitation

0.8 0.6 0.7 0.8 0.9 1.5 0.8 1.3 1.0 1.2 1.8 2.1 1.6

0.3 – 2.1 0.2 – 1.7 0.5 – 1.1 0.5 – 1.3 0.5 – 1.3 1.0 – 2.2* 0.4 – 1.3 0.9 – 1.9 0.7 – 1.5 0.8 – 1.8 1.2 – 2.6** 1.4 – 2.9** 1.1 – 2.4*

(OR = odds ratio; 95% CI = 95% confidence interval; *P < 0.05; **P < 0.01).

Table 4 Diagnostic testing for bipolar-II disorder of the independent predictor symptoms of major depressive episode and inside-depression hypomanic symptoms (mixed depression and depression with atypical features specifier are reported for comparison)

Irritable mood Racing/crowded thoughts Psychomotor agitation Hypersomnia Mixed depression Atypical depression

OR (95% CI)

SE%

SP%

PPV%

NPV%

2.5(1.8 – 3.5)** 2.4(1.7 – 3.3)** 2.0(1.3 – 2.8)** 1.9(1.3 – 2.8)** 3.2(2.3 – 4.5)** 2.7(1.9 – 3.8)**

60.6 75.7 34.3 36.9 63.5 53.0

62.7 43.5 79.3 77.1 65.3 70.8

69.4 65.2 69.9 69.3 71.9 71.7

53.2 56.1 46.3 46.7 56.1 51.8

(OR = odds ratio; 95% CI = 95% confidence interval; SE = sensitivity; SP= specificity; PPV = positive predictive value; NPV = negative predictive value; *P < 0.05; **P < 0.01).

Multiple logistic regression was used to find which symptoms were independent predictors of BP-II (Table 3). Among the MDE symptoms and the inside-MDE hypomanic symptoms, the significant independent predictors resulted to be hypersomnia, racing/crowded thoughts, irritability, and psychomotor agitation. The sensitivity, specificity, positive and negative predictive values for BP-II of the symptoms which were found to be independent predictors of BP-II (hypersomnia, racing/crowded thoughts, irritability, and psychomotor agitation) are presented in Table 4. Irritability had the most balanced combination of sensitivity and specificity. Psychomotor agitation had the highest specificity but the lowest sensitivity. Racing/crowded thoughts had the highest sensitivity but the lowest specificity. The positive predictive value of these symptoms was similar. It was around 70% for hypersomnia, irritability, and psychomotor agitation, and around 65% for racing/crowded thoughts. As a comparison, mixed depression had a balanced combination of sensitivity and specificity similar to that of irritability, and its positive predictive value was only a little higher (i.e., 71.9%). As a comparison, atypical depression had a positive predictive value similar to that of mixed depression (i.e., 71.7%). All the possible combinations of these symptoms had a sensitivity ranging from 58.8% to 89.1%, a specificity ranging from 32.1% to 61.2%, a positive predictive value ranging from 64.3% to 69.9%, and a negative predictive value ranging from 51.5% to 67.9%. The validity as BP-II markers of the MDE symptoms and of the inside-MDE hypomanic symptoms, found independent predictors of BP-II, was tested versus bipolar family history as the validator (Table 5). It resulted that all the predictor symptoms were significantly associated with bipolar family history. Table 5 Associations between bipolar family history (external validator) and depressive and hypomanic symptoms predictors of bipolar-II disorder OR (95% CI) Irritable mood Racing/crowded thoughts Psychomotor agitation Hypersomnia

2.1(1.4 – 3.2)** 1.9(1.2 – 2.9)** 1.6(1.0 – 2.3)* 1.7(1.1 – 2.6)**

(OR = odds ratio; 95% CI = 95% confidence interval; *P < 0.05; **P < 0.01).

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4. Discussion The study sample had the features often reported to distinguish BP-II and MDD (i.e., lower age at onset, more MDE recurrences, more atypical and mixed depressions, and more bipolar family history in BP-II) (Akiskal, 1996; Angst et al., 2002; Mitchell and Malhi, 2004), supporting the validity of the interview. Also the frequency of BP-II relative to MDD was in line with recent reports (Dunner and Tay, 1993; Hantouche et al., 1998; Manning et al., 1999; Rybakowski et al., 2005; Smith et al., 2005). 4.1. Symptoms of depression more common in BP-II versus MDD The MDE symptoms significantly more common in BP-II were weight gain, increased eating, hypersomnia, psychomotor agitation, worthlessness, and diminished ability to concentrate. The DSM-IV item for worthlessness includes also excessive or inappropriate guilt, and the item for diminished ability to concentrate includes also indecisiveness. The item for thoughts of deaths includes also suicidal ideation and attempt. These multi-symptom items have to be scored only once. The inside-MDE hypomanic symptoms significantly more common in BP-II were distractibility, racing/crowded thoughts, irritable mood, psychomotor agitation, more talkativeness, increased risky and goal-directed activities. These findings are in line with the often reported symptom differences between bipolar (types I and II) depression and MDD (Goodwin and Jamison, 1990; Akiskal, 1996; Perugi et al., 2003; Akiskal and Benazzi, 2003; Mitchell and Malhi, 2004). As age may impact the clinical picture of depression, and as there was a statistically significant age difference between BP-II and MDD, all the above symptom differences were tested by logistic regression controlled for age. Results showed no impact of age on the above symptom differences, further stressing the discriminant power of these symptoms. 4.2. Symptoms of depression as possible markers of BP-II Independent predictors of BP-II were hypersomnia, racing/ crowded thoughts, irritability, and psychomotor agitation. These symptoms were studied as possible symptoms markers of BP-II. Irritability had the most balanced combination of sensitivity and specificity for predicting BP-II. Psychomotor agitation had the highest specificity but the lowest sensitivity for predicting BP-II. Racing/crowded thoughts had the highest sensitivity but the lowest specificity for predicting BP-II. The positive predictive value (clinically more useful) was similar, and around 70% for hypersomnia, irritability, and psychomotor agitation (it was 65% for racing/crowded thoughts). All possible combinations of these symptoms had positive predictive values ranging from 64% to 70%, so there was no clinical utility in the combination of these symptoms, which led to a gain in sensitivity but a loss in specificity. By comparison, two useful cross-sectional clinical markers of BP-II such as mixed depression and atypical depression, had positive predictive

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values only a little higher (around 71%). So, the positive predictive values of hypersomnia, irritability, and psychomotor agitation were similar to those of mixed depression and of atypical depression. As identifying a symptom is simpler and quicker than making a diagnosis of mixed depression and atypical depression, the symptoms marker of BP-II found in the present study have clinical utility. The validity as BP-II markers of hypersomnia, irritability, psychomotor agitation, and racing/crowded thoughts was supported by the statistically significant associations with bipolar family history. However, these symptoms were not uncommon in the MDD sample, suggesting that these symptoms should be complemented by several other ‘‘markers’’ of BP-II (e.g., atypical depression, mixed depression, bipolar family history, young are at onset, many recurrences) to increase the probability of detecting BP-II. Study findings are also related to BP-II prevalence. A high BP-II prevalence will lead to a higher positive predictive value, a low BP-II prevalence will lead to a lower positive predictive value. Therefore, study findings are related to the populations studied and to the setting. In the present study, as in the previous community and outpatient studies reported in the introduction, BP-II versus MDD prevalence was high (around 50% versus 50%), and the positive predictive value was relatively high. In different settings, such as tertiary care settings, BP-II prevalence may be lower, and, as a result, the positive predictive value will be lower. Therefore, study findings should be related to the present study setting. Study results should be replicated in similar populations and settings, and also in different populations and settings. 4.3. Impact of depression symptom markers of BP-II Symptoms of depression, which could be possible markers of BP-II, were found in the present study. These symptoms markers of BP-II (hypersomnia, irritability, psychomotor agitation, and racing/crowded thoughts) could reduce the underdiagnosis and misdiagnosis of BP-II (Dunner, 2003), by stimulating a careful probing for history of hypomania. The clinical utility of facilitating the diagnosis of BP-II is high. Misdiagnosis of BP-II as MDD may have important negative treatment impacts (Akiskal and Pinto, 1999; Koukopoulos and Koukopoulos, 1999). Antidepressants used alone (i.e., no concurrent mood stabilising agents) may worsen the course of BP-II by inducing or facilitating mixed states, hypomanic episodes, and more frequent cycles (Altshuler et al., 1995; Bottlender et al., 2004; Benazzi and Akiskal, in press b). 4.4. Limitations A single interviewer limited the validity of the findings. However, reliability of BP-II diagnosis was found to be high when trained clinicians used semi-structured interviews as in the present study (Simpson et al., 2002), and clinicians using semi-structured interviews made more correct diagnoses of mood disorders, especially BP-II, compared to structured interviewing (Dunner and Tay, 1993; Brugha et al., 2001; Aalto-Setala et al., 2002). Family history assessment was not

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blind. However, a structured family history interview was used (Weissman et al., 2000), which should have reduced a possible bias. Furthermore, key informants were often present during the interview, further reducing a possible bias. The interview was conducted by a clinician studying and treating mood disorders for a long time, systematically using validated structured and semi-structured interviews for each new patient, supplemented by key informants. An interviewer’s bias is unlikely, as the present study aim had not been planned when the variables were collected for different study goals. Findings are related to a ‘‘pure’’ mood disorders sample, as several groups of patients were excluded (even if these patients are a minority in the study setting, i.e., substance-abuse disorders, borderline personality disorder, clinically significant general medical illnesses, and cognitive disorders). 5. Conclusions Findings suggest that some symptoms of depression, such as hypersomnia, racing/crowded thoughts, irritability, and psychomotor agitation, may be useful cross-sectional markers of BP-II, showing a positive predictive value around 70%. Assessing the presence of these symptoms in depression may reduce the risk of misdiagnosing BP-II as MDD (by inducing a careful probing for history of hypomania), and may improve the treatment of depression (as antidepressants alone may worsen the course of BP-II). References Aalto-Setala T, Haarasilta L, Marttunen M, Tuulio-Henrikson A, Poikolainen K, Aro H, et al. Major depressive episode among young adults: CIDI-SF versus SCAN consensus diagnoses. Psychol Med 2002;32: 1309 – 14. Agosti V, Stewart JW. Atypical and non-atypical subtypes of depression: comparison of social functioning, symptoms, course of illness, comorbidity and demographic features. J Affect Disord 2001;65:75 – 9. Akiskal HS. The prevalent clinical spectrum of bipolar disorders: beyond DSMIV. J Clin Psychopharmacol 1996;16(suppl 1):4S – 14S. Akiskal HS, Pinto O. The evolving bipolar spectrum: prototypes I, II, III, and IV. Psychiatr Clin North Am 1999;22:517 – 34. Akiskal HS, Benazzi F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 2003;73:113 – 22. Akiskal HS, Bourgeois ML, Angst J, Post R, Moller H-J, Hirschfeld R. Reevaluating the prevalence and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 2000;59(suppl 1):S5 – 30. Altman DG, Machin D, Bryant TN, Gardner MJ. Statistics with confidence. second edition. Bristol’ British Medical Journal books; 2000. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatr 1995;152:1130 – 8. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC’ American Psychiatric Association; 2000. Text Revision (DSM-IV-TR). Angst J, Gamma A, Sellaro R, Zhang H, Merikangas K. Toward validation of atypical depression in the community: results of the Zurich cohort study. J Affect Disord 2002;72:125 – 38. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003;73:133 – 46.

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