last updated 3/26/2024
Antidepressants can cause mixed states and make them worse. So treatment of mixed states focuses on using other antidepressant tools that don’t make mixed states worse. How this is done depends on whether an antidepressant is already in use.
I’m mixed, and not taking an antidepressant
If you’ve decided that the problem is a mixed state (depression with mixed features), and there’s no antidepressant already in use, then treatment options are pretty simple. Add a mood stabilizer with antidepressant effects (MSAE) — and the first option is a therapy, not a pill.
A mood stabilizer that’s not a pill
For most people with depression and mixed features, sleep is a problem. Sleep hours are not consistent. One way to make mood more stable is to push sleep toward a regular schedule. Not easy, for many people.
You can start by simply working on a regular bedtime and a regular rise time. Here’s a video to help you with that.
Or for more help, there’s a whole psychotherapy designed to help establish regular sleep times, as well as other regular social rhythms. If you can’t find a therapist who knows it, there’s also a workbook version of “Social Rhythm Therapy“
Mood Stabilizers with Antidepressant Effects (MSAE)
Mood stabilizers help prevent mood ups and downs. All except lamotrigine are anti-manic. Some have antidepressant as well as mood stabilizing effects.
| Mood Stabilizers with Antidepressant Effects | Advantages | Disadvantages |
| lamotrigine/Lamictal | Years of experience No side effects for most No big long-term risks | 1-in-2,000 chance of a very severe allergic reaction |
| low-dose lithium | Years of experience No side effects for most* Anti-suicide effects Lowers risk of dementia? | Blood testing required Can affect thyroid |
| quetiapine/Seroquel | Years of experience Usually helps sleep Fast | Weight gain common Sedation at first |
| lurasidone/Latuda | Less weight gain than quetiapine | Too antidepressant Still some weight gain |
Two other mood stabilizers have less reliable antidepressant effects: valproate/divalproex, and carbamazepine. Three other anti-manic medications (often called antipsychotics but they are also anti-manic) are: aripiprazole/Abilify, risperidone, and olanzapine. Olanzapine is the strongest, and also has antidepressant effects, but causes by far the most weight gain so comes last on this list.
Add an MSAE and observe
So treatment is simple: add an MSAE, and observe. Remember that regular sleep times (and other social rhythms) are also an MSAE. Among the pills, which to try first? Lamotrigine has the fewest side effects and no significant long term risks at all, so that seems to me to be the most logical place for most people to start. But quetiapine has better evidence for rapid antidepressant effects, so if that’s what’s needed, sometimes it might be worth taking on the weight gain risk.
Low-dose lithium is not the full-dose lithium used in manic-depressive illness (now called Bipolar I). It takes a little more direct management than lamotrigine or quetiapine. Or so some prescribers think. For now, recognize that it’s an option.
Lurasidone causes much less weight gain than quetiapine, but not zero; and it sometimes acts too much like an antidepressant, causing more mixed state symptoms. Lamotrigine can do this too, but probably much less often (fewer case reports).
I’m mixed, and taking an antidepressant
In a patient with depressed mixed state, if an antidepressant is already in use, there are two ways to proceed:
- Keep the antidepressant and add a strong anti-manic ; or
- Taper the antidepressant and add antidepressant tools as needed.
Keep the antidepressant and add a strong anti-manic
When an antidepressant has helped enough to be worth continuing, but mixed state symptoms are present, many prescribers will add an anti-manic to counterbalance the antidepressant. Most often they’ll choose aripiprazole or risperidone; more rarely olanzapine (because of its weight gain problems); and even more rarely valproate/divalproex (because it’s a little harder to manage, and because it can cause abnormalities in developing fetuses, so is avoided in women of reproductive age). Only a mood specialist would consider carbamazepine, because it is much more complicated to use.
So now the patient is on an antidepressant and aripiprazole or risperidone. What’s wrong with this approach? If the outcome is great…. that’s great. Any changes should be cautious, because sometimes getting a great outcome in mixed states is difficult. On the other hand, antipsychotics have significant long-term risks (metabolic effects that raise the risk of heart disease; and tardive dyskinesia). And, in my experience, most people dislike how it feels to be on one of these antipsychotics — it’s better than being mixed, but not back to their best function and pleasures in life.
So I prefer a different approach. The goal is to achieve mood stability, without depression, with the fewest number of medications and the lowest long-term risks.
Taper the antidepressant and use other antidepressant tools
If an antidepressant has improved the depression, but mixed state symptoms have developed, then in my experience, a good long-term outcome is unlikely unless the antidepressant is removed. If not, mood instability will develop, including a return of the depression despite the antidepressant. Or the mixed state symptoms will worsen. Adding an anti-manic (like an antipsychotic: risperidone, aripiprazole, quetiapine, or olanzapine) is one way to cope. But there’s another way: taper the antidepressant slowly, and use other antidepressant tools as needed. There are quite a few options:
- lamotrigine
- Fish oil
- Light therapies
- Self-change, particularly physical activity
- low-dose lithium
Lamotrigine: If mixed state symptoms are severe, then an anti-manic will be needed before the antidepressant taper begins. Lamotrigine is not strongly antimanic. But it is a mood stabilizer. So if symptoms are erratic, rapidly changing or mixing depression with anxiety, irritability, agitation and attention problems, lamotrigine is still a candidate worth considering. It’s not a direct solution to mixed state symptoms, but it’s a great long-term tool. The anxiety/irritability/agitation/attention problems might diminish as the antidepressant dose goes down, ultimately landing the patient on lamotrigine alone without exposure to any other medications/risks.
Fish oil: the logic here is the same as for lamotrigine. Omega-3s from fish oil are not anti-manic, but they are antidepressant in many people (multiple randomized trials say so) and strong evidence suggests they have a mood stabilizer effect.
Light therapies: dawn simulators are simple and inexpensive and harmless and have no side effects. Doesn’t that sound like a good idea. Dawn simulators have antidepressant effects (particularly in seasonal mood shifts, but also when they are used to help sleep timing move earlier). Light therapy using a “light box” is different: it can be too antidepressant, destabilizing mood. So in the context of mixed states, start with a dawn simulator and consider a using a light box only with great caution.
Self-change is hard under any circumstances, harder yet when depression or mixed state symptoms are present. See more specifics, including how-to’s and helpful tools, on the Self-change page. But note: changing sleep and physical activity is not impossible, even during a mixed state. A great first step is shifting toward very regular bed- and rise-times. Increasing physical activity is especially hard, but it’s also a well-researched antidepressant that doesn’t destabilize mood.
Low-dose lithium comes last here because it requires more management. But it has no major long-term risks if properly managed. But it can cause weight gain, though less than the antipsychotics aripiprazole and risperidone. It is worth considering when suicide is clearly a risk, because even very low doses of lithium have an anti-suicide effect (people just don’t attempt it as often; and even think about it less while on lithium. It’s interesting).
In summary: the idea is to taper the antidepressant and then add one or more of these other tools as needed while the antidepressant dose is going down. Here’s a key thought: sometimes, tapering the antidepressant is the main change needed. But it can take a long time. So sometimes these other tools are really needed just to “buy time”: to help maintain hope for improvement while the antidepressant dose goes down.
References
Balanzá-Martínez V, Fries GR, Colpo GD, Silveira PP, Portella AK, Tabarés-Seisdedos R, Kapczinski F. Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert review of neurotherapeutics. 2011 Jul 1;11(7):1029-47.