last updated 3/10/24
How broad is the spectrum of mixed states? Different answers lead to different treatment approaches.
Background for going beyond the DSM-5 definition
The 2013 DSM-5 says that any depression can have “Mixed Features”, meaning depression combined with some manic symptoms. This even applies to “plain “unipolar” depression, meaning “depression-that-is-not-bipolar”. Got it? You can have manic symptoms without having bipolar disorder. Confusing?
A simpler way to understand Mixed States was presented by a team of mood specialists in 2021. Starting from this simple idea:
they fancied it up a bit (vertical axis description is mine).
If you ignore the black diagnoses inside this yellow-blue graph, you see a spectrum from very mixed in the upper right, to not at all mixed in the lower left. Any number of manic symptoms counts. And any type of manic symptom counts.
In contrast, the DSM only allows the Mixed Features label when three or more manic symptoms are present; and some manic symptoms do not count, including anxiety, anger, agitation and attention problems. Why not? Because these symptoms are also seen in Major Depression. Thus they do not distinctly separate patients who are having a mixture of depression and manic symptoms from those who are having depression along. So they said.
But at least 3 studies published since the DSM-5 in 2013 have found these four symptoms (or their close relatives) to be very common in patients with depression. When these symptoms are allowed (rather than disallowed, as in the DSM), the number of patients who “qualify” for a mixed state broadens dramatically. And that broadens the number of people who might consider treating their depression as a mixed state.
What does this mean for treatment?
Antidepressants can make mixed states worse. Therefore broadening the definition of depressed mixed states means broadening the number of people whose depression should be treated without antidepressants.
But very often a person’s position on the mood spectrum is not clear. Other diagnostic explanations (PTSD, anxiety, attention deficits, “borderline”) must be considered, but for many people with depression, sorting mixed states from these other diagnoses is nearly impossible. (See why this is so difficult.)
That’s when you have to decide upon a treatment by comparing the risks of your options. The potential benefits will be about the same for any of the main diagnostic possibilities, because of the diagnostic uncertainty. Therefore, in general, you should consider low-risk and low-cost alternatives first and high risk/high cost alternatives last.
Lowest risk? That’s self-change and some kinds of psychotherapy, e.g. online CBT. One change particularly important for mixed states is a establishing regular sleep schedule. Tools for that in the links below.
Howa about pills? The medications for depressive mixed states are the “mood stabilizers with antidepressant effects”. For now, these include lamotrigine, low-dose lithium, quetiapine and perhaps lurasidone. Other mood stabilizers (divalproex, carbamazepine) do not have reliable antidepressant effects. Other anti-manic pills are also mood stabilizers, but their antidepressant effects are less or unpredictable (aripiprazole and risperidone). Olanzapine is also a mood stabilizer with antidepressant effects, but its side effects (weight gain, glucose increases) are common and large.
To summarize: mixed state treatments begin with consideration of self-change and psychotherapies, particularly creating a regular sleep schedule. Pill options are MSAE’s, mood stabilizers with antidepressant effects: lamotrigine, low-dose lithium, quetiapine and perhaps lurasidone.
How far down the mood spectrum from bipolar disorders toward plain depression should these mixed state treatment approaches be considered? Certainly for someone with a clear diagnosis of bipolar disorder. Not at all for a plain, unmixed depression (self-change and psychotherapies yes, but not lamotrigine. Other mood stabilizers might be considered for a plain, unmixed depression — but not as first steps).
What if your position on that spectrum is not clear? (How mixed is your depression? is some other diagnosis a better explanation?) Notice: self-change and psychotherapies do not make mixed states worse, so they should still be considered first, including the emphasis on a regular sleep schedule.
As for the pills though: it comes down to a comparison of the risks of antidepressants versus mood stabilizers with antidepressant effects. Different psychiatrists and psychiatric nurse practitioners will present these risks differently.
See my opinions about treatment for mixed states or a direct comparison of antidepressants versus lamotrigine.
References
Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, Gamma A, Young AH, BRIDGE Study Group. Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study. Archives of general psychiatry. 2011 Aug 1;68(8):791-9.
Frye MA, Helleman G, McElroy SL, Altshuler LL, Black DO, Keck Jr, MD PE, Nolen WA, Kupka R, Leverich GS, Grunze H, Mintz J. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. American Journal of Psychiatry. 2009 Feb;166(2):164-72.
Goldberg JF, Perlis RH, Ghaemi SN, Calabrese JR, Bowden CL, Wisniewski S, Miklowitz DJ, Sachs GS, Thase ME. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. American Journal of Psychiatry. 2007 Sep;164(9):1348-55.
Sani G, Vöhringer PA, Napoletano F, Holtzman NS, Dalley S, Girardi P, Ghaemi SN, Koukopoulos A. Koukopoulos׳ diagnostic criteria for mixed depression: a validation study. Journal of affective disorders. 2014 Aug 1;164:14-8.
Suppes T, Eberhard J, Lemming O, Young AH, McIntyre RS. Anxiety, irritability, and agitation as indicators of bipolar mania with depressive symptoms: a post hoc analysis of two clinical trials. International journal of bipolar disorders. 2017 Dec;5(1):1-1.
Targum SD, Suppes T, Pendergrass JC, Lee S, Silva R, Cucchiaro J, Loebel A. Major depressive disorder with subthreshold hypomania (mixed features): clinical characteristics of patients entered in a multiregional, placebo-controlled study. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2016 Jul 4;68:9-14.
Yatham, L.N., Chakrabarty, T., Bond, D.J., Schaffer, A., Beaulieu, S., Parikh, S.V., McIntyre, R.S., Milev, R.V., Alda, M., Vazquez, G. and Ravindran, A.V., 2021. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations. Bipolar disorders, 23(8), pp.767-788.