[Transcript edited for clarity]

Welcome to the Carlat Psychiatry webinar on diagnosing bipolar disorder. I'm Chris Aiken and I'm the Editor-in-Chief of The Carlat Psychiatry Report. I have no financial disclosures related to this material today. We're going to learn about six mood disorders and DSM, how to diagnose hypomania and some screening tools that can help you with that in practice.

Learning Objectives:

After this webinar, clinicians should be able to:

1. Describe six DSM-5 mood disorders

2. Illustrate how to screen for hypomania

3. Demonstrate an understanding of how to use screening tools for bipolar disorder

I'm going to start with a study that changed my own practice. About 20 years ago, when I started practice bipolar disorder was not on my radar. I set up to be a psychotherapist, and I thought that most of the mood swings that people diagnosed as bipolar two were really misdiagnosis of personality disorder.

And then this study shocked me. A group of mood disorder. Experts went into outpatient, psychiatric practices, about 15 of them armed with a handful of structured diagnostic instruments and rating scales, and other tools to enhance the diagnosis. And here's what they found. Before they interviewed these patients, the rate of bipolar II was 22%. And then with the structured assessment, the rate jumped to 40%. Now in my own practice, practically no one had bipolar II disorder. So I figured one of us must be wrong and I downloaded the rating scales they were using. Within a few months, I also came at the rate of 40%, much to my surprise, but that was backed up by about half a dozen other studies that show a rate amongst outpatients with depression or bipolar disorders in the 30-40% range. Primary care is a little less, but the rate trumps up to 50% when we look at treatment-resistant, depression and people are hospitalized for depression.

There are a lot of reasons for this discrepancy, and some of it is rooted in history. Going back before 1980, we did not have a bipolar disorder in the DSM. It was called manic depression, and that word was meant to encompass those with just depression, as well as those with mania. They were all lumped into one category. That changed in 1980 with DSM-III, which divided them into bipolar-I, the ones with full mania, and major depression, on the other hand.

But as soon as that book was published, papers started appearing suggesting that a whole group of patients in the middle between these two extremes were not captured by the current criteria, particularly those with mild mania or hypomania. So that came in 1994 with DSM-IV. Bipolar-II entered the spectrum of diagnoses, and later in 2013, we have even more added to the spectrum of mood disorders. For the first time with DSM-5, you can actually diagnose bipolar features in people who don't have bipolar disorder who just have regular unipolar depression. They might have brief hypomanias lasting less than four days or manic features sprinkled onto their depression.

 And these categories are important. For example, about 25% of people with recurrent depressions have some of those mixed features and they're more likely to get worse on antidepressants. Now I've suggested that what happened with DSM-5 is they adopted the spectrum approach to mood disorders where you see a full spectrum outlined here on the bottom from bipolar-I, then cyclothymia, and bipolar-II, and then some depressions with manic features and then full depression. You wouldn't know that by reading the book because they're all broken up into different chapters, but take a look at this. What do you see on the cover of the DSMs? Well, they did replace the Roman numerals with a “5,” but they also have a spectrum on the cover of the book, and the editor of DSM-5 David Kupfer said that depression and bipolar disorder are part of “a continuum with variable expressions of vulnerability to hypomania or mania” between them. It's very difficult to draw the line between them.

DSM-5 durations

Let's take a look more at the criteria they have for these six mood disorders in DSM-5. I'll start with two concepts that help to break them down, and you need to know these, so memorize these numbers. The first is the duration of the symptoms. Hypomania has to last at least four days, whereas mania has to last at least seven days, and then full depression is 14 days.

The next concept that separates these categories is how severe the impairment is. We're often told that mania has severe impairment where hypomania does not. But what does that mean? It's defined as mania would have required hospitalization back in the 1970s, but most of us didn't practice or don't remember those times. I'll give you a better rubric for separating the two.

Mania causes irreversible consequences in the person's life, whereas in hypomania, they can always take it back. They can apologize. They can undo the damage. They might go shopping, buy a lot of trinkets, but they save the receipts and can return them. But if you drive that sportscar off a parking lot, you're not going to be able to return it. And that's full mania.

There are other ways that these can have consequences on people's lives, from arrests that you can't get rid of on your record to losing your job because of the manic behavior to bankruptcy and divorce. Divorce is a tricky one because chronic mood swings, hypomania mixed states, depression of the type we see in bipolar-II can after many years wear down the marriage where it ends in divorce. But the differences that mania would cause divorce very quickly over a week of mania, where someone does things like has affairs, or gets violent – that directly leads to the divorce.

A lot of this is going to depend on the person's culture as you evaluate whether the consequences are irrevocable or not. For example, I treated a woman who was an evangelical Christian, and when she got manic, she threw the Bible across the room and ripped it up. Now for her, that meant irrevocable consequences because in her worldview, if you did that to the Bible, you would go to hell. And she was very frightened by her actions. I diagnosed that as a mania, whereas simply throwing the Bible across the room in someone who's not of that faith would just be in hypomania.

Bipolar disorders

Let's look in more detail at the criteria then. So bipolar-I requires full mania and there may or may not be depressions. Full mania lasts at least seven days and causes significant impairment. That's the irrevocable problems that causes. Or it could just have psychotic features that makes it mania, or it requires hospitalization—and if it does require hospitalization than any duration we'll do, you don't have to stick with the seven days.

Bipolar-II on the other hand is marked by hypomania, which must last at least four days. And it can be a little impairing and mild to moderate impairment, so if you ask the patient, they're likely to tell you it causes a big problem. Perhaps it causes strain in their marriage, but not of the irrevocable type we're talking about mania.

Here's another thing. You might notice that bipolar-II requires the presence of depression where bipolar-I does not. This is to make the diagnosis more conservative because hypomania almost can blend into normality. What if you met someone who was charismatic, outgoing, creative, didn't need much sleep, racing thoughts, talked with a bit of pressure? Are they just an eccentric creative individual or do they have bipolar disorder? Well, I would suggest that if they don't have recurrent depression, then you can pretty much throw those other signs out the window, and I wouldn't diagnose bipolar. Having the presence of recurrent depression gives us more assurance that these soft signs of hypomania really reflect a genuine bipolar mood disorder

Finally in DSM, we have cyclothymia disorder, which is originally conceptualized as a temperament, meaning that you're more or less that way throughout your life, cycling with brief depressions and brief hypomania—so here they don't require the four days of hypomania. These often overlap in people with cyclothymia disorder causing mixed states, making them agitated, irritable, anxious, tired, and wired.

The problem with cyclothymia is that it's very hard for these patients to predict how they're going to be from one day or one week to the next. They're very inconsistent. As one person told me, “I can do any job. I do great for a couple of weeks. And then I crash.”

Unipolar disorders

Turning to the unipolar disorders. We have a new one in the appendix of the book under “Conditions for Further Study” called depression with brief hypomania. As you do these rating scales, you'll start to notice a lot of patients who have distinct recurrent hypomanias, but they insist that it lasts less than four days. And we'll get to why that's important and a little bit.

You can also have depression with mixed features. In DSM, that means that you have depression with at least three manic features sprinkled on top, but they exclude a few of those signs like irritability, distractibility, and hyperactivity that cannot count for the diagnosis.

Then there's major depression, which also includes persistent depressive disorder, which replaces the old dysthymic disorder, a chronic temperamental depression.

You have three disorders in the unipolar section, two of which have bipolar features. And here's why that's important. This is a study showing that the longer the duration of hypomanic or manic symptoms, the more likely the patient is to get worse on an antidepressant.

 And among the true bipolars, type I and type II, the risk of getting worse is 30-40%, but even those who don't have bipolar disorder who have those brief hypomanias, it's a 10-15% chance of getting worse on an antidepressant. You'll see that with all kinds of markers for bipolar disorder, it's not a black or white division, but rather the risk of getting worse on an antidepressant just steadily rises as say, the family history of bipolar rises up or other features of bipolar rise up steadily.

How do we diagnose bipolar disorder?

The gold standard is with a structured diagnostic instrument, like the Mini 7.0, which uses this screening question: “Have you ever had a period of time when you were feeling 'up' or 'high' or 'hyper' and so active or full of energy or full of yourself that you got into trouble, or that other people thought you are not your usual self?” Well, that's quite a mouthful. What these structured instruments do is essentially translate the DSM criteria into regular language that you can use with your patients. I'd encourage you to look through the criteria yourself and translate it in a way that works for your patients. I've given you my own sense of how each of these symptoms look in real life. I encourage you to read that over on your own and translate those symptoms.

You can also use mental status exam to augment what you're doing. Here's a woman one year apart, the first year with depression and the second year with mania. She's almost unrecognizable between the two pictures. It affects every muscle in the body, these mood episodes. Let’s hear from a patient about it. “I will want to talk constantly. I will interrupt. I will jump from topic to topic in conversation without realizing that I'm doing it. I'm not realizing that that's probably quite rude. So it drives my mom crazy. It drives Chris crazy. Probably a poor choice of words because it looks like I'm ignoring what they're saying, but in my head, I'm finished that conversation. I want to go on to the next thing. So I'm like, come on, keep, keep up with me, keep up with me. We have stuff to talk about. We're going onto the next topic. My speech gets quicker. My thoughts are flying faster. But then when it gets less euphoric and more horrible and uncomfortable, all that stops. I don't want to talk to anyone. I don't want to have conversations. I don't want to see anyone because I just feel sort of this fiery energy that I cannot release and I don't want to target it at anyone. I don't want to be that snappy person that I become. I recognize that that behavior is not nice. I recognize that it can be mean. I just feel guilty if I snap at Chris…”

Six ways to miss hypomania

Despite these criteria and despite our best efforts and asking the right questions, it can be very easy to miss hypomania. I'm going to go over six ways that it can be missed. The first is the myth that hypomania or mania is a happy state. It's true. That euphoria expansive or elevated mood. Is part of the diagnostic criteria, but that part of the illness is very rare and brief and not likely to help you on the interview. Let's hear from Kay Redfield Jamison who wrote the two-volume text on bipolar and later revealed that she had the illness herself. She says, “I felt infinitely worse during mania than when, in the midst of my worst depressions.”

When you do the interview, it's better to focus on energy than emotions—high energy during mania and low energy during depression. If you do get into the emotions, you're going to find that people with hypomania or mania are more likely to have lability, meaning their mood swings quickly and reactively reacting the real situations, but overreacting into giddy laughter and happiness, and then sadness and anger and irritability and anxiety. That's more common than actual euphoria. And that's a feeling of being out of control. It's not a good feeling at all. And I think that's one of the most common experiences of bipolar disorder is just feeling like you've lost control over your mind. This is why patients often want to turn their mind off. They want sedatives or sleep meds to crash and get out of it. They don't want to feel those racing thoughts because they're often not racing with much pleasurable themes. That's a very frightening state. I can relate to it because I think I would rather lose control of my arm than lose control of my mind. From YouTube: “I feel so horrible. It's one of those moments where I just feel so crazy. I just feel crazy and realize how bad this.”

The next reason people miss hypomania is something called state dependent memory, which just means that it's hard to recall feelings from the past. Instead of looking for emotions, better to look for behaviors. I might ask them, “Are there times where you do much more than usual? Do you take on risks?” And then I'd be real specific, like driving aggressively, spending too much money, breaking the law,  or making major sudden life decisions or suddenly starting or stopping relationships. People don't just jump into new relationships. They also end them abruptly when they're in hypomanic states.

The next reason that the diagnosis is missed has to do with the human mind’s tendency to rationalize everything. I put these tennis balls up there because it represents an old psychology experiment where they gave people identical balls and asked them to choose. They are asked, “Why did you pick that one?” Even though the balls were identical, they would say things like, “Well, it looks shinier”; “It was softer;” “It looked newer.”

That gets to something we need to know in all of our psychiatric interviews. The DSM requires us to assess symptoms regardless of their context and the explanations for why they occur. This is very hard to do because we're human as well because we tend to look for explanations just as the patient does. I would argue that people with bipolar disorder do this even more because they've engaged in behaviors that are very difficult to explain that are quite against the grain of their culture.

They're even more drawn to rationalize. You'll know the patient is rationalizing or contextualizing when they use the word, “Yes, but…” after you asked them about hypomanic symptoms, such as, “Do you have times where you're much more excited and hyperactive and high energy and doing a lot?” “Yeah, but only when I have a lot to do,” or “Just when good things are happening to me,” or “When I'm out having a good time with my friends.” It's easy to dismiss the answers when they give those reasons. But in actuality, a lot of times that's what's happening during a hypomanic state. And if you see someone who's hypomanic and ask them why they're doing so much, they're likely to tell you because they have a lot to do.

What I'd look out for in particular is when patients say that some impulsive behavior like shopping, pornography, gambling, binge eating, they're only doing it to feel better during depression. This is what a depressive mixed state looks like because you have depression with impulsive behavior on top of it. During the hedonic drive is supposed to be way down. They're not supposed to be enjoying anything, so the fact that they're out there doing retail therapy and impulsively gambling tells you that something else is going on.

Another way we can miss hypomania is ambiguous answers. These are very common. You'll ask patients things like, “Do you ever have times where you're much more confident than usual, feeling on top of the world?” They might say, “Not really,” or “Sort of,” and that might very well mean yes, as worth exploring deeper because we're talking about symptoms that are very important because it can change the full direction of treatment, away from antidepressants and toward mood stabilizers. We want to take these answers seriously.

To remind myself of how important these answers are, I keep this image in my mind. Suppose I had asked someone, “Do you ever steal from your friends?” And they said, “Not really.” Well, I wouldn't really trust them after that kind of answer other answers that might mean yes, but we often discard as no. Or when the patient says, “Very rarely,” or “Not in a long time,” or “Only when I was in my 20s and I was young and exuberant.” Well, take a look at this. Here's the lifespan of bipolar disorder and you see, they very rarely have hypomanic or manic states. It's 4% in bipolar-II and 15% of the lifespan in bipolar-I. So when they say, “Very rarely,” that's a typical answer for bipolar.

A similar one is when the patient says, “Yeah, but only when I'm not depressed.” This is when you're interviewing a person with depression and you ask them, “Have you ever had times where you're much more active doing a lot more jumping into things, much more social?” And this is how they want to be, so they keep saying, Yes, but only when I'm not depressed, that's what I want to get to.”

Well, this is a tricky one and we do have an answer. A couple of months ago, we interviewed Gordon Parker in The Carlat Psychiatry Report and he published a new rating scale on those pages called the Sydney Bipolar Screener. What he did was basically take all of the items of hypomania and mania that people with only depression don't tend to integrate and turned it into a rating scale. The way he did that was by starting with a whole lot of symptoms, testing them out in patients who definitely had recurrent depression because he had seen them for a long time or his colleagues had, or those who definitely had bipolar disorder, again confirmed by long-term follow-up.

These were the symptoms that the people with bipolar tended to endorse while those with nonbipolar depression did not tend to endorse. He got a pretty good sensitivity and specificity out of it: 97% sensitivity and 96% specificity with a cutoff of 6. This is only one study, but that is a better result than we see with most self-rated scales, like the Mood Disorder Questionnaire, but here's a tip that might humble us. The Mood Disorder Questionnaire, a very popular self-rated scale for bipolar that you can download for free on the internet does a more accurate job of diagnosing bipolar disorder than the average psychiatric interview.

Another way that we can go wrong is by missing mixed states, and these are easy to miss because DSM tells us that mixed states happen when a person has symptoms of depression and symptoms of mania at the same time. The problem is that these symptoms look very different when they overlap together, and the DSM has no criteria set that will convey that to you—much the same as it's hard to describe the color green to you by telling you about yellow and blue.

Let's hear it again from a patient: “So that huge rush of energy that you might get with a mania or hypomania and areas like depression and sadness that you might get with the depression are combined together, and this is called a mixed mood. That is the dictionary definition of a mixed mirror. Mixed moods feel totally different, like you're being ripped apart at the seams. And for me, I get extremely angry and irritated, and I'm not angry or irritated at anyone. I am just angry and irritated at life. I go around and I have all of this excess energy, but the energy is really angry. It ends up resulting in these overblown movements that are somewhat harsh because I just don't have anywhere to put the energy that this mixed mood has me in. And then two minutes later, I might be crying about something in my life and not be able to stop and yet still be extremely irritable. I mean, other things the textbooks do not tell you is that when you run that fast and that hot and with hypomania or mania, when the energy hits you like that, the other thing that hits you like a freight train, at least for me, is fatigue. It's brutal to try to expend a day's worth of energy in an hour. And then somehow your body's not supposed to be tired, but your body is tired. And yet, somehow it still has an excess of energy. And so for me, there's this push-pull—sleep, get up, sleep, jump up and down. I can't sleep. I can't really jump up and down because of the I'm so tired. So, a mixed mood is not sticking symptoms in a bowl, mixing it up and voila, you have a cake with mixed mood. It's not like that. It's like the worst of one mood, plus the worst of the other mood, grating together to give you this one glorious thing called a mixed mood.”

I've spent the last 15 years collecting symptoms of mixed states as I've talked to patients, and I've put them here in a brief chart that summarizes how each of the manic symptoms looks different during a mixed state. I'll highlight a couple of them, but I'd encourage you to read this on your own. Think about impulsive behaviors during classic mania, pure mania. They're very productive—starting new relationships, starting new jobs, new activities. But during a mixed state, they're very destructive—destroying relationships, breaking television sets. And another one is confidence. How can you feel confident during a mixed state? This feels awful. Well, the patient is very unlikely to say that they feel confident. What might come across though is in their actions. They're very demanding and pushy and stubborn and assertive. They act confident, even though they don't feel confident.

In fact, in my experience, most people who have chronic mental illness don't feel confident at all. So this is one even in pure mania where you’re going to want to look for the behaviors rather than the feeling. I remember a patient who I kept asking him if he had times of feeling confident and he kept saying no. Finally, I learned that he'd started all these businesses out of nowhere and I said, “Doesn't it take a lot of confidence to do that?” Looking kind of puzzled, he said, “Yeah, I guess so.”

Another one is sleep. I would rephrase that question differently. It's not about the need for sleep. Most people with mania or hypomania want to sleep more. It's just that they can't and they don't—they desperately want to sleep. They want to turn their mind off and get out of this terrible feeling. And intuitively they know that if they slept more, it might treat this awful episode that's coming on. So instead of asking if they need less sleep, I would ask them if they're able to just keep going, even though they're not sleeping very much.

Bipolar markers

It's very hard to diagnose bipolar disorder. I've given you some tips to refine your interview questions, but I still miss it. It's still difficult. Another way we can augment their diagnosis is by looking for markers of bipolarity and there are two rating scales I'll go through that'll help you with that. Here are some of the common markers.

Bipolar, both type-I and type-II, is more likely to start in the teen years, whereas unipolar depression tends to start at age 30 to 40. People with bipolar are more likely to get worse on antidepressants; they're more likely to have a family history of bipolarity and recurrent mood episodes throughout their life; and to have comorbidities that are common in bipolar. It turns out nearly every psychiatric disorder is more common in bipolar disorder—addictions, anxiety disorders, OCD, panic, personality disorders, bulimia—all much more common in the bipolar population.

Rapid Mood Screen. The first rating scale is the Rapid Mood Screen, which indeed can be completed by the patient in about two minutes. It has some symptoms as well as some diagnostic markers, like age of onset. These six items were whittled down from a much longer list after testing it in patient populations. And the final test with a cutoff of four items gave you a pretty good sensitivity and specificity there with one caveat that it was only tested in bipolar-I disorder. We don't know if it's useful for detecting bipolar-II disorder and it might not be, you might have noticed some of those items asked if they had had the symptoms for at least a week, instead of at least four days.

Bipolarity Index. To better detect the full spectrum of bipolar illnesses, the rating scale I'd recommend is done by clinicians and it's called the Bipolarity Index. It divides the markers of bipolarity in five different sections. I'll go through them here. Each one is rated from zero to 20 and you add them all up for a score of 20 times five max of a hundred. First you look at episode characteristics, that's the characteristic symptoms. Do they have real mania or hypomania? Is it just subthreshold where you're suspicious of it, but you can't quite pin it down? Next is age of onset. Then there's the course of the illness and do they have comorbidities like substance use disorders that tend to go along with bipolar disorder? If they have bipolar symptoms, do they tend to keep repeating or did they just have them once very briefly making it less likely to have the diagnosis? And then their response to treatment. Did they get better on mood stabilizers? Did they get worse or have no response to antidepressants? And finally, family history.

One thing I like about this rating scale is it lets you categorize almost anything. For example, if you hear that the patient's father had recurrent depression and he was never diagnosed with bipolar, but he had a gambling problem, you're suspicious. Maybe he has it, maybe he doesn't. Well, in that case, there's still a category for them. It's just, they don't get as many points as if their father had truly diagnosed bipolar disorder. So out of a max score of a hundred, the cutoff for bipolar is 50. That gives you a very high sensitivity and specificity of 0.9, meaning that it both rules out false diagnoses of bipolar. and catches those that you might've missed.

And I'll just look at one section of this rating scale that’s included in your handout materials. I encourage you to read it through yourself, because it's going to give you a good sense of all the markers that are associated with bipolar disorder. Let's look at the episode characteristics. Take a patient, a woman with recurrent depression. She's had five episodes, so she gets two points for that. And she's also had an episode of postpartum depression and a lot of her depressions she's had atypical features like eating a lot and leaden paralysis and sleeping a lot. Well, those are more common in bipolar. They don't mean that you have bipolar, but they point the needle a little bit to that side. But we asked the questions about hypomania very carefully, and she definitely has many of those symptoms, but they've never lasted more than four days. She has what we call subthreshold hypomania. Now here's the important point about how you score this and tally it up. You see, she got two points for the recurrent depression and five points for having some of those other features. But you don't give her seven points. You only score each category based on the maximum point achieved. So she gets five points for episode characteristics. Now, remember there are five categories and you need to get a score of 50 to even cross the threshold. Each of these markers is moving the needle a little toward the bipolar side, but you have to have a whole lot of them to really make the diagnosis.

One thing I like about the Bipolarity Index is that it moves us away from the black-and-white question of “Does the patient have bipolar disorder or not?” Instead, we're asking, “How likely is it that they have bipolar disorder?” And you'll remember what I said earlier, that the more of these markers they have, the more likely they are to get worse on an antidepressant and the more likely they are to get a full recovery with a mood stabilizer.

Here's another thing I like about this index. It can be difficult to make this diagnosis and practice because patients feel stigmatized by it and that can create conflict with the patient, particularly when you're the one making the diagnosis. If a patient were to look at me, as they often do and say, “Do you think that I have bipolar disorder?” I can say, “I don't know. I'm never going to look inside your brain and find out, but what I've done today is a series of medical tests and the tests show that you have bipolar disorder. Now medical tests can be wrong, so let's keep an open mind as we go about this. But if we're going to give you a medication that affects your mind, let's start with something that those very same research studies found were more helpful when these tests were positive.”

I do believe that while this diagnostic expansion recognizing all the subtle shades of bipolar disorder can help us fine tune our treatments, it can also be harmful to patients. And I try to remember this from Nassir Ghaemi and Leston Havens: “The most noxious assumption that doctors can fulfill is the feeling by patients that we, their doctors, represent ‘the system,’ the status quo of power and privilege. We will label the patient as sick, and then send them through a rigmarole of diagnosis and treatment that will end up with their extrusion as a ‘patient,’ often without an active and productive role in society or a strong sense of self-worth.” So when these conversations come up, I often end them by telling the patient that these words are often misunderstood outside of the textbook—and they're not words that say much about who they are or their ideas—that in fact, if we look at bipolar disorder, what really separates it from other mood disorders is the circadian rhythm genes.

The strongest genetic association with bipolar is those genes seem to be defective and how they express themselves. Often patients can identify with that because if they have bipolar disorder, it's likely that their mood has gotten worse when they've traveled long distance or changed their schedule or the seasons change. And if they think of this as a broken biological clock, it also guides them towards the treatment approach that can be helpful in bipolar disorder, which is regulating their circadian rhythm, getting out of bed at regular times, and sleeping at regular times.

Videos courtesy of:

Imogen Walters. What hypomania feels like // bipolar disorder. June 13, 2018. Full video at YouTube: https://www.youtube.com/watch?v=eklKd-ZPQwY

Lizzie Reezay. Bipolar Day in a Life Mixed Episode. January 30, 2018. Full video at YouTube: https://www.youtube.com/watch?v=KDBetRGLd50

Natashia Tracy. Mixed Moods in Bipolar Disorder – What They Really Feel Like. April 4, 2017. Full video at YouTube: https://www.youtube.com/watch?v=cDv-yEQEQ2Q

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References

Hantouche EG et al, J Affect Disorder 1998;50:163–173

Francesca MM et al, Clin Pract Epidemiol Ment Health 2014;10:42–47

Manning JS et al, Arch Fam Med 1998;7(1):63-71

Vazquez GH et al, J Affect Disord 2018;225:756-760

Judd LL et al, Int J Neuropsychopharmacol 2003;6(2):127-137

Aiken CB et al, J Affect Disord 2015;177:59-64

Havens LL and Ghaemi NS, Am J Psychother 2005;59(2)137-147

Bubl E et al, Biol Psychiatry 2010;68(2):205-208

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