Journal Mobile Options
Table of Contents
Vol. 38, No. 5, 2005
Issue release date: September–October 2005
Psychopathology 2005;38:273–280

Psychopathologic Correlates of Suicidal Ideation in Major Depressive Outpatients: Is It All Due to Unrecognized (Bipolar) Depressive Mixed States?

Akiskal H.S. · Benazzi F.
aInternational Mood Center, University of California at San Diego, and bVeterans Administration Medical Center, San Diego, Calif., USA; cHecker Outpatient Psychiatry Research Center, Ravenna, and dDepartment of Psychiatry, National Health Service, Forli, Italy

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: Recent transatlantic concern about suicidality in patients receiving antidepressants prompted us to examine the psychopathologic correlates of suicidal ideation occurring in clinically depressed patients. Methods: The study sample, which consisted of 644 consecutive major depressive outpatients, of which 58.0% had bipolar II disorder (BP-II), was systematically interviewed with the SCID, in order to delineate the diagnostic and psychopathologic correlates of suicidal ideation. Results: Such ideation, which was present in 49.5% [and favoring BP-II vs. major depressive disorder (MDD)] at an odds ratio (OR) of 1.3 (95% confidence interval = 0.98–1.8), was clinically significantly associated with depressive mixed state (racing/crowded thoughts and psychomotor agitation/activation during index depression), mood lability, decreased self-esteem, anorexia, as well as melancholic and psychotic features. Multiple logistic regression of suicidal ideation versus depressive symptoms and intradepressive excitatory symptoms revealed that decreased self-esteem (OR = 3.3), racing/crowded thoughts (OR = 1.5), and psychomotor agitation/activation (OR = 1.4) were independent and clinically significant correlates of suicidal ideation, irrespective of depression severity. Discussion: From a psychopathologic standpoint, suicidality might be conferred by a combination of both the excited (mixed) depressive and agitated (melancholic) clusters. Trait mood lability appears to favor the genesis of these affective clusters. Within the framework of Kraepelinian psychiatry, both clusters represent depressive mixed states. Given that such states are more prevalent in BP-II, our data provide a possible explanation for the greater suicidality in BP-II patients reported in the literature. In light of the higher odds of suicidal ideation in BP-II versus MDD patients, we hypothesize that the higher prevalence of mental and psychomotor activation in BP-II might be one factor among others that favors the greater likelihood of the transition from suicidal ideation to suicidal action in BP-II. Our analyses delineate a mixed depressive substrate at risk for suicidality. To what extent, if any, antidepressant monotherapy might contribute to the genesis of such states and/or suicidality cannot be answered with the methodology of the present study.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Rihmer Z, Pestality P: Bipolar II disorder and suicidal behavior. Psychiatr Clin North Am 1999;22:667–673.
  2. Healy D, Whitaker C: Antidepressants and suicide: risk-benefit conundrums. J Psychiatry Neurosci 2003;28:331–337.
  3. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E: Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341–1345.
  4. Rosack J: FDA issues controversial black box warning. APA Psychiatric News, November 5, 2004, vol 39, pp 1, 48.
  5. American College of Neuropsychopharmacology: Executive summary: preliminary report of the task force on SSRIs and suicidal behavior in youth. January 21, 2004.
  6. Fawcett J, Scheftner W, Clark D, Hedeker D, Gibbons R, Coryell W: Clinical predictors of suicide in patients with major affective disorders: a controlled prospective study. Am J Psychiatry 1987;144:35–40.
  7. Maser JD, Akiskal HS, Schettler P, Scheftner W, Mueller T, Endicott J, Solomon D, Clayton P: Can temperament identify affectively ill patients who engage in lethal or near-lethal suicidal behavior? A 14-year prospective study. Suicide Life Threat Behav 2002;32:10–32.
  8. Benazzi F, Akiskal HS: Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. J Affect Disord 2003;73:33–38.
  9. Akiskal HS, Benazzi F: Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 2003;73:113–122.
  10. Akiskal HS, Bitar AH, Puzantian VR, Rosenthal TL, Walker PW: The nosological status of neurotic depression: a prospective three- to four-year examination in light of the primary-secondary and unipolar-bipolar dichotomies. Arch Gen Psychiatry 1978;35:756–766.
  11. Akiskal HS, Pinto O: The evolving bipolar spectrum: prototypes I, II, III, and IV. Psychiatr Clin North Am 1999;22:517–534.
  12. First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders – Clinician Version (SCID-CV). Washington, American Psychiatric Press, 1997.
  13. Koukopoulos A, Koukopoulos A: Agitated depression as a mixed state and the problem of melancholia. Psychiatr Clin North Am 1999;22:547–564.
  14. Williams JBW, Terman M, Link MJ, Amira L, Rosenthal NE: Hypomania Interview Guide (Including Hyperthymia). Current Assessment Version (HIGH-C). Norwood, Clinical Assessment Tools Packet, Center for Environmental Therapeutics, 1994.
  15. Weissman MM, Wickramaratne P, Adams P, Wolk S, Verdeli H, Olfson M: Brief screening for family psychiatric history. The family history screen. Arch Gen Psychiatry 2000;57:675–682.
  16. Akiskal HS, Bourgeois ML, Angst J, Post R, Moller H-J, Hirschfeld R: Re-evaluating the prevalence and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 2000;59(suppl 1):S5–S30.

    External Resources

  17. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4, Text Revision (DSM-IV-TR). Washington, American Psychiatric Press, 2000.
  18. Akiskal HS, Djenderedjian AH, Rosenthal RH, Khani MK: Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am J Psychiatry 1977;134:1227–1233.
  19. Dunner DL, Tay KL: Diagnostic reliability of the history of hypomania in bipolar II patients and patients with major depression. Compr Psychiatry 1993;34:303–307.
  20. Akiskal HS, Azorin JM, Hantouche EG: Proposed multidimensional structure of mania: beyond the euphoric-dysphoric dichotomy. J Affect Disord 2003;73:7–18.
  21. Benazzi F: Frequency of bipolar spectrum in 111 private practice depression outpatients. Eur Arch Psychiatry Clin Neurosci 2003;253:203–208.
  22. Benazzi F: Diagnosis of bipolar II disorder: a comparison of structured versus semistructured interviews. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:985–991.
  23. Benazzi F, Akiskal HS: Clinical and factor analytic-validation of depressive mixed states: a report from the Ravenna-San Diego collaboration. Curr Opin Psychiatry 2003;16(suppl 2):S71–S78.

    External Resources

  24. Benazzi F: Which could be a clinically useful definition of depressive mixed state? Prog Neuropsychopharmacol Biol Psychiatry 2002;26:1105–1111.
  25. Benazzi F: Bipolar II depressive mixed state: finding a useful definition. Compr Psychiatry 2003;44:21–27.
  26. Benazzi F: Family history validation of a definition of mixed depression. Compr Psychiatry 2005;46:159–166.
  27. Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Keller M, Warshaw M, Clayton P, Goodwin F: Switching from ‘unipolar’ to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry 1995;52:114–123.
  28. 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;73:133–146.
  29. Angst J, Gamma A, Endrass J: Risk factors for the bipolar and depression spectra. Acta Psychiatr Scand 2003;418:15–19.

    External Resources

  30. Benazzi F, Akiskal HS: A downscaled practical measure of mood lability as a screening tool for bipolar II. J Affect Disord 2005;84:225–232.
  31. Sato T, Bottlender R, Schroter A, Moller H-J: Frequency of manic symptoms during a depressive episode and unipolar ‘depressive mixed state’ as bipolar spectrum. Acta Psychiatr Scand 2003;107:268–274.
  32. Kraepelin E: Manic-Depressive Insanity and Paranoia. Edinburgh, Livingstone, 1921.
  33. Koukopoulos A: Ewald Hecker’s description of cyclothymia as a cyclical mood disorder: its relevance to the modern concept of bipolar II. J Affect Disord 2003;73:199–205.
  34. Altman DG, Machin D, Bryant TN, Gardner MJ: Statistics with Confidence, ed 2. Bristol, British Medical Journal Books, 2000.
  35. Rothman KJ, Greenland S: Modern Epidemiology, ed 2. Philadelphia, Lippincott Williams & Wilkins, 1998.
  36. Hosmer DW, Lemeshow S: Applied Logistic Regression. New York, Wiley, 2000.
  37. Schmidtke A, Bille-Brahe U, De Leo D, Kerkhof A (eds): Suicidal Behaviour in Europe: Results from the WHO/EURO Multicentre Study on Suicidal Behaviour. Cambridge, Hogrefe & Huber, 2001.
  38. Akiskal HS, Benazzi F, Perugi G, Rihmer Z: Agitated ‘unipolar’ depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord 2005;85:245–258.
  39. Akiskal HS, Hantouche E, Bourgeois M, Azorin JM, Sechter D, Allilaire JF, Lancrenon S, Fraud JP, Châtenet-Duchêne L: Gender, temperament and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN). J Affect Disord 1998;50:175–186.
  40. Hantouche EG, Akiskal HS, Lancrenon S, Chatenet-Duchene L: Mood stabilizer augmentation in apparently ‘unipolar’ MDD: predictors of response in the naturalistic French national EPIDEP study. J Affect Disord 2005;84:243–249.
  41. Caligiuri MP, Gentili V, Eberson S, Kelsoe J, Rapoport M, Gillin JC: A quantitative neuromotor predictor of antidepressant non-response in patients with major depression. J Affect Disord 2003;77:135–141.
  42. Strakowski SM, McElroy SL, Keck PE Jr, West SA: Suicidality among patients with mixed and manic bipolar disorder. Am J Psychiatry 1996;153:674–676.
  43. Goldberg JF, Garno JL, Portera L, Leon AC, Kocsis JH, Whiteside JE: Correlates of suicidal ideation in dysphoric mania. J Affect Disord 1999;56:75–81.
  44. Raskin A, Schulterbrandt J, Reatig N, McKeon JJ: Replication of factors of psychopathology in interview, ward behavior and self-report ratings of hospitalized depressives. J Nerv Ment Dis 1969;148:87–98.
  45. Andreasen NC, Grove WM: The classification of depression: traditional versus mathematical approaches. Am J Psychiatry 1982;139:45–52.
  46. Sullivan PF, Kessler RC, Kendler KS: Latent class analysis of lifetime depressive symptoms in the national comorbidity survey. Am J Psychiatry 1998;155:1398–1406.
  47. Sullivan PF, Prescott CA, Kendler KS: The subtypes of major depression in a twin registry. J Affect Disord 2002;68:273–284.
  48. Kendler KS, Eaves LJ, Walters EE, Neale MC, Heath AC, Kessler RC: The identification and validation of distinct depressive syndromes in a population-based sample of female twins. Arch Gen Psychiatry 1996;53:391–399.
  49. Korszun A, Moskvina V, Brewster S, Craddock N, Ferrero F, Gill M, Jones IR, Jones LA, Maier W, Mors O, Owen MJ, Preisig M, Reich T, Rietschel M, Farmer A, McGuffin P: Familiality of symptom dimensions in depression. Arch Gen Psychiatry 2004;61:468–474.
  50. Maj M, Pirozzi R, Magliano L, Bartoli L: Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome. Am J Psychiatry 2003;160:2134–2140.
  51. Perugi G, Akiskal HS, Micheli C, Toni C, Madaro D: Clinical characterization of depressive mixed state in bipolar-I patients: Pisa-San Diego collaboration. J Affect Disord 2001;67:105–114.
  52. Krabbendam L, Myin-Germeys I, De Graaf R, Vollebergh W, Nolen WA, Iedema J, Van Os J: Dimensions of depression, mania and psychosis in the general population. Psychol Med 2004;34:1–10.

    External Resources

  53. Akiskal HS, Mallya G: Criteria for the ‘soft’ bipolar spectrum: treatment implications. Psychopharmacol Bull 1987;23:68–73.
  54. Slama F, Bellivier F, Henry C, Rousseva A, Etain B, Rouillon F, Leboyer M: Bipolar patients with suicidal behavior: toward the identification of a clinical subgroup. J Clin Psychiatry 2004;65:1035–1039.
  55. Allen MH, Chessick CA, Goldberg JF: Bipolar disorder with and without suicidal ideation and behavior. New Research Abstract NR444, Am Psychiatr Assoc Annu Meet, New York, 2004.
  56. Busch KA, Fawcett J, Jacobs DG: Clinical correlates of inpatient suicide. J Clin Psychiatry 2003;64:14–19.
  57. Bottlender R, Sato T, Kleindienst N, Strausz A, Moller H-J: Mixed depressive features predict maniform switch during treatment of depression in bipolar I disorder. J Affect Disord 2004;78:149–152.
  58. Baldessarini RJ, Tondo L, Hennen J: Lithium treatment and suicide risk in major affective disorders: update and new findings. J Clin Psychiatry 2003;64(suppl 5):44–52.

    External Resources

  59. Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A: Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60:1079–1088.
  60. AkiskalH, HantoucheEG, AllilaireJF, Sechter D, BourgeoisM, AzorinJM, Chatenêt Duchêne L, LancrenonS: Validating antidepressant-associated hypomania (bipolar III): a systematic comparison with spontaneous hypomania (bipolar II). J Affect Disord 2003;73:65–74.
  61. Benazzi F, Akiskal HS: Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes. J Affect Disord 2001;67:115–122.
  63. Akiskal HS: Developmental pathways to bipolarity: are juvenile-onset depressions pre-bipolar? J Am Acad Child Adolesc Psychiatry 1995;34:754–763.
  64. Rihmer Z, Rutz W, Pihlgren H: Depression and suicide on Gotland. An intensive study of all suicides before and after a depression-training programme for general practitioners. J Affect Disord 1995;35:147–152.
  65. Isacsson G: Suicide prevention – A medical breakthrough? Acta Psychiatr Scand 2000;102:113–117.
  66. Rutz W: Preventing suicide and premature death by education and treatment. J Affect Disord 2001;62:123–129.
  67. Leon AC, Marzuk PM, Tardiff K, Teres JJ: Paroxetine, other antidepressants, and youth suicide in New York city: 1993 through 1998. J Clin Psychiatry 2004;65:915–918.
  68. Rihmer Z: Decreasing national suicide rates – Fact or fiction? World J Biol Psychiatry 2004;5:55–56.
  69. Yerevanian BI, Kock RJ, Feusner JD, Hwang S, Mintz J: Antidepressants and suicidal behavior in unipolar depression. Acta Psychiatr Scand 2004;110:452–458.
  70. Grunebaum MF, Ellis SP, Li S, Oquendo MA, Mann JJ: Antidepressants and suicide risk in the United States, 1985–1999. J Clin Psychiatry. 2004;65:1456–1462.
  71. Gunnell D, Harbord R, Singleton N, Jenkins R, Lewis G: Factors influencing the development and amelioration of suicidal thoughts in the general population. Cohort study. Br J Psychiatry 2004;185:385–393.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50