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Age at onset of bipolar II depressive mixed state
Psychiatry Research 103 Ž2001. 229᎐235
Age at onset of bipolar II depressive mixed state Franco BenazziU Department of Psychiatry, National Health Ser¨ ice (A.USL), P. Solieri 4, 47100 Forlı, ` Italy Received 29 July 2000; received in revised form 1 March 2001; accepted 22 April 2001
Abstract Depressive mixed state ŽDMS. Ža major depressive episode wMDEx with some concurrent hypomanic symptoms. is understudied. The aims of the study were to find if the prevalence of DMS, and its clinical correlates, in bipolar II depressed outpatients changed according to bipolar II age at onset. A consecutive sample of 92 bipolar II MDE outpatients were interviewed with the Structured Clinical Interview for DSM-IV. DMS was defined as an MDE with two or more concurrent hypomanic symptoms ŽDMS2.. Prevalence of DMS2 in bipolar II with onset after 30 and 40 years was significantly lower than prevalence in bipolar II with onset before 31 and 41 years. There was a significant negative association between DMS2 and age at onset. There were no significantly different clinical correlates between DMS2 in bipolar II with onset after 30 and before 31 years. Limitations of the study include use of a single interviewer, non-blind assessment, cross-sectional design and bipolar II diagnosis based on history. DMS2 was more likely in bipolar II with a younger age at onset. Different bipolar II ages at onset did not have an effect on DMS2 clinical correlates. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Bipolar; Mixed state; Onset
1. Introduction Depressive mixed state ŽDMS. wa major depressive episode ŽMDE. with some concurrent hypomanic symptoms ŽAkiskal et al., 1998.x is understudied ŽFreeman and McElroy, 1999. and is not classified in DSM-IV. In Kraepelin’s view, it was U
Corresponding author. Via Pozzetto 17, 48015 Castiglione di Cervia RA, Italy; Tel.: q39-335-6191852; fax: q39-054330069. E-mail address: [email protected] ŽF. Benazzi..
enough to have one of the three components of the affective states Žpsychomotor activity, mood and thinking. in a polarity opposite to the other two to have a mixed state ŽAkiskal et al., 1998.. Non-DSM-IV criteria for mixed mania ŽAkiskal et al., 1998; Freeman and McElroy, 1999. and DMS ŽKoukopoulos and Koukopoulos, 1999; Dayer et al., 2000; Benazzi, 2000a, 2001a,b,c. included full criteria mania or MDE with two or more concurrent opposite mood symptoms. DMS was more studied in bipolar I than in bipolar II. Bipolar II depression was found in 30᎐50% of
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F. Benazzi r Psychiatry Research 103 (2001) 229᎐235
depressed outpatients ŽAkiskal, 2000a; Benazzi, 1997a, 1999, 2001d. and bipolar II depression was reported often to have concurrent hypomanic symptoms ŽAkiskal, 2000a.. DMS2 ŽMDE with two or more concurrent hypomanic symptoms. was found to be common in bipolar II and in unipolar depressed outpatients ŽBenazzi, 2000a, 2001a,b,c.. DMS2 was present in 72% of bipolar II and in 49% of unipolar depressed outpatients ŽBenazzi, 2000a, 2001a,b,c.. The most common hypomanic symptoms in DMS2 were irritability, racing thoughts, distractibility and talkativeness, in line with DMS studies in different bipolar populations ŽAkiskal and Mallya, 1987; Akiskal, 1992, 1996, 1999, 2000b; Goodwin and Jamison, 1990; Koukopoulos et al., 1992; Perugi et al., 1997.. The study of DMS has important treatment implications. Antidepressants may worsen DMS and may induce mixed states, rapid cycling and manicrhypomanic episodes in bipolar depression ŽKoukopoulos and Koukopoulos, 1999; Kilzieh and Akiskal, 1999; Akiskal, 1996, 2000a; Benazzi, 1997b.. DMS may respond better to anticonvulsant mood stabilizers ŽAkiskal, 2000b.. Some antidepressant-resistant depressions may be DMS, which may respond to mood stabilizers and may be worsened by aggressive antidepressant treatment ŽAkiskal, 2000a.. Age at onset is an important variable in the study of mood disorder. It may support the subtyping of mood disorders ŽMcMahon et al., 1994; Goodwin and Jamison, 1990.. Differences in age at onset may be associated with different etiology, family history, clinical picture, outcome and treatment response ŽMcMahon et al., 1994; Goodwin and Jamison, 1990.. This study aims to find out if DMS2 prevalence and its clinical correlates, in bipolar II depressed outpatients, changed according to age at onset of bipolar II. No similar reports were found on PubMedrMedline.
2. Methods The study was conducted in one large outpatient private practice. A private practice setting
was chosen because it is more representative of mood disorder patients spontaneously seeking psychiatric treatment in Italy, where it is the first Žor the second, after family doctors. line of treatment of mood disorders and where the most severe mood patients are usually treated in national psychiatric health services or in university centers. Mood disorder patients in academic centers may not be representative of typical mood disorder patients ŽGoldberg and Kocsis, 1999. and the literature studied bipolar patients not representative of the larger universe of patients seen in clinical practice ŽAkiskal and Pinto, 1999.. Therefore, the present study sample may be more representative of patients seen in everyday clinical practice outside the centers treating the most difficult and the less representative mood disorder patients. A consecutive sample of 92 bipolar II outpatients, presenting spontaneously for major depressive episode ŽMDE. treatment, were studied in the last 12 months. The patients had not received psychopharmacotherapy for the index MDE, to avoid the inclusion of antidepressantinduced mixed states ŽAkiskal, 2000a.. Substance Žpresent or past. and severe personality disorder patients Ždiagnosed by clinical interview following DSM-IV criteria . were not included, because they may be confused with bipolar II and mixed states ŽAkiskal, 2000a.. Depressive mixed state ŽDMS. was defined as an MDE with two or more concurrent hypomanic symptoms ŽDMS2., following previous non-DSM-IV definitions of mixed states, which required at least two opposite mood symptoms during a major mood episode ŽBenazzi, 2000a, 2001a,b,c; Akiskal et al., 1998; Akiskal and Pinto, 1999; Akiskal, 2000b; Freeman and McElroy, 1999; Koukopoulos and Koukopoulos, 1999; Dayer et al., 2000.. Hypomanic symptoms during MDE lasted at least 1 week, appeared during the MDE Žwere not present before the MDE. and were present at the time of the interview. Hypomanic symptoms were not severe enough to cause marked impairment of functioning, thus ruling out that they were manic symptoms and that the index episode was mixed mania Žalso because only 6.1% of patients had the DSM-IV minimum num-
F. Benazzi r Psychiatry Research 103 (2001) 229᎐235
ber of symptoms required for the diagnosis of hypomania.. No patient had DSM-IV rapid cycling or cyclothymic disorder. Past hypomanic episodes had appeared many months or years before the index MDE. Patients were interviewed by a senior clinical and mood disorder research psychiatrist, during the first visit, with the Structured Clinical Interview for DSM-IV Axis I Disorders ᎏ Clinician Version, Mood Disorder module ŽSCID-CV. ŽFirst et al., 1997. and the Global Assessment of Functioning ŽGAF. scale ŽAmerican Psychiatric Association, 1994.. All patients were systematically interviewed with the SCID-IV for concurrent hypomanic symptoms. The DSM-IV 4-day minimum duration of hypomania wa cut-off not based on data ŽDunner, 1998.x was not followed. At least 2 days of hypomania were required for bipolar II diagnosis, on the basis of the following data: modal range duration of hypomania reported to be 1᎐3 days ŽAkiskal, 1996.; bipolar II disorder with hypomania of at least 2 days’ duration validated by positive family history for bipolar disorder ŽAngst, 1998; Akiskal et al., 1977.; diagnostic stability ŽCoryell et al., 1995.; and typical bipolar features ŽBaldessarini, 2000. Žlower age at onset, more atypical features, more recurrences than unipolar. ŽBenazzi, 2001e.. Most bipolar II patients had had hypomanias of short duration and all had had more than one hypomanic episode Žincreasing reliability of the diagnosis. ŽAkiskal, 2000a.. Often, family members or close friends supplemented the clinical information during the interview Žincreasing the reliability of the diagnosis. ŽAkiskal, 2000a.. Study variables were age, gender, age at onset of the first MDE, illness duration, recurrences Žmore than 3 MDEs., MDEr MDE without full interepisode recovery lasting more than 2 years Ždepression chronicity., axis I comorbidity, GAF, number of depressive and hypomanic symptoms, melancholic, atypical and psychotic features, individual DSM-IV hypomanic, MDE, melancholic and atypical symptoms. Axis I comorbid disorder diagnoses were made with the SCID-CV interview, when comorbid disorders were spontaneously reported by the patients, without systematic probing Žprobably leading to underreporting..
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Age at onset was defined as the age at onset of the first MDE according to DSM-IV criteria, a highly reliable onset definition of mood disorders ŽMcMahon et al., 1994.. The Kernel density estimate of age at onset found that most onsets were before 31 years Ž77.1%, 71r92., followed by a marked drop and then by two small peaks at approximately 40 and 50 years. This bipolar II age at onset curve was in line with the reported age at onset curve of bipolar ŽI q II. disorder ŽSchurhoff et al., 2000.. As a result, two cutoffs for age at onset were chosen: onset before 31 years and onset before 41 years. There is no standard age at onset cutoff in bipolar disorder studies to distinguish early and late onset. In the present study two age at onset cutoffs, based on the age at onset curve of the sample, are probably better than cutoffs based on the mean, or the median age at onset of the sample woften used in mixed age samples ŽYoung and Klerman, 1992.x. As age at onset in mood disorders is not normally distributed, the use of means or medians may be misleading and age at onset distribution is a better estimate of age at onset ŽMcMahon et al., 1994; Goodwin and Jamison, 1990.. To better study the relationship between DMS2 and age at onset, and to remove the bias related to the choice of cutoffs, logistic regression was also used, with age at onset as a continuous independent variable. The sample features are presented in Table 1. 2.1.1. Statistics The chi-square test for frequencies, linear regression for correlations, and logistic regression for associations were used ŽSTATA 5 statistical software, Stata Corporation, College Station, TX, USA, 1997.. The P values were two-tailed and the probability level was P- 0.05. This study complied with the principles set forth in the Declaration of Helsinki and written informed consent was obtained.
3. Results Prevalence of DMS2 in bipolar II with onset after 30 years Ž57.1%, n s 21. was significantly
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Table 1 Sample features Ž n s 92.
ing thoughts Ž79.4%., irritability Ž77.9%., distractibility Ž72.0% . and more talkativeness Ž36.7%..
Variable, mean ŽS.D.., % Female gender Age, years Age at onset first MDE, years Illness duration, years More than 3 MDEs Depression chronicity Axis I comorbidity GAF Psychotic features Melancholic features Atypical features DMS2 Hypomania N hypomanic symptoms N hypomanic symptoms in DMS2 Irritability Increased activity More pleasurable activities Decreased need for sleep Psychomotor agitation Grandiosity Distractibility More talkativeness Pressure to keep talking Flight of ideas Racing thoughts
66.3 42.4 Ž14.3. 26.1 Ž13.2. 16.4 Ž12.8. 77.1 45.6 46.7 50.5 Ž8.0. 7.6 18.4 45.6 73.9 6.1 2.6 Ž1.2. 3.1 Ž1.0. 61.9 3.2 2.1 4.3 13.0 0.0 59.7 28.2 1.0 2.1 70.6
lower than prevalence in bipolar II with onset before 31 years Ž78.8%, n s 71. Ž 2 s 3.9, d.f.s 1, Ps 0.046.. Prevalence of DMS2 in bipolar II with onset after 40 years Ž50.0%, n s 14. was significantly lower in prevalence than bipolar II with an onset before 41 years Ž78.2%, n s 78. Ž 2 s 4.8, d.f.s 1, P s 0.027.. Logistic regression, with DMS2 as an dependent variable and age at onset as an independent variable found a significant negative association Žodds ratio s 0.9, z s y2.0, Ps 0.042.. Logistic regression found that, in the DMS2 subsample Ž n s 68., onset after 30 years was not significantly associated with clinical study variables Žreported in Methods., apart from age Žodds ratio s 1.0, z s 3.0, Ps 0.003. and illness duration Žodds ratio s 0.9, zs y2.2, Ps 0.025.. Linear regression found that age at onset and age were significantly correlated w F Ž1, 90. s 42.4, P s 0.0000, r s 0.56, t s 6.5, Ps 0.000.. The most common hypomanic symptoms in DMS2 were rac-
4. Discussion Prevalence of hypomanic symptoms was high in the present study in bipolar II MDE patients. DMS2 was present in 73.9% of patients, in line with Akiskal’s report that most bipolar II depressions had concurrent hypomanic symptoms ŽAkiskal, 2000a.. The prevalence of DMS2 hypomanic symptoms was in line with studies on DMS in different bipolar populations ŽAkiskal and Mallya, 1987; Akiskal, 1992, 1996, 2000b; Goodwin and Jamison, 1990; Koukopoulos et al., 1992; Perugi et al., 1997.. Irritability, distractibility and racing thoughts were the most common hypomanic symptoms in the study sample. The same symptoms were reported to be the most common manicrhypomanic symptoms in bipolar spectrum outpatients ŽHirschfeld et al., 2000.. The age at onset curve of bipolar II was in line with the reported age at onset curve of bipolar ŽI q II. disorder ŽSchurhoff et al., 2000.. The finding of a progressive decrease of DMS2 prevalence in bipolar II following the increase of bipolar II age at onset and the significant negative association between DMS2 and bipolar II age at onset suggest that DMS2 may be more likely in bipolar II with younger age at onset. The finding may be related to the reported bipolar II prevalence decrease with increasing age among depressed outpatients ŽBenazzi, 2001d., meaning that hypomanic symptoms may be less likely to appear as age increases. In the present study, hypomanic symptoms were less likely during a bipolar II MDE as age at onset and age increased Ža strong correlation between age at onset and age was found in the present sample.. A decreased presence of hypomanic symptoms during MDE with increasing age at onset may be the result of brain changes with age, leading to a reduced ability to produce bipolar symptoms. More neurological abnormalities were reported in late onset vs. early onset bipolar I disorder ŽWylie et al., 1999; Young and Klerman, 1992; Chen et al., 1998; Hays et al.,
F. Benazzi r Psychiatry Research 103 (2001) 229᎐235
1998.. The finding of a higher prevalence of DMS2 in younger onset bipolar II may also be the result of an increased number of antidepressant treatments before inclusion Žincreased duration of illness., as antidepressants were reported to induce mixed states ŽAkiskal, 2000a; Koukopoulos and Koukopoulos, 1999.. However, the included patients had not received psychopharmacotherapy for the index MDE, excluding an increased sensitivity to antidepressant-induced mixed states as a cause of the index DMS2. Another finding was that DMS2 with onset after 30 years, compared with DMS2 with onset before 31 years, was not significantly associated with most clinical study variables. This finding suggests that a different age at onset of bipolar II may not have an effect on the clinical correlates of DMS2. A different age at onset may support the subtyping of mood disorders and may be associated with different etiology, family history, clinical picture, outcome and treatment response ŽMcMahon et al., 1994; Goodwin and Jamison, 1990.. Lower age at onset of bipolar disorder was reported to be associated with a greater family history of mood disorders, fewer brain changes on neuroimaging, more I-axis comorbidity, more personality disorders and fewer general medical and neurological disorders ŽSuppes et al., 2000; Wylie et al., 1999; Young and Klerman, 1992; Chen et al., 1998; Hays et al., 1998.. Mixed mania was reported to be associated with lower, similar, or higher age at onset than non-mixed mania ŽSuppes et al., 2000.. The results of the present study Žthat a different age at onset of bipolar II did not have an effect on the clinical correlates of DMS2. do not support the subtyping of bipolar II DMS2 according to age at onset, in line with a previous study reporting no clinical differences between early and late onset bipolar II ŽBenazzi, 2000b.. Findings also suggest that bipolar II DMS2 clinical correlates may be independent of age. 4.1.1. Limitations Single interviewer and non-blind, cross-sectional assessment may have reduced the validity of the findings. Age at onset may be subject to recall bias. A clear definition of onset wthe first MDE, which was reported to be a highly reliable
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definition of onset in mood disorders ŽMcMahon et al., 1994.x, use of diagnostic criteria for MDE ŽDSM-IV., use of a validated structured interview by a senior clinical and research psychiatrist, standard assessment of all consecutive patients, and clinical information supplemented by interview of family members or close friends may have reduced memory bias. The present bipolar II sample had typical bipolar features ŽBaldessarini, 2000. Žlower age at onset, more recurrences and more atypical features than a unipolar comparison group. ŽBenazzi, 2001e., suggesting that an interview during MDE Žwhen the MDE is not too severe as in most present study patients, whose mean GAF was 50. may still give valid clinical information. The clinical picture of DSM-IV hypomania is not clearly different from that of mania and differential diagnosis depends on severity, limiting reliability ŽAkiskal, 2000a.. Bipolar II diagnosis was based on history of hypomania was often happens ŽAkiskal, 2000a.x, limiting reliability ŽAkiskal, 2000a; Dunner and Tay, 1993.. The same features that may have reduced recall bias may also have reduced the reliability problem of the diagnosis of bipolar II ŽAkiskal, 2000a; Goodwin and Jamison, 1990.. References Akiskal, H.S., 2000a. Mood disorders: clinical features. In: Sadock, B.J., Sadock, V.A. ŽEds.., Kaplan and Sadock ’s Comprehensive Textbook of Psychiatry, 7th ed. Lippincott Williams and Wilkins, Philadelphia, pp. 28294᎐29391. Žon CD-ROM. Akiskal, H.S., 2000b. Distinctive mixed states of bipolar I, II and beyond. Annual Meeting of the American Psychiatric Association. Chicago, Industry Symposia. Abstract 噛20B. Akiskal, H.S., Pinto, O., 1999. The evolving bipolar spectrum: prototypes I, II, III, and IV. In: Akiskal, H.S. ŽEd.., Bipolarity: Beyond Classic Mania, Vol. 22. Psychiatric Clinics of North America, pp. 517᎐534. Akiskal, H.S., 1999. Spectrum of mixed states: with mania and with hypomania. Annual Meeting of the American Psychiatric Association. American Psychiatric Association, Washington, DC. Symposia Abstract 噛46C. Akiskal, H.S., Hantouche, E.G., Bourgeois, M.L., Azorin, J.M., Sechter, D., Allilaire, J.F., Lancrenon, S., Fraud, J.P., Chatenet-Duchene, L., 1998. Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study ŽEPIMAN.. Journal of Affective Disorders 50, 175᎐186.
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Akiskal, H.S., 1996. The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. Journal of Clinical Psychopharmacology 16 Žsuppl 1., 4S᎐14S. Akiskal, H.S., 1992. The distinctive mixed states of bipolar I, II, and III. Clinical Neuropharmacology 15, 632᎐633. Žsuppl 1, Pt. A. Akiskal, H.S., Mallya, G., 1987. Criteria for the ‘soft’ bipolar spectrum: treatment implications. Psychopharmacology Bulletin 23, 68᎐73. Akiskal, H.S., Djenderedjian, A.H., Rosenthal, R.H., Khani, M.K., 1977. Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. American Journal of Psychiatry 134, 1227᎐1233. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Press, Washington, DC. Angst, J., 1998. The emerging epidemiology of hypomania and bipolar II disorder. Journal of Affective Disorders 50, 143᎐151. Baldessarini, R.J., 2000. A plea for integrity of the bipolar disorder concept. Bipolar Disorders 2, 3᎐7. Benazzi, F., 2001a. Sensitivity and specificity of clinical markers for the diagnosis of bipolar II disorder. Comprehensive Psychiatry, in press. Benazzi, F., 2001b. Atypical depression with hypomanic symptoms. Journal of Affective Disorders 65, 179᎐183. Benazzi, F., 2001c. Major depressive episodes with hypomanic symptoms are common among depressed outpatients. Comprehensive Psychiatry 42, 139᎐143. Benazzi, F., 2001d. Bipolar II depression in late life: prevalence and clinical features in 525 depressed outpatients. Journal of Affective Disorders, in press. Benazzi, F., 2001e. Is 4 days the minimum duration of hypomania in bipolar II disorder? European Archives of Psychiatry and Clinical Neurosciences 251, 32᎐34. Benazzi, F., 2000a. Depressive mixed states: unipolar and bipolar II. European Archives of Psychiatry and Clinical Neurosciences 250, 249᎐253. Benazzi, F., 2000b. Early- versus late-onset bipolar II disorder. Journal of Psychiatry and Neuroscience 25, 53᎐57. Benazzi, F., 1999. Prevalence and clinical features of atypical depression in depressed outpatients: a 467-case study. Psychiatry Research 86, 259᎐265. Benazzi, F., 1997a. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. Journal of Affective Disorders 43, 163᎐166. Benazzi, F., 1997b. Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice. Journal of Affective Disorders 46, 73᎐76. Chen, S.T., Altshuler, L.L., Spar, J.E., 1998. Bipolar disorder in late life: a review. Journal of Geriatric Psychiatry and Neurology 11, 29᎐35. Coryell, W., Endicott, J., Maser, J.D., Keller, M.B., Leon, A.C., Akiskal, H.S., 1995. Long-term stability of polarity distinctions in the affective disorders. American Journal of Psychiatry 152, 385᎐390.
Dayer, A., Aubry, J-M., Roth, L., Ducrey, S., Bertschy, G., 2000. A theoretical reappraisal of mixed states: dysphoria as a third dimention. Bipolar Disorders 2, 316᎐324. Dunner, D.L., 1998. Diagnostic revisions for DSM-IV. In: Goodnick, P.L. ŽEd.., Mania. Clinical and Research Perspectives. American Psychiatric Press, Washington, DC, pp. 3᎐10. Dunner, D.L., Tay, K.L., 1993. Diagnostic reliability of the history of hypomania in bipolar II patients and patients with major depression. Comprehensive Psychiatry 34, 303᎐307. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1997. Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version ŽSCID-CV.. American Psychiatric Press, Washington, DC. Freeman, M.P., McElroy, S.L., 1999. Clinical picture and etiologic models of mixed states. In: Akiskal, H.S. ŽEd.., Bipolarity: Beyond Classic Mania, Vol. 22. Psychiatric Clinics of North America, pp. 535᎐546. Goldberg, J.F., Kocsis, J.H., 1999. Depression in the course of bipolar disorder. In: Goldberg, J.F., Harrow, M. ŽEds.., Bipolar Disorders. Clinical Course and Outcome. American Psychiatric Press, Washington, DC, pp. 129᎐147. Goodwin, F.K., Jamison, K.R., 1990. Manic-Depressive Illness. Oxford University Press, New York. Hays, J.C., Krishnan, K.R.R., George, L.K., Blazer, D.G., 1998. Age at first onset of bipolar disorder: demographic, family history and psychosocial correlates. Depression and Anxiety 7, 76᎐82. Hirschfeld, R.M.A., Williams, J.B.W., Spitzer, R.L., Calabrese, J.R., Flynn, L., Keck, P.E., Lewis, L., McElroy, S.L., Post, R.M., Rapport, D.J., Russell, J.M., Sachs, G.S., Zajecka, J., 2000. Development and validation of a screening instrument for bipolar spectrum disorder: the mood disorder questionnaire. American Journal of Psychiatry 157, 1873᎐1875. Kilzieh, N., Akiskal., H.S., 1999. Rapid-cycling bipolar disorder. In: Akiskal, H.S. ŽEd.., Bipolarity: Beyond Classic Mania, Vol. 22. Psychiatric Clinics of North America, pp. 585᎐607. Koukopoulos, A., Koukopoulos, A., 1999. Agitated depression as a mixed state and the problem of melancholia. In: Akiskal, H.S. ŽEd.., Bipolarity: Beyond Classic Mania, Vol. 22. Psychiatric Clinics of North America, pp. 547᎐564. Koukopoulos, A., Faedda, G., Proietti, R., D’Amico, S., de Pisa, E., Simonetto, C., 1992. Mixed depressive syndrome. Encephale 18, 19᎐21 Žspec no 1.. McMahon, F.J., Stine, O.C., Chase, G.A., Meyers, D.A., Simpson, S.G., DePaulo, J.R., 1994. Influence of clinical subtype, sex, and lineality on age at onset of major affective disorder in a family sample. American Journal of Psychiatry 151, 210᎐215. Perugi, G., Akiskal, H.S., Micheli, C., Musetti, L., Paiano, A., Quilici, C., Rossi, L., Cassano, G.B., 1997. Clinical subtypes of bipolar mixed states: validating a broader European
F. Benazzi r Psychiatry Research 103 (2001) 229᎐235 definition in 143 cases. Journal of Affective Disorders 43, 169᎐180. Schurhoff, F., Bellivier, F., Jouvent, R., Mouren-Simeoni, M.C., Bouvard, M., Allilaire, J.F., Leboyer, M., 2000. Early and late onset bipolar disorders: two different forms of manicdepressive illness? Journal of Affective Disorders 58, 215᎐221. Suppes, T., Dennehy, E.B., Gibbons, E.W., 2000. The longitudinal course of bipolar disorder. Journal of Clinical Psychiatry 61 Ž9., 23᎐30.
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Age at onset of bipolar II depressive mixed state Franco BenazziU Department of Psychiatry, National Health Ser¨ ice (A.USL), P. Solieri 4, 47100 Forlı, ` Italy Received 29 July 2000; received in revised form 1 March 2001; accepted 22 April 2001
Abstract Depressive mixed state ŽDMS. Ža major depressive episode wMDEx with some concurrent hypomanic symptoms. is understudied. The aims of the study were to find if the prevalence of DMS, and its clinical correlates, in bipolar II depressed outpatients changed according to bipolar II age at onset. A consecutive sample of 92 bipolar II MDE outpatients were interviewed with the Structured Clinical Interview for DSM-IV. DMS was defined as an MDE with two or more concurrent hypomanic symptoms ŽDMS2.. Prevalence of DMS2 in bipolar II with onset after 30 and 40 years was significantly lower than prevalence in bipolar II with onset before 31 and 41 years. There was a significant negative association between DMS2 and age at onset. There were no significantly different clinical correlates between DMS2 in bipolar II with onset after 30 and before 31 years. Limitations of the study include use of a single interviewer, non-blind assessment, cross-sectional design and bipolar II diagnosis based on history. DMS2 was more likely in bipolar II with a younger age at onset. Different bipolar II ages at onset did not have an effect on DMS2 clinical correlates. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Bipolar; Mixed state; Onset
1. Introduction Depressive mixed state ŽDMS. wa major depressive episode ŽMDE. with some concurrent hypomanic symptoms ŽAkiskal et al., 1998.x is understudied ŽFreeman and McElroy, 1999. and is not classified in DSM-IV. In Kraepelin’s view, it was U
Corresponding author. Via Pozzetto 17, 48015 Castiglione di Cervia RA, Italy; Tel.: q39-335-6191852; fax: q39-054330069. E-mail address: [email protected] ŽF. Benazzi..
enough to have one of the three components of the affective states Žpsychomotor activity, mood and thinking. in a polarity opposite to the other two to have a mixed state ŽAkiskal et al., 1998.. Non-DSM-IV criteria for mixed mania ŽAkiskal et al., 1998; Freeman and McElroy, 1999. and DMS ŽKoukopoulos and Koukopoulos, 1999; Dayer et al., 2000; Benazzi, 2000a, 2001a,b,c. included full criteria mania or MDE with two or more concurrent opposite mood symptoms. DMS was more studied in bipolar I than in bipolar II. Bipolar II depression was found in 30᎐50% of
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depressed outpatients ŽAkiskal, 2000a; Benazzi, 1997a, 1999, 2001d. and bipolar II depression was reported often to have concurrent hypomanic symptoms ŽAkiskal, 2000a.. DMS2 ŽMDE with two or more concurrent hypomanic symptoms. was found to be common in bipolar II and in unipolar depressed outpatients ŽBenazzi, 2000a, 2001a,b,c.. DMS2 was present in 72% of bipolar II and in 49% of unipolar depressed outpatients ŽBenazzi, 2000a, 2001a,b,c.. The most common hypomanic symptoms in DMS2 were irritability, racing thoughts, distractibility and talkativeness, in line with DMS studies in different bipolar populations ŽAkiskal and Mallya, 1987; Akiskal, 1992, 1996, 1999, 2000b; Goodwin and Jamison, 1990; Koukopoulos et al., 1992; Perugi et al., 1997.. The study of DMS has important treatment implications. Antidepressants may worsen DMS and may induce mixed states, rapid cycling and manicrhypomanic episodes in bipolar depression ŽKoukopoulos and Koukopoulos, 1999; Kilzieh and Akiskal, 1999; Akiskal, 1996, 2000a; Benazzi, 1997b.. DMS may respond better to anticonvulsant mood stabilizers ŽAkiskal, 2000b.. Some antidepressant-resistant depressions may be DMS, which may respond to mood stabilizers and may be worsened by aggressive antidepressant treatment ŽAkiskal, 2000a.. Age at onset is an important variable in the study of mood disorder. It may support the subtyping of mood disorders ŽMcMahon et al., 1994; Goodwin and Jamison, 1990.. Differences in age at onset may be associated with different etiology, family history, clinical picture, outcome and treatment response ŽMcMahon et al., 1994; Goodwin and Jamison, 1990.. This study aims to find out if DMS2 prevalence and its clinical correlates, in bipolar II depressed outpatients, changed according to age at onset of bipolar II. No similar reports were found on PubMedrMedline.
2. Methods The study was conducted in one large outpatient private practice. A private practice setting
was chosen because it is more representative of mood disorder patients spontaneously seeking psychiatric treatment in Italy, where it is the first Žor the second, after family doctors. line of treatment of mood disorders and where the most severe mood patients are usually treated in national psychiatric health services or in university centers. Mood disorder patients in academic centers may not be representative of typical mood disorder patients ŽGoldberg and Kocsis, 1999. and the literature studied bipolar patients not representative of the larger universe of patients seen in clinical practice ŽAkiskal and Pinto, 1999.. Therefore, the present study sample may be more representative of patients seen in everyday clinical practice outside the centers treating the most difficult and the less representative mood disorder patients. A consecutive sample of 92 bipolar II outpatients, presenting spontaneously for major depressive episode ŽMDE. treatment, were studied in the last 12 months. The patients had not received psychopharmacotherapy for the index MDE, to avoid the inclusion of antidepressantinduced mixed states ŽAkiskal, 2000a.. Substance Žpresent or past. and severe personality disorder patients Ždiagnosed by clinical interview following DSM-IV criteria . were not included, because they may be confused with bipolar II and mixed states ŽAkiskal, 2000a.. Depressive mixed state ŽDMS. was defined as an MDE with two or more concurrent hypomanic symptoms ŽDMS2., following previous non-DSM-IV definitions of mixed states, which required at least two opposite mood symptoms during a major mood episode ŽBenazzi, 2000a, 2001a,b,c; Akiskal et al., 1998; Akiskal and Pinto, 1999; Akiskal, 2000b; Freeman and McElroy, 1999; Koukopoulos and Koukopoulos, 1999; Dayer et al., 2000.. Hypomanic symptoms during MDE lasted at least 1 week, appeared during the MDE Žwere not present before the MDE. and were present at the time of the interview. Hypomanic symptoms were not severe enough to cause marked impairment of functioning, thus ruling out that they were manic symptoms and that the index episode was mixed mania Žalso because only 6.1% of patients had the DSM-IV minimum num-
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ber of symptoms required for the diagnosis of hypomania.. No patient had DSM-IV rapid cycling or cyclothymic disorder. Past hypomanic episodes had appeared many months or years before the index MDE. Patients were interviewed by a senior clinical and mood disorder research psychiatrist, during the first visit, with the Structured Clinical Interview for DSM-IV Axis I Disorders ᎏ Clinician Version, Mood Disorder module ŽSCID-CV. ŽFirst et al., 1997. and the Global Assessment of Functioning ŽGAF. scale ŽAmerican Psychiatric Association, 1994.. All patients were systematically interviewed with the SCID-IV for concurrent hypomanic symptoms. The DSM-IV 4-day minimum duration of hypomania wa cut-off not based on data ŽDunner, 1998.x was not followed. At least 2 days of hypomania were required for bipolar II diagnosis, on the basis of the following data: modal range duration of hypomania reported to be 1᎐3 days ŽAkiskal, 1996.; bipolar II disorder with hypomania of at least 2 days’ duration validated by positive family history for bipolar disorder ŽAngst, 1998; Akiskal et al., 1977.; diagnostic stability ŽCoryell et al., 1995.; and typical bipolar features ŽBaldessarini, 2000. Žlower age at onset, more atypical features, more recurrences than unipolar. ŽBenazzi, 2001e.. Most bipolar II patients had had hypomanias of short duration and all had had more than one hypomanic episode Žincreasing reliability of the diagnosis. ŽAkiskal, 2000a.. Often, family members or close friends supplemented the clinical information during the interview Žincreasing the reliability of the diagnosis. ŽAkiskal, 2000a.. Study variables were age, gender, age at onset of the first MDE, illness duration, recurrences Žmore than 3 MDEs., MDEr MDE without full interepisode recovery lasting more than 2 years Ždepression chronicity., axis I comorbidity, GAF, number of depressive and hypomanic symptoms, melancholic, atypical and psychotic features, individual DSM-IV hypomanic, MDE, melancholic and atypical symptoms. Axis I comorbid disorder diagnoses were made with the SCID-CV interview, when comorbid disorders were spontaneously reported by the patients, without systematic probing Žprobably leading to underreporting..
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Age at onset was defined as the age at onset of the first MDE according to DSM-IV criteria, a highly reliable onset definition of mood disorders ŽMcMahon et al., 1994.. The Kernel density estimate of age at onset found that most onsets were before 31 years Ž77.1%, 71r92., followed by a marked drop and then by two small peaks at approximately 40 and 50 years. This bipolar II age at onset curve was in line with the reported age at onset curve of bipolar ŽI q II. disorder ŽSchurhoff et al., 2000.. As a result, two cutoffs for age at onset were chosen: onset before 31 years and onset before 41 years. There is no standard age at onset cutoff in bipolar disorder studies to distinguish early and late onset. In the present study two age at onset cutoffs, based on the age at onset curve of the sample, are probably better than cutoffs based on the mean, or the median age at onset of the sample woften used in mixed age samples ŽYoung and Klerman, 1992.x. As age at onset in mood disorders is not normally distributed, the use of means or medians may be misleading and age at onset distribution is a better estimate of age at onset ŽMcMahon et al., 1994; Goodwin and Jamison, 1990.. To better study the relationship between DMS2 and age at onset, and to remove the bias related to the choice of cutoffs, logistic regression was also used, with age at onset as a continuous independent variable. The sample features are presented in Table 1. 2.1.1. Statistics The chi-square test for frequencies, linear regression for correlations, and logistic regression for associations were used ŽSTATA 5 statistical software, Stata Corporation, College Station, TX, USA, 1997.. The P values were two-tailed and the probability level was P- 0.05. This study complied with the principles set forth in the Declaration of Helsinki and written informed consent was obtained.
3. Results Prevalence of DMS2 in bipolar II with onset after 30 years Ž57.1%, n s 21. was significantly
232
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Table 1 Sample features Ž n s 92.
ing thoughts Ž79.4%., irritability Ž77.9%., distractibility Ž72.0% . and more talkativeness Ž36.7%..
Variable, mean ŽS.D.., % Female gender Age, years Age at onset first MDE, years Illness duration, years More than 3 MDEs Depression chronicity Axis I comorbidity GAF Psychotic features Melancholic features Atypical features DMS2 Hypomania N hypomanic symptoms N hypomanic symptoms in DMS2 Irritability Increased activity More pleasurable activities Decreased need for sleep Psychomotor agitation Grandiosity Distractibility More talkativeness Pressure to keep talking Flight of ideas Racing thoughts
66.3 42.4 Ž14.3. 26.1 Ž13.2. 16.4 Ž12.8. 77.1 45.6 46.7 50.5 Ž8.0. 7.6 18.4 45.6 73.9 6.1 2.6 Ž1.2. 3.1 Ž1.0. 61.9 3.2 2.1 4.3 13.0 0.0 59.7 28.2 1.0 2.1 70.6
lower than prevalence in bipolar II with onset before 31 years Ž78.8%, n s 71. Ž 2 s 3.9, d.f.s 1, Ps 0.046.. Prevalence of DMS2 in bipolar II with onset after 40 years Ž50.0%, n s 14. was significantly lower in prevalence than bipolar II with an onset before 41 years Ž78.2%, n s 78. Ž 2 s 4.8, d.f.s 1, P s 0.027.. Logistic regression, with DMS2 as an dependent variable and age at onset as an independent variable found a significant negative association Žodds ratio s 0.9, z s y2.0, Ps 0.042.. Logistic regression found that, in the DMS2 subsample Ž n s 68., onset after 30 years was not significantly associated with clinical study variables Žreported in Methods., apart from age Žodds ratio s 1.0, z s 3.0, Ps 0.003. and illness duration Žodds ratio s 0.9, zs y2.2, Ps 0.025.. Linear regression found that age at onset and age were significantly correlated w F Ž1, 90. s 42.4, P s 0.0000, r s 0.56, t s 6.5, Ps 0.000.. The most common hypomanic symptoms in DMS2 were rac-
4. Discussion Prevalence of hypomanic symptoms was high in the present study in bipolar II MDE patients. DMS2 was present in 73.9% of patients, in line with Akiskal’s report that most bipolar II depressions had concurrent hypomanic symptoms ŽAkiskal, 2000a.. The prevalence of DMS2 hypomanic symptoms was in line with studies on DMS in different bipolar populations ŽAkiskal and Mallya, 1987; Akiskal, 1992, 1996, 2000b; Goodwin and Jamison, 1990; Koukopoulos et al., 1992; Perugi et al., 1997.. Irritability, distractibility and racing thoughts were the most common hypomanic symptoms in the study sample. The same symptoms were reported to be the most common manicrhypomanic symptoms in bipolar spectrum outpatients ŽHirschfeld et al., 2000.. The age at onset curve of bipolar II was in line with the reported age at onset curve of bipolar ŽI q II. disorder ŽSchurhoff et al., 2000.. The finding of a progressive decrease of DMS2 prevalence in bipolar II following the increase of bipolar II age at onset and the significant negative association between DMS2 and bipolar II age at onset suggest that DMS2 may be more likely in bipolar II with younger age at onset. The finding may be related to the reported bipolar II prevalence decrease with increasing age among depressed outpatients ŽBenazzi, 2001d., meaning that hypomanic symptoms may be less likely to appear as age increases. In the present study, hypomanic symptoms were less likely during a bipolar II MDE as age at onset and age increased Ža strong correlation between age at onset and age was found in the present sample.. A decreased presence of hypomanic symptoms during MDE with increasing age at onset may be the result of brain changes with age, leading to a reduced ability to produce bipolar symptoms. More neurological abnormalities were reported in late onset vs. early onset bipolar I disorder ŽWylie et al., 1999; Young and Klerman, 1992; Chen et al., 1998; Hays et al.,
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1998.. The finding of a higher prevalence of DMS2 in younger onset bipolar II may also be the result of an increased number of antidepressant treatments before inclusion Žincreased duration of illness., as antidepressants were reported to induce mixed states ŽAkiskal, 2000a; Koukopoulos and Koukopoulos, 1999.. However, the included patients had not received psychopharmacotherapy for the index MDE, excluding an increased sensitivity to antidepressant-induced mixed states as a cause of the index DMS2. Another finding was that DMS2 with onset after 30 years, compared with DMS2 with onset before 31 years, was not significantly associated with most clinical study variables. This finding suggests that a different age at onset of bipolar II may not have an effect on the clinical correlates of DMS2. A different age at onset may support the subtyping of mood disorders and may be associated with different etiology, family history, clinical picture, outcome and treatment response ŽMcMahon et al., 1994; Goodwin and Jamison, 1990.. Lower age at onset of bipolar disorder was reported to be associated with a greater family history of mood disorders, fewer brain changes on neuroimaging, more I-axis comorbidity, more personality disorders and fewer general medical and neurological disorders ŽSuppes et al., 2000; Wylie et al., 1999; Young and Klerman, 1992; Chen et al., 1998; Hays et al., 1998.. Mixed mania was reported to be associated with lower, similar, or higher age at onset than non-mixed mania ŽSuppes et al., 2000.. The results of the present study Žthat a different age at onset of bipolar II did not have an effect on the clinical correlates of DMS2. do not support the subtyping of bipolar II DMS2 according to age at onset, in line with a previous study reporting no clinical differences between early and late onset bipolar II ŽBenazzi, 2000b.. Findings also suggest that bipolar II DMS2 clinical correlates may be independent of age. 4.1.1. Limitations Single interviewer and non-blind, cross-sectional assessment may have reduced the validity of the findings. Age at onset may be subject to recall bias. A clear definition of onset wthe first MDE, which was reported to be a highly reliable
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definition of onset in mood disorders ŽMcMahon et al., 1994.x, use of diagnostic criteria for MDE ŽDSM-IV., use of a validated structured interview by a senior clinical and research psychiatrist, standard assessment of all consecutive patients, and clinical information supplemented by interview of family members or close friends may have reduced memory bias. The present bipolar II sample had typical bipolar features ŽBaldessarini, 2000. Žlower age at onset, more recurrences and more atypical features than a unipolar comparison group. ŽBenazzi, 2001e., suggesting that an interview during MDE Žwhen the MDE is not too severe as in most present study patients, whose mean GAF was 50. may still give valid clinical information. The clinical picture of DSM-IV hypomania is not clearly different from that of mania and differential diagnosis depends on severity, limiting reliability ŽAkiskal, 2000a.. Bipolar II diagnosis was based on history of hypomania was often happens ŽAkiskal, 2000a.x, limiting reliability ŽAkiskal, 2000a; Dunner and Tay, 1993.. The same features that may have reduced recall bias may also have reduced the reliability problem of the diagnosis of bipolar II ŽAkiskal, 2000a; Goodwin and Jamison, 1990.. References Akiskal, H.S., 2000a. Mood disorders: clinical features. In: Sadock, B.J., Sadock, V.A. ŽEds.., Kaplan and Sadock ’s Comprehensive Textbook of Psychiatry, 7th ed. Lippincott Williams and Wilkins, Philadelphia, pp. 28294᎐29391. Žon CD-ROM. Akiskal, H.S., 2000b. Distinctive mixed states of bipolar I, II and beyond. Annual Meeting of the American Psychiatric Association. Chicago, Industry Symposia. Abstract 噛20B. Akiskal, H.S., Pinto, O., 1999. The evolving bipolar spectrum: prototypes I, II, III, and IV. In: Akiskal, H.S. ŽEd.., Bipolarity: Beyond Classic Mania, Vol. 22. Psychiatric Clinics of North America, pp. 517᎐534. Akiskal, H.S., 1999. Spectrum of mixed states: with mania and with hypomania. Annual Meeting of the American Psychiatric Association. American Psychiatric Association, Washington, DC. Symposia Abstract 噛46C. Akiskal, H.S., Hantouche, E.G., Bourgeois, M.L., Azorin, J.M., Sechter, D., Allilaire, J.F., Lancrenon, S., Fraud, J.P., Chatenet-Duchene, L., 1998. Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study ŽEPIMAN.. Journal of Affective Disorders 50, 175᎐186.
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