ODD Clinical Trial

This post is a sort of advertisement, except that no one's getting paid anything. A colleague of mine and his group just got a 2 year grant to conduct a trial of Regulation Focused Psychotherapy (RFP) for the treatment of Oppositional Defiant Disorder in children ages 5-12. This is the flyer:

That's the advertisement part. I think it's a great idea. But just to be clear, not only am I not being paid, I'm not involved in the study in any way except feeling pleased about it, and writing this post.

Why do I think it's a great idea? The American Academy of Child and Adolescent Psychiatry has a brochure about ODD. It describes treatment for ODD, which includes a combination of Parent-Management Training Programs and Family Therapy, Cognitive Problem-Solving Skills Training, Social-Skills Programs and School-Based Programs, plus or minus medication.

These are all useful tools, but none of them addresses the underlying affects, and difficulty in regulating these affects, that children with ODD experience. That's where RFP comes in.

The group conducting the study recently published the Manual of Regulation-Focused Psychotherapy for Children (RFP-C) with Externalizing Behaviors: A Psychodynamic Approach.

In it, they describe the way, "RFP-C enables clinicians to help by addressing and detailing how the child’s externalizing behaviors have meaning which they can convey to the child," and more specifically, that RFP-C can:

• Achieve symptomatic improvement and developmental maturation as a result of gains in the ability to tolerate and metabolize painful emotions, by addressing the crucial underlying emotional component.
• Diminish the child’s use of aggression as the main coping device by allowing painful emotions to be mastered more effectively.
• Help to systematically address avoidance mechanisms, talking to the child about how their disruptive behavior helps them avoid painful emotions.
• Facilitate development of an awareness that painful emotions do not have to be so vigorously warded off, allowing the child to reach this implicit awareness within the relationship with the clinician, which can then be expanded to life situations at home and at school.

That's my pitch. So if you know anyone in the New York City area who could benefit from this trial, whether child, parent, educator or clinician, please get this information to them.

Thanks.

Outside In

In the context of my working on building my own practice website, I found a NY Times article, Inner Peace? The Dalai Lama Made a Website for That, compelling to read.

The website is, Atlas of Emotions, and it's not really about inner peace. It's more about the Dalai Lama's notion of emotions as reactive internal events that prevent inner peace, combined with information about the five emotions considered universal by the 149 experts surveyed for this purpose.

The emotions are:

Anger
Fear
Disgust
Sadness
Enjoyment

The site was conceived by the Dalai Lama as a "map of the mind", and developed by Dr. Paul Ekman (for $750,000), who conducted the survey, and has done pioneering work in nonverbal behaviors, especially facial expressions. He now has a company called the Paul Ekman Group, or PEG, which will teach you, for a fee, to read people's expressions and determine if, for example, they are lying. He was a major consultant for Inside Out, the Pixar movie that illustrates the emotional life of a girl named, Riley (I assume based on the expression, "Living the life of Riley," meaning the good life). He was also consultant and inspiration for the main character on the TV series, "Lie to Me", which I know nothing about.

The site is primarily visual, with the imagery designed by a company called, Stamen, that creates data visualizations. It's interesting that the colors used to depict the five emotions on the site:

match the colors of the corresponding characters in Inside Out:

I probably shouldn't be including either of these images without permission, but the Disney-fication was just so striking. Then again, we do associate colors with feelings, like red with anger, blue with sadness, and green with disgust, and red and green, at least, are related to changes in skin color that occur with their associated emotions. I don't know about purple with fear or yellow/orange with enjoyment.


The way the site works is you land on the home page, with those five circles of emotion, which are called, "continents". Remember, this is supposed to be a map. If you click on a continent, you get a brief description. For example, Sadness brings up, "We're saddened by loss."

You also get a menu to the right which lists, Continents, States, Actions, Triggers, Moods, and Calm. If you go to States, after you've clicked on Sadness, you get a graph of various states related to sadness, with overlaps, from least intense to most. The least intense for Sadness is Disappointment, "A feeling that expectations are not being met." The most intense is Anguish, "Intense agitated sadness."

There are left and right arrows to switch to other basic emotions, but also a down arrow, corresponding to the menu on the right, with more about the emotion you're looking at. The next one down is Actions, with another visual including a range of possible actions for each given state. For anguish, you can seek comfort, which is considered a constructive action. You can mourn, which is ambiguous. And you can withdraw, which is destructive.

This is a good illustration of one of the main limitations of the site-that it oversimplifies, but that probably makes it more widely accessible.

The next down is Triggers, which are either universal, like losing a loved one, or learned, like perceiving a loss of status.

And next down is Moods, the "longer lasting cousins" of emotions. For Sadness, the corresponding mood is Dysphoria.

That's as deep as the graphics go. The only thing left is calm, which you access from the right hand menu. It has nothing but a short description:

Experiencing Calm

A calm, balanced frame of mind is necessary to evaluate and understand our changing emotions. Calmness ideally is a baseline state, unlike emotions, which arise when triggered and then recede.

The only other feature of the site is a link to the "Annex", where you can find the scientific basis for the work, some more complicated definitions, the signals of emotional display, and a page of "Psychopathology", which lists various DSM diagnoses related to each emotion.

I wasn't thrilled with this page. For one thing, I disagreed with some of the categorization. For example, as an anxiety disorder, OCD was listed under Fear. But etiologically, at least from an analytic standpoint, OCD is more about a way of dealing with aggression, so I would have listed it under Anger. It also lists Mania under enjoyment, with a qualification about it being pathological enjoyment. But I don't think this is what's actually meant by the term, Enjoyment.

And this page doesn't mention the DSM, even though it includes diagnoses like Disruptive Mood Dysregulation Disorder (DMDD).


Overall, I have mixed feelings about the Atlas of Emotions. On the one hand, it recognizes that we usually don't know why we feel what we feel, or do what we do, and that's useful to know. To quote the NY Times quoting the Dalai Lama:

“We have, by nature or biologically, this destructive emotion, also constructive emotion,” the Dalai Lama said. “This innerness, people should pay more attention to, from kindergarten level up to university level. This is not just for knowledge, but in order to create a happy human being. Happy family, happy community and, finally, happy humanity.”

On the other hand, the goal is a calm state:

“When we wanted to get to the New World, we needed a map. So make a map of emotions so we can get to a calm state.”

I think this calm state is supposed to be an absence of emotion, either good-feeling or bad-feeling, a Buddhist ideal, so emotion is viewed as the enemy:

“Ultimately, our emotion is the real troublemaker,” he said. “We have to know the nature of that enemy.”

When I read this, I was reminded of the talk I attended, that I wrote about in Laughing Rats, where Jaak Panksepp noted that, "Most learning takes place through affective shifts." So if we contain our emotions, do we prevent ourselves from learning new things?

And in that same talk, Jean Roiphe noted that, "Ego functioning often involves "taming" certain affects, especially through thought and language, but it also involves intensifying some affects, so that people can feel truly alive. A full human life can't be reduced to an all or nothing switch of feeling in response to external events."

Also, I'm not sure "calm" isn't an emotion.

Maybe I just have trouble with this because I'm so steeped in a culture of neurotically exaggerated emotions, so the ideal of inner peace isn't just unattainable, it's laughably unapproachable, which, for me, quickly turns into undesirable.

NAC

I've been hearing a lot about N-Acetylcysteine (NAC) in the treatment of psychiatric disorders, so I thought it would be worth looking into.

A 2015 systematic review in Neuroscience and Biobehavioral Reviews has the following abstract:

N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.


I'm not sure how they drew their conclusions. They have a rating system called, Grade of Recommendation (GOR), from A-best, to D-worst, and N-no studies identified. They also state, at least for some disorders, whether they recommend NAC for treatment, from Yes to No, with Mixed in between.

They found only 1 GOR of A, for Bipolar disorder, and even that they recommended as Mixed.

The B/Mixed were:

Addiction-Cannabis
Addiction-Cocaine
Autism
Depressive Disorder
Impulse Control-Trichotillomania
Schizophrenia.

Specifically:

-In one study of NAC in treating and preventing symptoms during the maintenance phase of Bipolar Disorder, when compared to placebo, the NAC group demonstrated a significant improvement on the Montgomery–Asberg Depression Scale (MADRS), Bipolar Depression Rating Scale (BDRS).

-Cannabis-dependent adolescents and young adults given NAC and counseling had significantly fewer positive urine cannabinoid tests than those given placebo and counseling.

-There may or may not have been a reduction in cravings for Cocaine.

-Children with Autism had less irritability.

-A large randomized controlled trial in individuals with major depressive disorder (MDD) and MADRS score ≥ 18 showed improvement in multiple outcome measures – in the NAC group when compared to placebo add on treatment to usual treatment for 12 weeks.

-In a medium sized trial, significant improvements were found on the Massachusetts General Hospital Hair Pulling Scale, the Psychiatric Institute Trichotillomania Scale and the CGI in participants who received NAC as compared to the placebo group.

- I can't figure out from the paper what NAC did for patients with Schizophrenia.


Everything else was worse.

However, NAC was pretty well-tolerated, with no serious side effects, so it's probably worth a try in conditions not responding well to other treatments. At least, I think that's their conclusion. Also, other than the IV form used in acetaminophen overdose, and the Sub-Q form used in ALS studies, NAC is sold over the counter as an oral medication, with doses ranging from 2-2.4g/day.

Posited mechanisms of action for NAC include effects on:

Oxidative Stress
Mitochondrial Dysfunction
Inflammatory Mediators
Glutamate Neurotransmission
Long Term Neuroadaptation
Dopamine Neurotransmission
Serotonergic Neurotransmission

Check out this visual:

http://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(13)00002-3

To get into a little more clinical nitty-gritty, there are a number of trials posted on clinicaltrials.gov, most without results.

One that did have results looked at NAC in alcohol dependence, with the primary outcome  measure Alcohol consumption in percentage of heavy drinking days:

No statistical analysis was provided.

Another was NAC in pediatric trichotillomania:

Again, no statistical analysis.

However, when I plug the raw data into 1 Boring Old Man's table,  (see also DIY Study Evaluation) I get:

The trichotillomania study had a p value of 0.185, a Cohen's D effect size of 0.433, and a 95% CI of -0.202 to 1.068 (In case it's too hard to read). So there's no statistically significant difference.

The Alcohol study's data was weird, with no calculable p value, and negative Cohen's D's, so then I tried change in means, which was negative, and that got p=0.533; Cohen's D=0.190; CI (-0.403-0.782). I'm not sure if that's a legitimate calculation on my part.

Basically, the numbers are bad, and I only decided to include the spreadsheet as practice at evaluating a study.

So now I ask myself, "Would I prescribe or recommend NAC?" Based on this post, I'd have to say maybe. I'd probably stick to the conditions I listed above. Maybe I'd use it as an add-on for depressive symptoms in between bipolar episodes, or in unipolar depressed patients stable on medication but with some residual symptoms. I might suggest it to patients trying to stop using cannabis or cocaine. I don't treat children, but I think if I did, I'd feel more comfortable prescribing NAC for irritability than risperdal. If I ever had a patient with trichotillomania, I'd be willing to try it. And maybe as an adjunct for anxiety or something in schizophrenia.

The bottom line is probably that it won't hurt, and it might help.