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Associate Clinical Professor
Washington University School of Medicine
St Louis, Missouri
Midwest Research Group
St. Louis, Missouri
Greg W. Mattingly, MD: speaker fees: AbbVie, Alkermes, Corium, Eisai, Intracellular, Ironshore, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Sunovion, Supernus, Takeda, Trispharma; consulting fees: AbbVie, Acadia, Alkermes, Axsome, Corium, Eisai, Ironshore, Intracellular, Janssen, Lundbeck, Neos, Neurocrine, Noven, Otsuka, Redax, Roche, Rhodes, Sage, Sirona, Sunovion, Supernus, Takeda, Teva, Trispharma; funds for research support: AbbVie, Acadia, Alkermes, Akili, Axsome, Boehringer, Emalex, Idorsia, Janssen, Karuna, Lumos Labs, Medgenics, NLS-1 Pharma AG, Redax, Relmada, Roche, Sage, Sirtsei, Sunovion, Supernus, Takeda, Teva.
When we think about bipolar disorder, we often have this idea of the patient who comes in and is floridly manic. That patient who we saw in training, who got hospitalized—maybe they were hallucinating, maybe they were brought in by the police. That patient who couldn’t stop talking, wasn’t sleeping—that florid version of a patient who is suffering a manic episode.
As we all know, that’s a very small portion of the illness. The more common version of what we see in clinical practice involves patients struggling with bipolar depression or bipolar disorder with mixed symptoms. These may not be as straightforward to diagnose and treat.
Differential Diagnosis: Unipolar vs Bipolar Depression
We know that early on in the illness, people will cycle; they may have high cycles, or they may have low cycles. Their brain may get stuck at either of those poles, and by definition, to be diagnosed with bipolar 1, a patient has to be stuck in a manic episode for at least 7 days or even hospitalized. For bipolar 2, an even more common condition, a patient has to be manic or hypomanic for 4 days or less and never had to be hospitalized for it.
Those manic or hypomanic poles are only a small part of the illness. Most of the illness, what people cycle in and out of, is low levels of depression or stubborn depressions that won’t go away. If most of the illness is spent depressed rather than manic or hypomanic, then depression is quite often the chief presentation for many of our patients. Of course, this is why we, as healthcare professionals, sometimes miss the diagnosis. If the chief complaint is “I’m depressed” or “this depression is breaking up my marriage” or “this depression has made me consider suicide,” then many people lean toward accepting that complaint at face value and diagnosing unipolar depression.
To help avoid a missed diagnosis, I teach my residents, my medical students, and the advanced practice providers who work with us to remember that depression is a chief complaint, but it’s not always a diagnosis. When depression is the chief complaint, we should be curious about it: What type of depression do we have here? Do we have unipolar depression that may respond to antidepressants? Do we have bipolar depression where antidepressants, by themselves, are the wrong treatment, and possibly even worse than no treatment? Or do we have depression with mixed symptoms?
Bipolar Depression Symptoms
The symptoms that we use to diagnose bipolar depression are the same that we use for unipolar depression—it’s those 9 symptoms on the PHQ-9. To qualify, a patient has to have 5 or more of those symptoms and have been “stuck” in them for at least 2 weeks. Since these symptoms are identical to those for unipolar depression, it makes sense that people can miss the diagnosis.
What’s different between the two is the clinical history. People with bipolar depression will typically have an earlier onset of illness. For example, if you’re seeing somebody in their 20s and they say, “Listen, I’ve struggled with this stuff since I was a kid, since I was a teenager,” that should increase your suspicion that this could be bipolar depression. Bipolar depression also tends to have more episodes throughout somebody’s life. As you go through their clinical history, keep an eye out for cycling in and out of episodes—some of those episodes with quick onset—that should also increase your suspicion that this is bipolar depression.
If someone has had what we call “antidepressant misadventures” or has tried antidepressants and they “just didn’t stick” or increased their irritability, that, too, should increase your suspicion for bipolar depression.
Finally, genetics can be used to help make an accurate diagnosis. The genetic heritability of bipolar disorder is approximately 75%, with unipolar depression it’s approximately 40%. When you look at the family of someone who’s affected by the bipolar spectrum, you’ll find many people affected with various types of mood disorders—depression, bipolar 1, bipolar 2—approximately twice as many family members vs the family members of a patient with unipolar depression.
The next thing to tease out in bipolar disorder are mixed symptoms. In the DSM‑5, mixed symptoms means a patient is in one pole—either depressed or manic/hypomanic—and on top of that, they have 3 or more symptoms of the opposite domain. For example, patients with bipolar depression and mixed symptoms might be depressed, sad, and dysphoric but can’t shut their mind off. Their minds are racing, they’re impulsive, they may be irritable and erratic, but they also may be depressed, sad, and dysphoric.
Why is that important? Because the more mixed symptoms patients have, even if their current episode is depressed, the more likely that their long‑term history points to a diagnosis of bipolar. So when you screen with the MDQ and you start seeing more of those mixed episodes show up on top of a patient’s depressive episode, it increases your suspicion that, down the road, this person may be diagnosed with bipolar disorder.
Now, why is correct diagnosis and differential between unipolar and bipolar depression so important? Because if someone has bipolar depression, with or without mixed features, quite often the worst treatment is an antidepressant. In a large study of patients with mixed symptoms, patients confirmed that the worst response to medicine they had was to an antidepressant. The middle ground was mood stabilizers, and their best response had been to low-dose atypical antipsychotics. These were people who had not yet had a full‑blown manic episode. This has held true in various other studies that I’ve been a part of.
What may be a surprise to many of you is that mood stabilizers have not been shown to work if the patient is in a depressive episode with bipolar disorder. They’ve never been shown to be effective for getting patients out of that episode. They help to prevent cycling down the road but not to help get a patient out of a bipolar depression episode.
There are currently 5 medicines approved for the bipolar depression spectrum, all of which are various versions of atypical antipsychotics. Now, how do I pick and choose among those 5?
Part of what we should be looking at is what a patient has tried in the past. We also need to consider their current symptoms. Maybe the current symptom is their brain “just won’t shut off,” and even though they’re depressed, they just can’t sleep. In that case, I may lean toward a sedating agent.
Sedation can be tricky, though. At the beginning, sedation can be your friend with a medicine; in the long term, sedation tends to be your enemy. Over time, highly sedating compounds tend to have lower functional outcomes: It’s harder for patients to work, to learn, and to do their jobs.
I also consider 2 adverse events—weight gain and sexual function—because these tend to be primary concerns for patients. Some of our options for bipolar depression tend to have significant weight gain effects and destabilize the appetite, which a patient may be highly concerned about. A few of the newer options tend to be very metabolically friendly, either weight neutral or even leading to a little bit of weight loss. If a patient is concerned about weight gain or is already obese, I may choose one of those options. In terms of sexual function, a number of the atypicals will raise prolactin, which can obviously can cause hormonal changes in both women and men. Some of the available agents have a more tolerable hormonal and sexual adverse event profile and can be considered.
Thinking about the world of bipolar disorder, we need to identify where our patients “live,” whether they are primarily cycling in and out of depression or having mixed episodes; avoid the treatment mistakes like missing the diagnosis and prescribing antidepressants; and finally, consider the risk-to-benefit profile for the 5 agents that have been shown effective in bipolar depression.