Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Depression following mania

Yatham et al.1 recently reported on a controlled trial in bipolar disorder-I (BD-I) patients treated for acute mania with mood stabilizers (lithium or valproate) plus an antipsychotic (olanzapine or risperidone) to remission for 2–6 weeks, followed by discontinuation of the antipsychotic agent to placebo at randomization or 6 months later, or continuation on all treatments for 12 months. Reported survival functions (their Figure 2) indicate that more prolonged use of antipsychotics limited the risk of mania substantially, and similarly, if continued for six or 12 months, with lesser prevention of depression. Based on the reported survival functions, risks of depression were higher and rose earlier than for mania: ~40 vs 10% at 3 months (χ2=13.1, P=0.0003) without antipsychotic treatment, but with mood stabilizer continued. However, treatment with the atypical antipsychotics appeared not to increase the early risk of depression, as has been reported previously.2

The excess of depression over mania observed in the study, even with mood-stabilizer treatment, calls for comment. It may be that depression shortly following recovery from mania is not a random event. Instead, it may represent a biphasic, mania-depression cycle as a manifestation of the natural history of the disorder. Kraepelin3 proposed that ‘exhaustion’ following mania, rather than being a consequence of severe illness, is ‘obviously only a case of the transition to depression peculiar to the disease.’ This pattern of the polarity of illness episodes accords with reported course sequences in BD.4, 5, 6, 7, 8 One-third to half of BD-I patients (strikingly similar to the 40% observed by Yatham et al.1) follow a biphasic course in which depressive episodes occur within weeks after manias, and are then followed by illness-free intervals (mania-depression-interval, MDI pattern).4 The proportion of such patients probably is even greater if selection is based on having a recent index manic episode, as in the study by Yatham et al.1 In addition, approximately one-fifth to one-quarter of BD-I patients follow the opposite sequence (depression-mania-interval, DMI).4 This distinction is of more than theoretical interest in that the MDI course sequence shows a more favorable response to mood-stabilizing treatments.4, 5, 6, 7, 8, 9 Based on a meta-analysis of six long-term trials, responsiveness to such treatment was 71% superior among MDI versus DMI patients.9 The more beneficial effect of mood stabilizers and antipsychotics in MDI than DMI patients may reflect suppression of mania, with consequent avoidance of usually associated depression.10

In general, bipolar depression has been far more difficult to treat and prevent than mania or hypomania.11, 12, 13 Moreover, we suggest that depression following mania in the MDI course-sequence: (a) often is a component of a biphasic manic-depressive cycle; (b) may be virtually inevitable once mania has occurred; (c) requires distinction from sporadic bipolar depressive episodes; and (d) represents a particular therapeutic target.


  1. 1

    Yatham LN, Beaulieu S, Schaffer A, Kauer-Sant'Anna M, Kapczinski F, Lafer B et al. Mol Psychiatry 2015 [Epub ahead of print 13 October]..

  2. 2

    Vieta E, Angst J, Reed C, Bertsch J, Haro JM . J Affect Disord 2009; 118: 118–123.

    Article  Google Scholar 

  3. 3

    Kraepelin E . Manic Depressive Insanity and Paranoia. E. & S. Livingstone, Edinburgh: Edinburgh, Scotland, 1921, pp 73–74.

    Google Scholar 

  4. 4

    Kukopulos A, Reginaldi D, Laddomada P, Floris G, Serra G, Tondo L . Pharmakopsychiatr Neuropsychopharmakol 1980; 13: 156–157.

    CAS  Article  Google Scholar 

  5. 5

    Grof P, Haag M, Grof P, Haag H . Prog Neuropsychopharmacol Biol Psychiatry 1987; 11: 199–203.

    CAS  Article  Google Scholar 

  6. 6

    Haag H, Heidorn A, Haag M, Greil W . Prog Neuropsychopharmacol Biol Psychiatry 1987; 11: 205–208.

    CAS  Article  Google Scholar 

  7. 7

    Maj M, Pirozzi R, Starace F . J Affect Disord 1989; 17: 237–241.

    CAS  Article  Google Scholar 

  8. 8

    Faedda GL, Baldessarini RJ, Tohen M, Strakowski SM, Waternaux C . Am J Psychiatry 1991; 148: 1237–1239.

    CAS  Article  Google Scholar 

  9. 9

    Koukopoulos A, Reginaldi D, Tondo L, Visioli C, Baldessarini RJ . J Affect Disord 2013; 151: 105–110.

    CAS  Article  Google Scholar 

  10. 10

    Koukopoulos A, Ghaemi SN . Eur Psychiatry 2009; 24: 125–134.

    Article  Google Scholar 

  11. 11

    Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M et al. Bipolar Disord 2013; 15: 1–44.

    CAS  Article  Google Scholar 

  12. 12

    Forte A, Baldessarini RJ, Tondo L, Vázquez G, Pompili M, Girardi P . J Affect Disord 2015; 178: 71–78.

    Article  Google Scholar 

  13. 13

    Vázquez GH, Holtzman JN, Lolich M, Ketter TA, Baldessarini RJ . Eur Neuropsychopharmacol 2015; 25: 1501–1512.

    Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to L Tondo.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tondo, L., Baldessarini, R. Depression following mania. Mol Psychiatry 21, 990 (2016).

Download citation

Further reading


Quick links