TCPR: Dr. Aiken, before we get into some of the controversies about the bipolar spectrum, can you give us a brief history of bipolar disorder?

Dr. Aiken: Certainly. The modern conception of bipolar disorder dates to the early 20th century, mainly to German psychiatrist Emil Kraepelin, who was a very astute observer. Kraepelin noticed that some patients in his psychiatric hospital had a chronic psychosis, which he labeled “dementia preocox” (we now call it schizophrenia), whereas others had episodic psychosis, usually with some mood disorder, and these he labeled “manic-depressive psychosis.” This large category included some patients that we would now recognize as having “pure” unipolar depression, some with bipolar disorder, and many who were somewhere in between these extremes.

 

TCPR: So, it sounds like Kraepelin was the original proponent of the bipolar spectrum idea!

Dr. Aiken: In a sense he was. He believed that depression and mania were part of a “single morbid process,” and interestingly, this was the mainstream conception of manic depression until 1980 and DSM-III. If you look at DSM-II from 1968, it defines manic-depressive illness as “a single disorder of mood, either extreme depression or elation, that dominates the mental life of the patient.”

 

TCPR: That’s very true. So what else did we learn from Kraepelin?

Dr. Aiken: Kraepelin did try to split the extremes of mania and depression into different illnesses, but he could not arrive at a satisfactory way of doing so because he saw so much overlap between them, particularly through mixed states. He had a keen eye for these mercurial states, noticing how his depressed patients often had various symptoms of “excitation,” even if they never had pure mania. He even complained that his contemporaries were more interested in the “pure forms” than they were in the mixed states. When a lot of research is done on the pure forms of all psychiatric disorders, I think we can hear that kind of controversy today. But practicing psychiatrists tend to see patients with a mix of many features that fit into different categories. That can make it difficult to translate the results of clinical trials into the real world of the patients who show up in our office (Kennedy-Martin T et al, Trials 2015;16:495).

 

TCPR: Then what happened with DSM-III?

Dr. Aiken: DSM-III completely split manic depression into the unipolar and bipolar sides. This wasn’t done rashly; it was based on 20 years of research showing that the extreme ends of the disorders differ in their family histories, treatment response, and course of illness. DSM-III took a categorical approach to mood disorders—but that isn’t necessarily incompatible with a dimensional approach. I think it makes sense to most people to say that, at the distal ends, depression and bipolar disorder are very different illnesses and need different treatment. You wouldn’t give a bipolar I manic an antidepressant, and you wouldn’t give a pure dysthymic Depakote, but in between there’s an overlap.

 

TCPR: Certainly I was trained with the conception that bipolar disorder is its own category, and to some extent, that’s still how I practice. But I’m noticing more articles in the literature about the different “flavors” of bipolar. And in DSM-5 there are so many diagnostic choices: manic episodes, manic with mixed features, hypomanic episodes, depressive with mixed features, depressive episodes. These categories do sound like they probably have more fidelity to the actual patients that I see, but on the other hand, it becomes confusing and hard to reliably diagnose patients when we have so many labels to choose from.

Dr. Aiken: I fully agree, and with DSM-5, as you pointed out, there are so many categories that, if you line them all up, they almost look like a spectrum—particularly if you include “recurrent depression with brief hypomanias,” which is listed in the appendix and refers to people with hypomanias that last less than 4 days.

 

TCPR: What is the definition of this new mixed features category?

Dr. Aiken: DSM-5 defines depression with mixed features as a patient who meets criteria for depression and who also has “at least 3 manic symptoms during a depression.” A quarter of unipolar depressives have mixed features by that definition, but the actual rate falls 2- to 3-fold because of a controversial decision that the DSM-5 committee made to exclude from the diagnosis symptoms of irritability, distractibility, and agitation. Either way, trying to appreciate mixed states from the separate manic and depressive criteria is like trying to visualize green by looking at yellow and blue. The original description by Koukopoulos, one of the founders of the concept, captures it much better: “The patient complains of anxiety, inner tension, irritability, anger, despair, suicidal impulses, crowded or racing thoughts, rumination, and insomnia.” (Koukopoulos A et al, Encephale 1992;1(1):19–21). They are “tired and wired”—driven to do something, but they don’t know what to do.

 

TCPR: For me, that sounds like it could describe any number of my patients who I would normally diagnose with severe depression. How would I differentiate mixed depression from severe depression with anxious features?

Dr. Aiken: Yes, it’s a difficult diagnosis to make. One clue is exactly what you said—severity. Mixed states are more severe. They have the highest rate of suicide of any bipolar condition. With higher rates of side effects and lower rates of response, treatment is difficult. The interview is colored with desperation. These patients want you to do something now, whereas most depressed patients have a sense of hopelessness and must be convinced that you can even do anything to help. Last week, I saw someone in a mixed state. I suggested that she try blue-light filtering glasses to help her manic symptoms. She immediately said, “I’ll go out and buy 10 of them!” That’s not what depressed people say. They say, “Yeah, that’s not gonna work. Nice try, doc.” They’re more negative and hopeless, whereas those with mixed features are impulsive and seek quick relief, such as with benzos, substance abuse, self-cutting—which can release endogenous opioids—and, in the worst cases, suicide. Even if it’s disorganized, the impulsivity of mania tends to be pleasurable or productive. In mixed states, that impulsivity is destructive.

 

TCPR: So it sounds like, if you see a lot of these patients, you can start to more easily recognize mixed features. That’s a result of repetition and practice. But I know there are also evidence-based guidelines and scales to help those of us who have less experience with these patients. Can you tell us about these?

Dr. Aiken: Yes, the symptoms are hard to pin down. They shift rapidly and cross into other diagnostic categories such as ADHD, PTSD, GAD, and Cluster B personality disorders. A new treatment guideline by Stahl and ­colleagues recommends taking a “probabilistic approach” to diagnosis that relies on both signs and symptoms. The Bipolarity Index is a tool that lets you rate signs of the illness on a 100-point scale (Here's the PDF version of the Bipolarity Index). The index lists 5 main features that increase the probability that a patient has some form of bipolar disorder: episode characteristics, age of onset, course of illness, family history, and treatment response (Stahl SM et al, CNS Spectr 2017;22(2):203–219).

 

TCPR: How was this index developed? What data was it based on?

Dr. Aiken: The index was developed by a consensus of experts led by Gary Sachs at Massachusetts General. They gathered features that were associated with bipolar disorder, or with conversion from unipolar to bipolar, from large epidemiologic studies. Those insights have held up as the research has grown, most recently with the international BRIDGE study that looked at bipolar features in over 8,000 patients. Involving 3,305 patients, the Bipolarity Index itself has been validated in 4 studies across 4 continents. It has a very high sensitivity as well as specificity for bipolar disorder—both in the 0.9 range—which means it doesn’t expand the bipolar diagnosis; it also helps to rein it in by identifying patients who endorse symptoms of mania but may not have a true bipolar diagnosis. That’s a common problem in conditions such as ADHD, PTSD, and borderline personality disorder.

 

TCPR: Can we dig down a little into some of the Bipolarity Index items? Maybe you could help us understand some of the more high-yield items and how to ask about them. For example, let’s look at age of onset. How does age of onset have anything to do with the possibility of bipolar disorder?

Dr. Aiken: In bipolar, the average age of onset is 15 to 20, and in unipolar it’s 30 to 40 (Sadock BJ. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 9th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009). That’s a high-yield item that can easily be gathered by asking clients how old they were when their depression or their other manic symptoms (described in clients’ own words) began.

 

TCPR: Give us some of the other robust associations.

Dr. Aiken: If I had to choose 3 questions to ask in a quick interview, I would ask about age of onset, family history, and response to medications. In terms of family history, the way I often phrase the question is, “Was anyone in your family diagnosed with bipolar disorder, or did anyone have depression but also problems with anger, impulsivity, or other out-of-control behaviors?” In terms of medication response, I’ll ask, “Have you ever taken an antidepressant that made you feel much worse—agitated, irritable, anxious, wired, unable to sleep, or just more depressed?” It’s important to rule out side effects there, but it’s also important to understand that antidepressants are more likely to cause mixed states than pure manias—and for most patients, that just feels like a more severe depression. If the responses to all 3 of these questions were positive, and the patient had recurrent depression, I’d be strongly suspicious of a bipolar diathesis.

 

TCPR: Let’s drill down a bit into the medication response item. I’ll often get a medication history from someone and hear that the patient didn’t respond to several antidepressants, and usually my conclusion is treatment-resistant depression rather than bipolar disorder.

Dr. Aiken: Right, there are many reasons why a patient may not respond to antidepressants, and bipolar is just one of them, so by itself that would only add 5 points to the patient’s score on the index. It takes a score of at least 50 to indicate a strong probability of bipolar disorder.

 

TCPR: Thank you for your time, Dr. Aiken.