Vol 2 #10

Alan Eppel

The introduction  of a category for “Depression with Mixed Features” in DSM 5 has opened a Pandora’s box of confusion.

This new category threatens to undermine Leonard’s original division of manic-depressive illness into bipolar and unipolar types.

The new definitions mean that comparisons with existing literature will not be possible.

Early definitions of mixed states include those of Kraeplin who in 1921 described six subtypes of mixed states.

  1. Depressive or anxious mania
  2. Excited or agitated depression
  3. Mania with poverty of thought
  4. Manic Stupor
  5. Depression with Flight of Ideas
  6. Inhibited Mania


Depressive or anxious mania was characterized by an anxiously despairing mood with overactivity and restlessness, flight of ideas.

Excited or agitated depression was described as an anxious despondent and irritable mood; agitated overactivity with ringing of the hands and crying out loud; poverty of thought and delusions.

Mania with poverty of thought was described as elated mood and irritation. Overactivity with excitement and impulsivity. Slowness of thought and difficulty with recall.

Mania with Stupor consisted of elation and marked motor retardation.

Depression with Flight of Ideas comprised depressed mood, motor retardation, delusions and flight of ideas when writing.

Inhibited Mania included elation and motor retardation punctuated by violent outbursts and flight of ideas.

While the above classifications are no longer used it is possible to identify core symptom of mixed states. The DSM 5 criteria appear arbitrary and unnecessary.

The purpose of diagnosis is to determine appropriate treatment. Diagnostic categories are not created to expand the market for specific pharmacological agents.

The bipolar unipolar distinction has been helpful in delineating differing prognoses and treatment responses. Specifically mood stabilizers are the mainstay of pharmacological treatment in bipolar disorder. First-line agents include lithium, valproate and lamotrigine. Antipsychotic medications have demonstrated effectiveness but have a large side effect burden. Quetiapine may be the least harmful if there is a failure of response to first-line mood stabilizers. Most importantly it has been established that antidepressants are ineffective in bipolar disorder and potentially harmful. Antidepressants may lead to cycle acceleration, mood switches and mixed states.

Mixed states may have a higher rate of completed suicide. The combination of profoundly dysphoric mood with racing thoughts and extreme agitation creates an unbearable subjective state that contains both the motivational content and the energy required to make a lethal suicide attempt.

It is of interest to note that in a paper written in 1936 Gerald Jameison reviewed 100 cases of completed suicide. Thirty six of the patients who completed suicide after discharge from hospital were diagnosed with manic depressive psychosis. This group included 10 of whom we would now diagnose with unipolar depression and 11 patients with periods of mania and depression. There were 15 patients diagnosed with mixed manic-depressive states.

Jameison believed that patients in mixed states were the most dangerous with regard to suicide risk because of the combination of depressive symptoms and  “a mental alertness associated with tense, apprehensive  and restless behavior”.

The introduction of depression with mixed features in DSM 5 is a retrograde step and the motivation for doing so is suspect. Most studies on treatment of depression with mixed features with antispsychotic medications have been carried out by authors with multiple conflicts of interest. Depression in combination with symptoms of mania or hypomania is clearly within the bipolar spectrum and should be treated accordingly. There is no imperative to advocate the use of recently developed and highly priced antipsychotic medications when standard mood stabilizers and in particular valproate have been found to be very effective.


Ghaemi SN, Gilmer WS, Goldberg JF, Zablotsky B, Kemp DE, Kelley ME, Bauer AD, Fleck J, Filkowski MM, Stan VA, Dunn RT. Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study. J Clin Psychiatry. 2007 Dec;68(12):1840-4.

Golden JC, Goethe JW, Woolley SB. Complex psychotropic polypharmacy in bipolar disorder across varying mood polarities: A prospective cohort study of 2712 inpatients. J Affect Disord. 2017 Oct 15;221:6-10. doi:10.1016/j.jad.2017.06.005. Epub 2017 Jun 13.

Goodwin F, Redfield Jamison K. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd edition Oxford 2007 P.72-77.

Jameison GR.  Suicide and Mental Disease: a clinical analysis of one hundred cases. Archives  Neurology Psychiatry 36, p.1-12, 1936.

Koukopoulos A, Sani G, Nassir Ghaemi N. Mixed features of depression: why DSM-5 is wrong (and so was DSM-IV)  British Journal of Psychiatry Jul 2013, 203 (1) 3-5. 2013 DOI:10.1192/bjp.bp.112.124404

Mokhber N, Lane CJ, Azarpazhooh MR, Salari E, Fayazi R, Shakeri MT, Young AH. Anticonvulsant treatments of dysphoric mania: a trial of gabapentin, lamotrigine and carbamazepine in Iran. Neuropsychiatr Dis Treat. 2008 Feb;4(1):227-34.

Suppes T, Brown E, Schuh LM, Baker RW, Tohen M. Rapid versus non-rapid cycling as a predictor of response to olanzapine and divalproex sodium for bipolar mania and maintenance of remission: post hoc analyses of 47-week data. J Affect Disord. 2005 Dec;89(1-3):69-77. Epub 2005 Oct 25.

Tohen M, Gold AK, Sylvia LG, Montana RE, McElroy SL, Thase ME, Rabideau DJ, Nierenberg AA, Reilly-Harrington NA, Friedman ES, Shelton RC, Bowden CL, Singh V, Deckersbach T, Ketter TA, Calabrese JR, Bobo WV, McInnis MG. Corrigendum to bipolar mixed features – Results from the comparative effectiveness for bipolardisorder (Bipolar CHOICE) study.

Journal of Affective Disorders 217 (2017) 183-189. J Affect Disord. 2017 Aug 18. pii: S0165-0327(17)31687-7. doi: 10.1016/j.jad.2017.08.032

Weisler RH, Cutler AJ, Ballenger JC, Post RM, Ketter TA. The use of antiepileptic drugs in bipolar disorders: a review based on evidence from controlled trials. CNS Spectr. 2006 Oct;11(10):788-99.

Yerevanian BI, Koek RJ, Mintz J. Bipolar pharmacotherapy and suicidal behavior. Part I: Lithium, divalproex and carbamazepine. J Affect Disord. 2007 Nov;103(1-3):5-11. Epub 2007 Jul 12.



Print Friendly, PDF & Email