A New Biomarker for Treatment Response in Major Depression? Not Yet.

Is a laboratory test or brain scanning method for diagnosing psychiatric disorders right around the corner? How about a test to choose the best method of treatment? Many labs around the world are working to solve these problems, but we don't yet have such diagnostic procedures (despite what some might claim). A new study by McGrath et al. (2013) might be a step in that direction, but the results are very preliminary and await further validation.

The principal investigator of that study is Dr. Helen Mayberg, a leader in neuroimaging studies of major depression. She and her colleagues have pioneered the use of deep brain stimulation (DBS) as a treatment for severe, intractable depression, which was "the culmination of 15 years of research using brain imaging technology," says Dr. Mayberg.


Psychotherapy or Drugs?

The choice of treatment modality in depression, as in other psychiatric disorders, is by trial and error. If one drug doesn't work, switch to another one. If your insurance covers it, a short course of evidence-based psychotherapy¹ might be in order.

The whole concept of a DSM-based classification scheme for mental illnesses has come under fire, especially with the release of the new Diagnostic and Statistical Manual. In the real world, psychiatric disorders don't always show such clear boundaries; overlap and co-morbidity are common. The National Institute of Mental Health has endorsed a new approach, the Research Domain Criteria project, that incorporates dimensions of observable behavior along with neurobiological measures.

Here's where the new work by McGrath et al. (2013) fits in. Their goal was...

To identify a candidate neuroimaging “treatment-specific biomarker” that predicts differential outcome to either medication or psychotherapy.

Fewer than 40% of depressed patients remit with their first course of treatment, so this would be an important advance. A more scientific way of choosing among possible treatment options would benefit patients and society at large.

The study (registered at clinicaltrials.gov, NCT00367341) enrolled a total of 82 depressed people. The neuroimaging method might surprise some of you: FDG-PET to measure glucose metabolism -- not the popular and trendy resting state fMRI to examine functional connectivity or any sort of fMRI activation study. However, the authors cite an established literature using this technique in studies of antidepressant treatment response.

Patients diagnosed with moderate to severe depression (a score of 18 or more on the Hamilton Depression Rating Scale, HDRS) received a PET scan and were randomized to receive 12 weeks of either cognitive behavioral therapy (CBT, n=41) or escitalopram (Lexapro, n=39), an SSRI antidepressant. Sixty-three patients completed this phase and also had a PET scan. The endpoint considered a successful response to treatment was remission (HDRS score of 7 or less), while non-response was a change in HDRS of 30% or less. Partial responders were omitted, leaving the final groups as follows:

• CBT remission, n=12
• escitalopram remission, n=11
• CBT nonresponse, n=9
• escitalopram nonresponse, n=6

Right away we see that the number of patients in each group is very small, particularly for a study designed to identify biomarkers that will generalize to a larger population. Let me repeat that: a successful biomarker must generalize to an independent population. We haven't seen that here, so any conclusions drawn from this paper must be considered very preliminary.

How was the biomarker identified? The PET images were co-registered with the corresponding structural MRIs. A whole brain analysis identified regions showing a treatment × outcome interaction (at a significance level of p<.001 uncorrected). Six regions met this uncorrected standard: right anterior insula, right inferior temporal cortex, left amygdala,² left premotor cortex, right motor cortex, and precuneus (medial superior parietal lobe). Most of these are pretty surprising, but even more surprising is that the rostral anterior cingulate (and subgenual cingulate, BA 25) were not involved:

Contrary to past published studies,⁶³ the rostral anterior cingulate did not discriminate the outcome subgroups in either the main effect or interaction analyses. A post hoc examination of responder and nonresponder differences within each treatment arm did reveal a nonsignificant rostral cingulate activity difference, with metabolism in responders greater than nonresponders, but solely in the escitalopram group. While consistent with past reports, this finding did not meet the TSB [treatment-specific biomarker] criteria defined for the current study, ie, a region whose activity can differentiate both good and poor outcomes for both treatments.

- click on image for a larger view -

Effect sizes are shown in the table above. The brain regions were ranked in order of size of activation (which doesn't make sense for the amygdala), and the right anterior insula was chosen as the best potential biomarker because.... it had the largest cluster size? Or because it did marginally better than the other regions in terms of effect size (although this was not shown statistically).  As a hub for interoceptive awareness, attention, and emotion, the anterior insula makes the most sense scientifically (Craig, 2009). Certainly, it would be odd if glucose metabolism in the right motor cortex could predict response to CBT or SSRI...

At any rate, right insula hypometabolism at baseline was associated with remission to CBT and poor response to SSRI, and vice versa for hypermetabolism. There was overlap between the groups as shown below, but increasing the chances of successful treatment (even with no guarantees) would be better than a completely trial-and-error approach.³

Figure 3A (modified from McGrath et al., 2013). Right anterior insula as the optimal treatment-specific biomarker candidate.  A. Scatterplot of insular activity from individual subjects in the remitter (REM) and nonresponder (NR) groups. Note: the anterior insula is the only region where the interaction subdivides patients into hypermetabolic (region/whole-brain mean >1.0) and hypometabolic (region/whole-brain mean <1.0) subgroups.


A Nature news story says that Brain scan predicts best therapy for depression, but that would be a premature conclusion at best. Although this study might be considered promising, the results must be validated in larger independent samples of patients who are assigned to treatments according to their baseline insula PET scans.

With the newly prominent nattering nabobs of neuroimaging negativity, it's important to remember that it's not all neuroprattle and bunk. Some of this research is trying to alleviate human suffering.


Further Reading

The Sad Cingulate

Sad Cingulate on 60 Minutes and in Rats

The Sad Cingulate Before CBT

Deep Brain Stimulation for Bipolar Depression

Is CBT Worthless?

Where Are the Clinical Tests for Psychiatric Disorders?

The Dark Side of Diagnosis by Brain Scan


ADDENDUM (6/14/2012): David Dobbs has an excellent post on the same study, Talk Therapy or Pill? A Brain Scan May Tell What’s Best.  Dobbs has written extensively about Dr. Mayberg and her work, including A Depression Switch? – New York Times and Depression’s wiring diagram.


Footnotes

¹ But read LawsDystopiaBlog by Professor Keith Laws to see how flimsy the "evidence base" can sometimes be.

² An earlier experiment showed that the amygdala might be a region that could help predict CBT response, using fMRI and response to emotional words.

³ Not to be a pedantic stick in the mud, but the combination of drugs and therapy is often the most successful.


References

Craig AD. (2009). How do you feel--now? The anterior insula and human awareness. Nat Rev Neurosci. 10:59-70.

McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, Craddock RC, & Mayberg HS (2013). Toward a Neuroimaging Treatment Selection Biomarker for Major Depressive Disorder. JAMA psychiatry (Chicago, Ill.), 1-9 PMID: 23760393

How to Measure Female Desire

A Sexual Laboratory of One's Own, 
aka A Clean Well-Lighted Place for Sex

Psychophysiologic studies of sexual response should be done in a comfortable, well-designed laboratory to minimize subject anxiety and discomfort (Woodard & Diamond, 2009, Fig. 5).



How do scientists measure the physiological aspects of sexual arousal in women? A 2009 paper by Woodard and Diamond reviewed 45 years of research using instruments that measure female sexual function. These devices include the vaginal photoplethysmograph (right), vaginal and labial thermistors, pressure/compliance balloons, clitoral electromyography, and the electrovaginogram. For a full list, see Table 1 at the bottom of this post.

The authors note that these physiological measures do not correlate very well with subjective ratings of sexual arousal. Furthermore, clinicians who treat women with sexual dysfunctions are of two minds. Some say the distinction between female desire and arousal may be artificial (see DSM-5 changes, p. 13), while others maintain that the merger of female sexual arousal disorder (FSAD) with Hypoactive Sexual Desire Disorder (HSDD) will be disastrous (Clayton et al., 2012).

The previous post about Lybrido and Lybridos, the drugs in clinical trials for HSDD, talked briefly about Emotional Brain, the Dutch drug company that is developing them. Putting aside the many objections to the HSDD diagnosis for now, and the fact that the trials pathologize sexual boredom within marriage, the company has conducted some interesting studies¹ to assess sexual desire.

Foremost among these is the development of an at-home testing environment, or ambulatory lab, to conduct studies of sexual function (Bloemers et al., 2010).

Fig. 1 (Bloemers et al., 2010). Schematic overview of the ambulatory measurement setting. (1) Generic laptop, (2) genital probe, (3) wireless sensor system, (4) handheld computer, and (5) secure central database.


The participants must be so much more comfortable watching hardcore porn and measuring their own vaginal pulse amplitude and clitoral blood volume in the privacy of their homes, without the prying eyes of hoards of scientists in white lab coats (although some people might be into that).

And that's what was found, for the most part (Bloemers et al., 2010):

The results of this study support our hypothesis that in healthy controls, clitoral and subjective laboratory measures of sexual arousal show stronger increases to erotic stimuli in the home environment than in the environment of the institutional laboratory. This effect was apparent in response to hardcore stimuli, but not to erotic fantasy. ... To our knowledge, this is the first study that investigates ecological validity of sexual psychophysiological measures by comparing those assessed in the institutional laboratory to those assessed at home with an ambulatory laboratory.

Footnote

¹ Albeit flawed studies, from a cognitive perspective (especially their implementation of an 'Emotional Stroop' task). I am not particularly qualified to comment on other aspects of this research.


References

Bloemers, J., Gerritsen, J., Bults, R., Koppeschaar, H., Everaerd, W., Olivier, B., & Tuiten, A. (2010). Induction of Sexual Arousal in Women Under Conditions of Institutional and Ambulatory Laboratory Circumstances: A Comparative Study Journal of Sexual Medicine, 7 (3), 1160-1176 DOI: 10.1111/j.1743-6109.2009.01660.x

Woodard, T., & Diamond, M. (2009). Physiologic measures of sexual function in women: a review Fertility and Sterility, 92 (1), 19-34 DOI: 10.1016/j.fertnstert.2008.04.041

Lybrido for Low Libido?

A feature article in last week's New York Times Magazine served as an extended ad for a new book by Daniel Bergner, What Do Women Want? Adventures in the Science of Female Desire. It's filled with post-fashionable pop neuroscience and simplistic neurotransmitter stereotypes that rival those of Naomi Wolf (including her infamous “dopamine is the ultimate feminist chemical in the female brain” quote). The focus of Bergner’s article is on pharmaceutical treatments for the controversial diagnosis of Hypoactive Sexual Desire Disorder (HSDD), particularly the subtly named Lybrido (along with its younger sister, Lybridos).

The heavy-handed branding of Lybrido and Lybridos (both 'working titles') was fascinating to me. While trying to identify the marketing firm behind it, I discovered the trademark was abandoned 6 years ago by Emotional Brain, the Dutch drug company developing them. Finding the active ingredients in Lybrido and Lybridos wasn’t readily apparent from the Emotional Brain site. Nor was it immediately evident from the NYT article, which even used obfuscatory language:

“Female Viagra” is the way drugs like Lybrido and Lybridos tend to be discussed. But this is a misconception.

Actually, this is not a misconception. Both drugs contain a major male sex hormone plus a second ingredient: Lybrido is testosterone + sildenafil (Viagra), while Lybridos is testosterone + buspirone (a serotonin 5-HT_1A receptor partial agonist). The two formulations are in clinical trials for variants of HSDD identified by Emotional Brain researchers and described in a three part series published in the Journal of Sexual Medicine. These pilot studies used the related PDE5 inhibitor, vardenafil (Levitra). PDE5 inhibitors are widely used to treat erectile dysfunction, so claims that Lybrido doesn’t affect physical function in women are disingenuous:

Viagra meddles with the arteries; it causes physical shifts that allow the penis to rise. A female-desire drug would be something else. It would adjust the primal and executive regions of the brain. It would reach into the psyche.

Do Viagra and testosterone replacement therapy reach into the male psyche? Hmm? I don't think so.

HSDD is a diagnosis that can be given to women who have a low (or nonexistent) libido and are distressed about it. Dr. Petra Boynton has written extensively about the problematic aspects of the HSDD diagnosis and the screening tools used to assess it, as well as the medicalization of sex for pharmaceutical marketing purposes. An earlier post provided thorough coverage of issues concerning the safety and effectiveness of the Intrinsa testosterone patch, including its rejection by the FDA.

Nevertheless, plenty of women have voluntarily enrolled in the Lybrido trials. Bergner interviewed some of them to determine the reasons for seeking out an experimental treatment:

Every woman raised a mix of possible reasons. There were the demands of graduate school, the demands of children, the demands of work, medical issues, men who weren’t always as kind or nearly as engaged as they could be. But at bottom there seemed to be one common cause: they had all grown tired of sex with their long-term partners.

Why medicalize boredom within marriage?

…Lori Brotto, a psychologist at the University of British Columbia who has worked clinically with scores of H.S.D.D. patients and who recently led the American Psychiatric Association’s attempt to better delineate the condition in The Diagnostic and Statistical Manual of Mental Disorders. (H.S.D.D. is being reconceived as sexual interest/arousal disorder, S.I.A.D.) “The impact of relationship duration is something that comes up constantly,” she told me about her therapy sessions. “Sometimes I wonder whether it” — H.S.D.D. — “isn’t so much about libido as it is about boredom.”

Basically, to participate in the trials, a woman has to be in a stable, long-term monogamous relationship. How many female patients have tried couples counseling before turning to drugs? Or did they all take their advice from the Daily Mail?

'Women have a responsibility to keep their libidos high for their husbands': Could 'female Viagra' save YOUR marriage?

What efforts have the husbands expended to improve the sexual relationship, what work have they put in to make themselves more desirable to their wives? Are they taking a pill to make them less loutish?

[Lybrido developer Adriaan] Tuiten didn’t openly acknowledge monogamy as the core of the desire problem, but he knew he couldn’t use single subjects who might well find new lovers during the course of the trials. Their results might have to be tossed out because, with or without chemical aids, new lovers bring surges of lust.

Did the clinical trials for Viagra require men to be monogamous?


Dopamine Is Impulse; Serotonin Is Inhibition and Organization

How do the drugs work to restore female desire? Based on very little evidence, they purportedly restore the balance of dopamine and serotonin, despite taking a sledgehammer approach. Here's where Mr. Bergner devolves into dopamine/serotonin stereotypes that are just as bad as those from Naomi Wolf, but more boring. Divorced from the personal, unable to understand the phenomenology of female desire from the inside, Bergner is left with sterile rehashes of rat lust from Ms. Wolf's guru, Dr. James G. Pfaus. He even resorts to the old 'SSRIs simply cure depression by increasing serotonin' saw:

...And then there’s serotonin, dopamine’s foil. It allows the advanced regions of the brain, the domains that lie high and forward, to exert what is termed executive function. Serotonin is a molecule of self-control. It instills calm, stability, coherence (and, too, a sense of well-being, which is why S.S.R.I.'s, by bathing the brain in serotonin, can counter depression). Roughly speaking, dopamine is impulse; serotonin is inhibition and organization. And in sexuality, as in other emotional realms, the two have to work in balance. If dopamine is far too dominant, craving can splinter into attentional chaos. If serotonin overwhelms, the rational can displace the randy.

I guess he hasn't seen the data on the important role of dopamine in executive function in 'the advanced regions of the brain' (e.g., Prefrontal dopamine and behavioral flexibility: shifting from an “inverted-U” toward a family of functions and Dopamine D₂ receptor modulation of human response inhibition and error awareness).

Bergner continues:

To help predict which women will most benefit from which drug, Tuiten has blood drawn from each subject and examines genetic markers related to brain chemistry. Tuiten also asks subjects questions about their comfort with sexual feelings and fantasies. Since our dopamine and serotonin networks are reinforced or attenuated by all we learn, all we think and do, he believes that the answers may provide clues about a given woman’s neurotransmitter systems, which he uses as part of his diagnostic method.

The three part series in the Journal of Sexual Medicine might be worth a future post to describe the methods Tuiten et al. use to guide treatment and decide who gets which drug.


Dr. Helen Fisher, advisor for chemistry.com, developed the concept of four neurotransmitter “archetypes” in her quest for a better, more scientific brand of matchmaking.



Each of these chemistry types is associated with a dominant neurotransmitter or hormone (serotonin, testosterone, dopamine, estrogen). But she knows this is a metaphor and not to be taken literally. "We're a combination of all four systems," Fisher says in a USA Today article.


Neuroplasticity: It's a Girl Thing

Let's conclude with the most puzzling brain-based explanation for HSDD: it's neuroplasticity! I couldn't comprehend the logic of this paragraph, no matter how hard I tried. It's one of those sex-and-relationship-type accounts that's seemingly neuro-related but really devoid of actual neuroscientific content:

This interplay of experience and neural pathways is widely known as neuroplasticity. The brain is ever altering. And it is neuroplasticity that may help explain why hypoactive sexual desire disorder is a mostly female condition, why it seems that women, more than men, lose interest in having sex with their long-term partners. If boys and men tend to take in messages that manhood is defined by sex and power, and those messages encourage them to think about sex often, then those neural networks associated with desire will be regularly activated and will become stronger over time. If women, generally speaking, learn other lessons, that sexual desire and expression are not necessarily positive, and if therefore they don’t think as much about sex, then those same neural networks will be less stimulated and comparatively weak. The more robust the neural pathways of eros, the more prone you are to feel lust at home, even as stimuli dissipate with familiarity and habit.

The book What Do Women Want? Adventures in the Science of Female Desire will be released tomorrow. I doubt that Ecco will be sending me a review copy.


Further Reading:

Media HSDD: "Hyperactive Sexual Disorder Detection"

Underwear Models and Low Libido

Feminist Dopamine, Conscious Vaginas, and the Goddess Array

Of Mice and Women: Animal Models of Desire, Dread, and Despair

Can Pot Smoking Counter the Negative Metabolic Consequences of Atypical Antipsychotics?

DISCLAIMER: This is a hypothetical question and not a medical recommendation. But it might be an idea worth investigating in epidemiological studies.


Everyone knows that pot gives you the munchies. So the paradoxical finding that marijuana use is associated with a lower prevalence of obesity and diabetes came as a quite surprise to me. Now, a new study has concluded that pot smokers also have lower fasting insulin levels and smaller waistlines (Penner et al., 2013).

I'll let the authors summarize the clinical significance of their study (Penner et al., 2013):

• Marijuana use is increasingly common, and use of medical marijuana is now legal in 19 states and the District of Colombia.
• Despite its associations with increased appetite and caloric intake, marijuana use also is associated with lower body mass index and prevalence of diabetes.
• In a nationally representative survey population, we found current use of marijuana to be associated with lower levels of fasting insulin, lower insulin resistance (homeostasis model assessment of insulin resistance), and smaller waist circumference.

More complete coverage of this article is available at Addiction Inbox and Time Healthland.


Marijuana Use and Mental Illness

Some other observations that I will attempt to string together:

• Cannabis use (and misuse) is higher among individuals with schizophrenia and bipolar disorder (Green et al., 2005; Lev-Ran et al., 2013).

I will not address the issue of whether cannabis use is a risk factor for psychosis here.¹ In fact, all of my observations will be related to the metabolic effects of marijuana and not to its psychoactive properties and possible detrimental effects on mental health.

• People with schizophrenia and bipolar disorder are often on atypical antipsychotic drugs, which are notorious for causing significant weight gain that can lead to high cholesterol, hypertension, diabetes and metabolic syndrome.

Although cigarette smoking, alcohol use, unhealthy diet, and lack of exercise may contribute to shorter life expectancy in patients with serious mental illnesses (Lawrence et al., 2013), one has to wonder about the effects of atypicals on physical health.² These drugs can have a very positive effect on mental health, but it comes at a cost.

• Interestingly, cannabis use is not associated with greater mortality. In fact, the opposite has been reported by Koola et al. (2012), who "observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments."

A total of 762 patients with a psychotic disorder were included in that study. All were on atypical antipsychotics, and 39% used marijuana (although this is often under-reported). The authors speculated on the potential health benefits of cannabis, including its anti-inflammatory effects. However, they didn't mention reductions in obesity and diabetes as possible causes of lower mortality in cannabis users. This association bears further investigation, in my view.

• Nevertheless, eliminating marijuana to counteract the increase in appetite brought on by atypicals seems like common sense. In fact, this has been proposed as a specific behavioral intervention (Werneke et al., 2013).

Those authors assumed that cannabis contributes to the weight gain caused by the prescription medication, which I also assumed (until reading the new papers cited here). But this relationship hasn't really been studied (Werneke et al., 2013):

As the endocannabioid system is linked to increased appetite and cannabioid receptor antagonists can induce weight loss [15] cannabis consumption will most likely potentiate antipsychotic-associated weight gain. As the prevalence of cannabis use in people suffering from psychosis is so high, the contribution of cannabis to weight gain in this population is likely to be significant. Surprisingly, this link between cannabis and weight gain remains largely ignored at present.

• A recent paper in Medical Hypotheses (of all places) takes the opposite stance and proposes cannabis as a weight loss drug (Le Foll et al., 2013):

We recently discovered that the prevalence of obesity is paradoxically much lower in cannabis users as compared to non-users and that this difference is not accounted for by tobacco smoking status and is still present after adjusting for variables such as sex and age. Here, we propose that this effect is directly related to exposure to the Δ⁹-tetrahydrocannabinol (THC) present in cannabis smoke. We therefore propose the seemingly paradoxical hypothesis that THC or a THC/cannabidiol combination drug may produce weight loss and may be a useful therapeutic for the treatment of obesity and its complications.

These authors have filed a patent application for 'Use of marihuana and compounds therein for treating obesity' (which they acknowledge in the paper).

• One of the same authors (Le Foll) has also published on 'Cannabis use and cannabis use disorders among individuals with mental illness' (Lev-Ran et al., 2013), which they found to be particularly high in individuals with Bipolar I disorder (especially in men). 

Many of these bipolar cannabis users are probably on atypical antipsychotics. This information was not reported in the paper, but it might be available in the National Epidemiologic Survey on Alcohol and Related Conditions (although this is not certain).


To be completely clear, I am not advocating the use of marijuana by persons with schizophrenia or bipolar disorder. Rather, I am suggesting that the relationship between atypical antipsychotics and variables such as body mass index, waist circumference, insulin, glucose, and diabetes be compared between groups who do use cannabis vs. those who don't. If there is a benefit in the pot smokers, perhaps there could be a psychiatrically safe, cannabis-derived compound for weight loss in the future. Isn't that more likely than the development of 'third generation' antipsychotics that do not cause substantial weight gain?


Footnotes

¹ Interested readers can consult these articles and posts.

² See also Rising Mortality Rates for People with Serious Mental Illness and Improving the Physical Health of People With Serious Mental Illness.


References

Green B, Young R, Kavanagh D. (2005) Cannabis use and misuse prevalence among people with psychosis. Br J Psychiatry 187:306-13.

Koola, M., McMahon, R., Wehring, H., Liu, F., Mackowick, K., Warren, K., Feldman, S., Shim, J., Love, R., & Kelly, D. (2012). Alcohol and cannabis use and mortality in people with schizophrenia and related psychotic disorders. Journal of Psychiatric Research, 46 (8), 987-993 DOI: 10.1016/j.jpsychires.2012.04.019

Lawrence D, Hancock KJ, Kisely S (2013). The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers. BMJ 2013; 346 (Published 21 May 2013).

Le Foll, B., Trigo, J., Sharkey, K., & Strat, Y. (2013). Cannabis and Δ9-tetrahydrocannabinol (THC) for weight loss? Medical Hypotheses, 80 (5), 564-567 DOI: 10.1016/j.mehy.2013.01.019

Lev-Ran, S., Le Foll, B., McKenzie, K., George, T., & Rehm, J. (2013). Cannabis use and cannabis use disorders among individuals with mental illness, Comprehensive Psychiatry DOI: 10.1016/j.comppsych.2012.12.021

Penner, E., Buettner, H., & Mittleman, M. (2013). The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults. The American Journal of Medicine DOI: 10.1016/j.amjmed.2013.03.002

Werneke U, Taylor D, Sanders TA. (2013). Behavioral interventions for antipsychotic induced appetite changes. Curr Psychiatry Rep. 15(3):347.

The Mental Health of Lonely Marijuana Users

Mr. Lonely ¹

Does Smoking Pot Offer Relief to the Lonely?  A new paper by the original Tylenol and social pain researchers claims that it does (Deckman et al., 2013). Let's take a closer look.

Comfortably Numb: Marijuana Use Reduces Social Pain, Research Finds

Marijuana use buffers people from experiencing social pain, according to research published online on May 14 in Social Psychological and Personality Science.

"Prior work has shown that the analgesic acetaminophen, which acts indirectly through CB1 receptors, reduces the pain of social exclusion," Timothy Deckman of the University of Kentucky and his colleagues wrote in the study. "The current research provides the first evidence that marijuana also dampens the negative emotional consequences of social exclusion on negative emotional outcomes."

You could be forgiven if you thought, as I initially did, that the University of Kentucky IRB must hold a liberal view on the administration of controlled substances to undergrads participating in psychology experiments. But that's not what happened here... the data are entirely correlational, based on self-report, and largely problematic (in my view).


Marijuana Lowers Self-Worth and Worsens Mental Health in Those Who Are Not Lonely

That's my interpretation of the article, which is SO clunky compared to the fun and breezy query, Can Marijuana Reduce Social Pain? ²

The paper begins with the premise that "Social and physical pain share common overlap at linguistic, behavioral, and neural levels" (Deckman et al., 2013). So let's give a pain reliever to reduce the sting of rejection!  A critique of the original work asked why the authors chose Tylenol, as opposed to an NSAID like aspirin, ibuprofen, or naproxen. In the current study they tried to develop a mechanistic account of why acetaminophen might reduce social pain:

Prior research has shown that acetaminophen—an analgesic medication that acts indirectly through cannabinoid 1 receptors—reduces the social pain associated with exclusion. Yet, no work has examined if other drugs that act on similar receptors, such as marijuana, also reduce social pain.

The problem is that acetaminophen's mechanism of action is surprisingly unclear (Toussaint et al., 2010). One prominent hypothesis claims that Tylenol might exert its analgesic effects through descending serotonergic pathways at the level of the spinal cord. In fact, the paper that Deckman et al. cited in favor of cannabinoid 1 (CB₁) receptors describes a very complex pathway that includes indirect involvement of CB₁, with actual pain suppression occurring in the spinal cord. ³

An even more basic question: if acetaminophen acts through CB₁ receptors, then why isn't it a potential drug of abuse, or known by experienced pharmanauts for its psychoactive properties?  The drug experience vault Erowid says:

Acetaminophen is a non-salicylate analgesic and antipyretic (pain killer and fever reducer). It is a common over-the-counter pain medication found in hundreds of products around the world. At higher doses it is known to cause liver-damage and has a low therapeutic index (ratio of effective dose to toxic dose), making it dangerous when included in recreationally used pharmaceuticals [e.g., Tylenol with codeine]. It is not known to be psychoactive.

On the other hand, we all know that cannabis is psychoactive. The design of the cannabis study included cross-sectional national survey data, a two year longitudinal survey of 400 high school students, and a Mechanical Turk-implemented version of cyberball, an online game to simulate social exclusion. In all cases, participants reported their marijuana use, and this was related to the variables of interest.

I'll focus on the national survey data in this post, which comprised Study 1 (Marijuana Use Buffers Lonely People From Lower Self-Worth and Self-Rated Mental Health) and Study 2 (Marijuana Use Predicts Fewer Major Depressive Episodes Among the Lonely).

Study 1 used data from the National Comorbidity Survey: Baseline (NCS-1), 1990-1992 (ICPSR 6693), which you can download for yourself. The survey recruited 8,098 individuals from the ages of 15 to 54 living in the U.S., and included over 4,000 variables. Only four variables were chosen for the present study: self-reported loneliness (1= often, 4 = never), marijuana use (0 = none, 1 = daily, 8 = once or twice a year), self-worth (1 = high, 4 = low), and overall mental health (1 = excellent, 5 = poor).

Loneliness was used as a proxy for social pain. Contrary to what the headlines suggested, the impact of pot smoking on social pain was not directly examined. Instead, the study assessed the effects of loneliness (high, low), marijuana use (high, low) and their interaction on self-worth and mental health.

Loneliness and pot smoking interacted to predict feelings of self-worth [B = 0.03, t(5609) = 2.20, p = .03]. Given the huge number of participants, this level of statistical significance is not very impressive.

Fig. 1 (modified from Deckman et al., 2013). Study 1: Marijuana use moderates the relationship between loneliness and self-reported feelings of self-worth. [NOTE: items were reverse-scored for display purposes.]


For lonely people, the amount of pot smoked didn't make too much of a difference in their self-worth (see red arrow above).  For socially connected people, greater marijuana use resulted in lower self-worth, although it's not clear this was significant (pairwise statistical tests were not reported).

I also question how the High Marijuana Use and Low Marijuana Use groups were determined, because over 5,000 participants did not smoke pot at all in the last 12 months. Does the heavy use group combine those who smoke 6 joints a year with those who smoke daily?

Table depicting the mean level of loneliness (1=often to 4=never) for participants at 9 levels of pot smoking (0=none, 1=daily, 8=once or twice a year). Unlike the figure above, the values were not reverse-scored. Data from the National Comorbidity Survey: Baseline (NCS-1), 1990-1992 (ICPSR 6693).


In the lonely group, the frequency of marijuana use had even less of an impact on self-rated mental health. In contrast, heavy pot use resulted in worse mental health among the socially connected. A modest loneliness by marijuana use interaction was observed for mental health [B = 0.03, t(5609) = 2.07, p = .04], similar to what was seen for self-worth.

Fig. 2 (modified from Deckman et al., 2013). Study 1: Marijuana use moderates the relationship between loneliness and self-reported mental health. [NOTE: items were reverse-scored for display purposes.]


Looking at Fig. 2 above, it's clear that marijuana use does not buffer the lonely from the negative consequences of social pain: the black circle and gray square are overlapping. But the authors interpret this result differently:

Marijuana use buffered the lonely from both negative self-worth and poor mental health. This evidence suggests that at relatively high levels of social pain, marijuana use lessens negative consequences of social pain.

As part of the six sentence Discussion of Study 1, they point out one weakness to motivate Study 2:

This study contained some limitations. First, it only assessed self-ratings of both self-worth and mental health. If marijuana use weakens the relationship between social pain and self-reported psychological well-being, then there should also be a lower rate of validated clinical diagnoses of poor psychological well-being.
. . .
To address the limitation of Study 1, Study 2 sought to show that marijuana buffered lonely participants from experiencing a standardized diagnosis of poor psychological well-being. Study 2 used a different nationally representative sample from Study 1 to test this hypothesis.

HOWEVER, the dataset used in Study 1 has extensive information on DSM-III-R diagnoses (including depression) for the majority of participants, so I'm not sure why this wasn't included. Study 2 used data from the National Comorbidity Survey Replication (NCS-R; Kessler & Merikangas, 2004), a different national sample of 10,000 respondents.

Speaking of replication, Deckman et al. should have been able to completely replicate the pot × loneliness analyses for self-worth, self-rated mental health, and DSM depression in both National Comorbidity Samples. I'm not sure why they didn't.

For Study 2, non-users were excluded (unlike in Study 1). The final sample included 537 participants with info on loneliness, marijuana use, and whether they experienced a major depressive episode during the past year. Once again, the results demonstrated that if you're lonely, smoking a lot vs. a little pot will not affect whether you'll experience a major depressive event (red arrow below). If you're not lonely, heavy marijuana use increases the risk of major depression.

Fig. 3 (modified from Deckman et al., 2013). Study 2: Marijuana use moderates the relationship between loneliness and a having a DSM-IV major depressive event in the past 12 months.


Study 3, a survey of 400 high school students, was the most puzzling of all. At Time 1 the students were asked about loneliness, lifetime marijuana use, and depression. Two years later, they were asked again about depression, using the Behavior Assessment System for Children (second edition), but not about marijuana use and loneliness (which could have changed drastically in 2 years).

At any rate, lonely heavy pot users were the least depressed of all at Time 2. I'm not sure how to interpret this; the pattern differs from what was seen in adults. Maybe the lonely heavy pot users at Time 1 bonded with their peer group over two years and were no longer lonely at Time 2.

Fig. 4 (modified from Deckman et al., 2013). Study 3: Marijuana use moderates the relationship between loneliness and depression over 2 years in adolescents. 


Conflicting earlier studies in adolescents have suggested that lonely high school students are more likely (Page, 2000) and less likely (Grunbaum et al., 2000) to use marijuana. A recent study indicated that heavy marijuana users are more likely to engage in self-injury (Giletta et al., 2012), but this was true only for Americans and not for Dutch and Italian students. I imagine there's a huge literature on these issues, but it wasn't addressed at all in the present paper.

Overall, I don't think the authors have demonstrated that marijuana reduces social pain, at least not in adults. They used a very select set of questions from huge, comprehensive national surveys and then called this a limitation of the study:

Another potential limitation to some of the above studies lies in how social pain was measured. In Studies 1–3, single-item measures of loneliness were used as a proxy for social pain. These studies use large community sample data sets and thus our ability to include numerous measures was limited.

There were many other questions that could have assessed social pain in NCS-1 and NCS-R, including a series of questions about friendships, e.g. "How much do your friends really care about you--a lot, some, a little, or not at all?"

Has this paper advanced the agenda of the social pain/physical pain isomorphists? We already knew that opiates were good at alleviating both types of pain. And it's a truism to say that people turn to alcohol and all sorts of recreational drugs to dull the pain of a lonely existence. For the most part, we assume this isn't a healthy way to cope. Some studies suggests that depression is decreased in heavy marijuana users (Denson & Earleywine, 2006) but others find an increase (Pacek et al., 2013).

In sum, Deckman et al., (2013) presented evidence that heavy marijuana use is detrimental to the mental health of socially connected individuals and not especially effective in buffering lonely users from social pain.


Footnotes

¹ However, please note that highly reliable source TMZ claims "Akon doesn't drink ... Akon doesn't smoke ... but Akon was pretty damn surprised when he found out his pal Justin Bieber might be doin' both."

² University press offices!! I'm sure you'd love to hire me to write your press releases. Price quotes are available upon request, please leave a comment.

³ You might also want to know something about the distribution of CB₁ receptors in the anterior cingulate cortex, the purported locale of physical/social pain overlap.

⁴ Survey questions were:

LONELY - During the past 30 days how often did you feel lonely?
POT - On the average, how often in the past 12 months have you used marijuana or hashish? Just
WORTHY - I feel I am a person of worth, at least equal with others.
MENTAL HEALTH - How would you rate your overall mental health? Is it excellent, very good, good, fair, or poor?

Data for these four questions were available from 5,631 participants. Ratings were standardized, reverse-scored, and analyzed using weighted least squares regression.


References

Deckman, T., DeWall, C., Way, B., Gilman, R., & Richman, S. (2013). Can Marijuana Reduce Social Pain? Social Psychological and Personality Science. DOI: 10.1177/1948550613488949

Dewall CN, Macdonald G, Webster GD, Masten CL, Baumeister RF, Powell C, Combs D, Schurtz DR, Stillman TF, Tice DM, Eisenberger NI. (2010). Acetaminophen reduces social pain: behavioral and neural evidence. Psychol Sci. 21:931-7.

Toussaint K, Yang X, Zielinski M, Reigle K, Sacavage S, Nagar S, Raffa R. (2010). What do we (not) know about how paracetamol (acetaminophen) works? Journal of Clinical Pharmacy and Therapeutics 35 (6), 617-638.

What RDoC Research Might Look Like

The month of May is a violent thing
In the city their hearts start to sing
Well, some people sing, it sounds like they're screaming
I used to doubt it, but now I believe it

Month Of May
   ------The Arcade Fire

Today is Mental Health Month Blog Day, sponsored by the American Psychological Association (APA). It's designed to:

...educate the public about mental health, decrease stigma about mental illness, and discuss strategies for making lasting lifestyle and behavior changes that promote overall health and wellness.

If the public has been following the recent hullabaloo about how to diagnose mental illnesses, they might be confused about the current and future direction of the field. How did we get here?

As most of you know, the American Psychiatric Association (the other APA) is about to release its updated Diagnostic and Statistical Manual of Mental Disorders, the much maligned DSM-5. Weeks before the big launch, however, the National Institute of Mental Health (NIMH) stole the show by announcing that it will be re-orienting its research away from DSM categories:

...While DSM has been described as a “Bible” for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been “reliability” – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.

Instead, the Research Domain Criteria (RDoC) framework would become the preferred method for organizing biologically-based research on mental illnesses, with the ultimate goal of constructing a new classification scheme.

This caused quite a commotion, leading many to comment on NIMH's shocking repudiation of DSM-5. However, to long-time observers of RDoC's development, this was not a surprise. And the initial lack of clarity on the distinction between the RDoC Dimensional Approach for Research vs. DSM-5 for Diagnosis didn't help matters, nor did the uncertainty about whether NIMH would fund DSM-based research at all.¹

NIMH issued a press release on May 13 to clarify its position:

DSM-5 and RDoC: Shared Interests

Thomas R. Insel, M.D., director, NIMH
Jeffrey A. Lieberman, M.D., president-elect, APA

NIMH and APA have a shared interest in ensuring that patients and health providers have the best available tools and information today to identify and treat mental health issues, while we continue to invest in improving and advancing mental disorder diagnostics for the future.

Today, the APA's Diagnostic and Statistical Manual of Mental Disorders (DSM), along with the International Classification of Diseases (ICD) represents the best information currently available for clinical diagnosis of mental disorders  Patients, families, and insurers can be confident that effective treatments are available and that the DSM is the key resource for delivering the best available care. The NIMH has not changed its position on DSM-5. As NIMH’s Research Domain Criteria (RDoC) project website states, “The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”

Yet, what may be realistically feasible today for practitioners is no longer sufficient for researchers. Looking forward, laying the groundwork for a future diagnostic system that more directly reflects modern brain science will require openness to rethinking traditional categories. It is increasingly evident that mental illness will be best understood as disorders of brain structure and function that implicate specific domains of cognition, emotion, and behavior. This is the focus of the NIMH’s Research Domain Criteria (RDoC) project. RDoC is an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioral science to the problem of mental illness.

So what is RDoC, and how might it be applied to new research projects? From the DSM perspective of categorical disorders (e.g, schizophrenia, major depression, and obsessive compulsive disorder), RDoC embraces diagnostic messiness. Patients previously excluded from a study due to comorbidities, or because they don't meet full criteria? Misfits from the "Not Otherwise Specified" (NOS) category? Now they're in. Specifically, the instructions for RFA-MH-14-050 state:

Priority will be given to applications that have a well-justified plan to include patients from multiple diagnostic groups (including Not Otherwise Specified and forme fruste diagnoses) as appropriate for explicating the dimensions and constructs of interest in the study design. Studies that include patients from a single diagnostic group may also be considered if there is a particularly strong justification for examining constructs of interest within one diagnostic category.  A defensible approach might be to study all patients presenting themselves at a specialty clinic, e.g., mood disorders clinic, anxiety clinic, or psychotic disorders clinic, regardless of whether they meet criteria for a particular DSM diagnosis.

One potential pitfall of this approach is the money required to enroll huge numbers of patients. If commonalities in cognitive function or brain circuitry or especially genetic risk factors are to emerge from studying all patients with mood disorder-like symptoms, then sample sizes must be very large to overcome potential noise in the system(s).

The applicant would propose to study one or more of the five different domains, or constructs, that have been fleshed out at NIMH Workshops:

Negative Valence Systems
Positive Valence Systems
Cognitive Systems
Systems for Social Processes
Arousal/Regulatory Systems

The possible units of analysis run the gamut from genes to circuits to behavior, and the studies should use specific tasks (paradigms) and self-report measures, as shown in the Negative Valence Systems matrix below.

Draft Research Domain Criteria Matrix

Animal models of active threat ("fear") like the startle response are pretty well established and would allow a much more detailed analysis of mechanisms, from genes to behavior. In the realm of human research, one example of a proposed project for RFA-MH-14-050 is:

• Evaluation of the relationship between measures of exaggerated fear response, reports of overall distress and anxiety, and chronicity of internalizing disorders

This project could study common and unique aspects of the startle response in patients with phobias, panic disorder, OCD, generalized anxiety, and major depression ("internalizing disorders"), as described in this review article (Vaidyanathan et al.  2011).

Another recent review tackles the neurobiology of reward, which falls under the rubric of Positive Valence Systems. It's a 43 page tour de force with 756 references (Dichter et al., 2012):

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

The idea is to find common neurobiological substrates of altered reward circuitry that cut across DSM-esque categories (e.g., drug and alcohol use disorders, serious gambling problems, mania), where individuals seek out reward without regard to the consequences. At the other end of the spectrum is anhedonia, or the inability to feel pleasure from previously rewarding activities. Anhedonia is often (but not always) seen in major depression and schizophrenia, two disorders usually considered to have little overlap.

Will RDoC succeed in carving out a new nosology and generating a new guidebook? Will it lead to diagnostic tests that can identify specific cognitive, emotional, motivational, or social weaknesses that can be treated with targeted pharmaceuticals, deep brain stimulation, and/or improved psychotherapies?

This quote from Chapter 1 of a 2002 white paper collection indicates the DSM-5 revision committee (a joint APA / NIMH production) didn't exactly expect that all of its goals would be reached (PDF):

"Given the relatively short time frame for generating breakthrough research findings between now [1999] and the probable publication of DSM-V in 2010 [2013], it is anticipated that some of the research agendas suggested in these chapters might not bear fruit until the DSM-VI or even DSM-VII revision processes!"

So don't hold your breath, unless you want to experience severe anoxia.


Footnotes

¹ See the Appendix for a compendium of quotes.


References

Dichter, G., Damiano, C., & Allen, J. (2012). Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings Journal of Neurodevelopmental Disorders, 4 (1) DOI: 10.1186/1866-1955-4-19

Vaidyanathan, U., Nelson, L., & Patrick, C. (2011). Clarifying domains of internalizing psychopathology using neurophysiology Psychological Medicine, 42 (03), 447-459 DOI: 10.1017/S0033291711001528


Appendix

May 6
Matthew Herper (Forbes reporter covering science and medicine): “I spoke to NIMH. This is a broadening, not an exclusion.” ...

DSM-5 Task Force member Dr.  David J. Kupfer strikes back in the NYT, blaming NIMH and the sluggish rate of scientific progress: “The problem that we’ve had in dealing with the data that we’ve had over the five to 10 years since we began the revision process of D.S.M.-5 is a failure of our neuroscience and biology to give us the level of diagnostic criteria, a level of sensitivity and specificity that we would be able to introduce into the diagnostic manual.”


May 7
“Some people have the idea that we’re trying to ditch or diss the DSM and that’s not a fair assessment,” says Insel.

Dr. Bruce Cuthbert: “The sensationalist headlines out there are entirely misleading, and we will continue to support DSM-based research as we increase our portfolio of RDoC grants. RDoC is intended to inform future versions of the ICD and DSM; we have no intention of coming out with a competing system. The implication of this is that the fruits of RDoC are likely to be taken up into the ICD/DSM piecemeal rather than in one entire set, at such times as the evidence for various aspects becomes strong enough to warrant changes to the nosologies.”

Dr. Thomas Insel: “We cannot ‘ditch’ or ‘reject’ terms like schizophrenia or bipolar. We just need to view them as constructs, perhaps including many different disorders that require different treatments or obscuring disorders than cut across the current categories. A symptom-only system will not be sufficient for identifying brain disorders—whether the initial label is dementia or schizophrenia.”

Dr. Cuthbert: “As with most shifts in science, changes in research priorities require a transition. Because almost all clinical researchers today grew up with the DSM system both clinically and in research, it will take some time to get a “feel” for the relationships between DSM disorders and various kinds of RDoC phenomena (both in terms of the types of symptoms, and in overall severity), learn how to write grant applications with the new criteria, and evolve new review criteria. So, there will be a period of some time while these crosswalks are worked out.”


May 8
Dr. Cuthbert: “Using DSM diagnoses for research has become a de facto standard ever since the DSM-III came out in 1980. What we are trying to do is to study neural systems directly because they cut across lots of the dsm disorders. ... We are moving in a new direction. That doesn’t mean that next month we’ll stop accepting DSM diagnoses. It rather is a shift in emphasis.”