Physiological Test Predicts Effectiveness of Talk Therapy For Depression

[A] quick, inexpensive, and easy to administer physiological measure, pupil dilation in response to emotional words, not only reflects activity in brain regions involved in depression and treatment response but can predict which patients are likely to respond to cognitive therapy[.]. . . activity in the brain's cortical emotion regulatory systems is strongly related to pupil size when people are viewing emotion-laden words . . . It is because of this relationship between eye and brain that pupil measurements predict the response to cognitive therapy."

Cognitive therapy is a type of psychotherapy designed to help individuals overcome difficulties by modifying negative or irrational thoughts and behavior, which, in turn, can improve mood and reduce stress. It is usually completed in weekly sessions, with 10-20 sessions being effective for most individuals who benefit.

From here, citing Greg J. Siegle, Stuart R. Steinhauer, Edward S. Friedman, Wesley S. Thompson, Michael E. Thase. "Remission Prognosis for Cognitive Therapy for Recurrent Depression Using the Pupil: Utility and Neural Correlates." Biological Psychiatry, 2011; 69 (8): 726 DOI: 10.1016/j.biopsych.2010.12.041.

The abstact of the paper provides more details:

Although up to 60% of people with major depressive disorder respond to cognitive therapy (CT) in controlled trials, clinicians do not routinely use standardized assessments to inform which patients should receive this treatment. Inexpensive, noninvasive prognostic indicators could aid in matching patients with appropriate treatments. Pupillary response to emotional information is an excellent candidate, reflecting limbic reactivity and executive control. This study examined 1) whether pretreatment assessment of pupillary responses to negative information were associated with remission in CT and 2) their associated brain mechanisms.

We examined whether pretreatment pupillary responses to emotional stimuli were prognostic for remission in an inception cohort of 32 unipolar depressed adults to 16 to 20 sessions of CT. Twenty patients were then assessed on the same task using functional magnetic resonance imaging. Pupillary responses were assessed in 51 never-depressed controls for reference.

Remission was associated with either low initial severity or the combination of higher initial severity and low sustained pupillary responses to negative words (87% correct classification of remitters and nonremitters, 93% sensitivity, 80% specificity; 88% correct classification of high-severity participants, p < .01, 90% sensitivity, 92% specificity). Increased pupillary responses were associated with increased activity in dorsolateral prefrontal regions associated with executive control and emotion regulation. For patients with higher severity, disruptions of executive control mechanisms responsible for initiating emotion regulation, which are indexed by low sustained pupil responses and targeted in therapy, may be key to remitting in this intervention. These mechanisms can be measured using inexpensive noninvasive psychophysiological assessments.

The small study obviously needs to be replicated in a larger sample before being used on a widespread basis, but the 88% rate at which this simple test determines if high severity depressed patients will respond to cognitive therapy, compared to a 60% response rate in the absence of screening, is a major improvement for a technique that requires no investment in drugs or equipment and only minimal additional training for mental health practitioners. This test could spare more than half of severely clinically depressed individuals time and misery trying cognitive therapy that is unlikely to be effective for them, allowing them to use alternative therapies like drug treatments that are likely to be more effective for them immediately, while allowing about half of severely clinically depressed individuals to receive cognitive therapy, knowing that it has a very high probability of being successful, and avoiding the need for them to undergo a psychiatric drug treatment regime that is unnecessary for their recovery. The fact that the benefit is statistically significant at the 99% level in this small study also makes a study calculated to replicate this result look like a promising good investment.

Given that clinical unipolar depression is one of the most common mental health conditions, and is by far the most common one that is not typically congenital, which makes it disproportionately likely to be a condition dealt with by a primary care physician as opposed to a specialist mental health care professional, this kind of advance has particularly great practical relevance. Also, since unipolar depression is so common, the cost savings to the health care system of a diagnostic tool for determining what kind of treatment will be most effective could be an evidence based medicine technique that could make a material dent in the overall cost of mental health care.

Since this is a diagnostic approach, rather than a drug or device, it also doesn't need a long and costly approval process from the Food and Drug Administration. Funding of a simple large scale replication of this study which could be completed in a year or two, would be enough to include this diagnostic technique as part of the standard by the book treatment regime for unipolar depression nationally. Of course, since this isn't an approach would have a biotech company backing it, this kind of study almost necessarily would need to be funded by the public sector, for example, through a National Institute of Mental Health (NIHM) grant.

The real value of treatment effectiveness prediction tools as a means to improve the quality of patient care while reducing health care costs, a field which is coming into its own as a subfield of psychiatry and psychology, also suggests another funding possibility. Health insurance companies have historically viewed themselves primarily as financial institutions and as institutions through which patients can collectively bargain for provider health care pricing. But, the health insurance industry might be well advised to develop and fund a non-profit research foundation to develop treatment effectiveness prediction tools that do not have drug companies or medical equipment makers to fund them, as a way to promote health enhancing quality control.

The benefits of this little study aren't just practical in an immediate sense either. This is some of the hardest empirical evidence yet that there are medically relevant subtypes of unipolar depression in existence, with some indication of what the underlying neurological basis of that subtyping might involve. One of the deep issues in psychiatric classification of mental health conditions, for which the DSM-IV is the current industry standard, is that diagnosis of psychiatric conditions is almost entirely based upon non-physiological symptoms. It is entirely possible that some common DSM-IV conditions are really a cluster of separate conditions with similar symptoms but different causes (and hence different courses of treatment that are likely to be effective), and that other common DSM-IV conditions currently viewed are in fact merely distinctive syndromes that arrives when separate co-morbid conditions are present.

For example, this study shows that there are at least two types of unipolar depression, one of which is talk therapy responsive and one of which is not. This very likely indicates that the causes of the two types of unipolar depression are different. If this insight in incorporated into prior research on the causes of unipolar depression, the sometimes muddy and contradictory theories about what causes unipolar depression and how it can best be addressed might be clarified. One leading theory regarding the cause of unipolar depression conceptualizes it as a situation where prolonged stress and anxiety cause the body's normal responses to stress to shut down and try the new strategy of becoming depressed to deal with the situation. This might be a primary causal mechanism in one but not the other of subtypes of unipolar depression. If so, somewhat muddy data linking this cause to depression might become much more definitive with regard to the relevant subtype of depression, while clearing the decks for a search for one or more alternative causal mechanisms for the other subtype of depression.

Another possibility is that the pupil dilation response to emotion laden words may be a congenital element of a person's personality that is present even in the absence of unipolar depression. If this is the case, this trait might be one of many that is routinely tested for in children or young adults along with traits like blood type. Children with the trait might be at higher risk for the cognitive therapy responsive subtype of depression. Similarly, medical records could indicate which children are at risk for non-responsiveness to cognitive therapy as a treatment for unipolar depression. Since the physiological test for this trait is quite objective and easy to administer on a mass basis, it might also be possible to see if this trait corrolates with other mental health conditions, particularly those which are often co-morbid with unipolar depression (a co-mordidity pattern that might be more stark when restricted to a particularly subtype of depression), and to determine if it has a hereditary component. Patterns of co-morbidities associated with a particular subtype of unipolar depression might shed insight into the causal mechanism of a variety of mental health conditions which in turn might shed light on the kind of treatment regimes that are likely to be effective for those co-morbid mental health conditions.

Indeed, it might even be possible to provide these children or young adults, on a prophylactic basis, the kind of cognitive training that people with unipolar depression receive after they are diagnosed to help these individuals deal with situations that could lead to clinical depression before they happen.

There is no obvious reason that the benefits of cognitive behavioral therapy, which boils down to teaching people habits of thinking and mental tools for coping with certain kinds of problematic cognitive habits or tendencies, in general, can't be almost as effective when administered in advance as they are when administered as therapy after the fact. It might be possible to put together a set of empirically validated cognitive behavioral therapy regimes into a comprehensive set of coping skills that could be transmitted on a mass basis in a manner not unlike the model by which we instruct people in first aid, CPR, rescue breathing, the use of abdominal thrusts to respond to choking incidents, the proper way to respond to house fires, tornados and tsunamis, or suicide and bullying prevention programs. People who experience cognitive behavioral therapy responsive conditions anyway may benefit for refresher instruction and may be able to make more sense of what these therapies involve when they actually have the conditions that they are designed to alleviate, but it isn't unreasonable to think that this kind of public health preparedness model could materially reduce the overall incidence and impact of many common mental health conditions, some of which are subclinical or would otherwise never be diagnosed as such.

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The Sociology of Brain Disorder Treatment

There are two medical specialties that deal with brain disorders and conditions. One is neurology. The other is psychiatry. Where does one draw the line between the two?

Neuroskeptic compares the number of articles on particular conditions in leading academic journals for each specialty (Neurology and the American Journal of Psychiatry), to look empirically at how the line has been drawn within the medical profession.

The division doesn't seem to be very strongly linked to the extent that a condition is biologicallly based. As he notes:

Schizophrenia, which is probably considered "the most neurological" psychiatric disorder, is in fact the least talked about in Neurology.

Both mental retardation and autism are middle ground between the two specialties, with mental retardation leaning towards neurology, and autism leaning towards psychiatry.

Eyeballing the data, one way to think of the way that the conditions have been allocated is that psychiatrist deal with conditions that influence your personality and social interactions, other than pure cognition, while neurologists deal with other conditions and conditions that impact pure cognition.

This explains the mental retardation v. autism divide, for example. While both have a cognitive function element, explaining the neurological interest in both conditions, what distinguishes an autism diagnosis from a mental retardation diagnosis that is not autism is the diagnostic and treatment focus on how autism affects personality, social interaction and empathy, particularly in the case of autism spectrum disorders like Asperger's, where IQ is often in the normal range.

The gray area for ADHD, likewise, can be explained as a product of the lingering ambiguity over whether to think of the condition as a personality disorder that is a cogential part of who someone is, or as a developmental disorder of something large is part of a larger cognition process.

Psychaitry is concerned with "who you are" while neurology is concerned with "what you are" even though there isn't obviously any fundamental difference between the kind of brain functions that lead to schizophrenia and those that lead to congential epilepsy. The looming question behind Neuroskeptic's post is whether the divide says more about perhaps unfounded biases about mental health that pervade even the supposedly enlightened medical profession, than it does about science.

There are other ways to see the distinction, of course. One is that neurologists deal with issues that are believed to be exclusively "hardware" issues, while a core issue for psychiatrists is to parse "hardware" from "software" issues and address each appropriately. Some conditions may not neatly fit that divide today simply because historical ambiguity led a condition to be assigned to one category or the other, and given that all of the physicians involved have a similar allopathic medical background and training, there is no compelling reason to upset the apple cart of institutional and funding and bureaucratic arrangements based on the distinction at this point, even if it isn't terribly logical.

In the same way, no one is urgently pushing to have responsibility for counterfeiting enforcement removed from the duties of the United States Secret Service even though this doesn't logically have much to do with is primary responsibility to provide bodyguard protection to the President and other senior federal officials and candidates, because the skill set for the two tasks is similar.

Still, the divide has a strong impact on treatment modality. Neurologists use drugs and sometimes surgery, while seeing little place for therapy. Psychiatrists, while also prescribing drug treatments, recognize the value of psychological talk therapies as a complementary treatment modality to a much greater extent.

A footnote to the post in the study is also interesting:

"Gathering" this data took me 15 minutes. 20 years ago, it would have taken... well, you'd have had to read and manually categorize 30,000 abstracts. Even at 2 minutes per abstract (bare minimum) that's, er, 1000 man-hours of work.

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What Is Mind Control And Why Should We Care?

The blog "Science Not Fiction" has an interesting post on whether mood influencing drugs are a form of mind control.  The original post argues that they are not.  In a length comment, I argue that the distinction is not as clear as the author of the post suggests.

Drugs can influence decision making to the same extent as variety of other factors from money to threats of violence.

The distinction between legitimate and illegitimate ways of influencing someone's decision making is one that is relevant to a wide array of legal issues because voluntariness in decision making is a key legal issue in wide variety of legal contexts from substantive criminal law issues like consent as a defense to rape charges, to the criminal procedure issue of the admissibility of a confession or validity of a plea bargin, to trusts and estates law, to health care law, to contract law, and more.

In these bodies of law, some kinds of decision influencing factors are considered to be legitimate, while others are seen as making consent ineffectual and amounting to duress or undue influence or fraud.

Rather than asking whether drugs constitute mind control, we should instead ask "when is it legitimate to use drugs to influence a person's decision making process?"

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The Case Against The Label "Borderline Personality Disorder"

There is an established mental health disorder with the name "Borderline Personality Disorder."  This label has its critics.  See also here.

First, the category itself is questionable, because it is so often co-morbid with other conditions, doesn't have a fixed core of symptoms found in every person given that diagnosis, and is often confused with conditions like bipolar disorder, which can present similarly.  It is a muddy diagnosis that may not have a common cause or a common suitable treatment that fudges inadequacies in the diagnostic system.

Arguably, this is a feature and not a flaw.  Nobody in the clinical community is claiming seriously that people who are diagnosed with Borderline Personality Disorder by qualified psychiatrists who are doing their job properly do not have a mental health condition.   Once one is diagnosed with "something," the specific treatment plan may be rather ad hoc in any case, tailored to what works and the individualized presentation in the patient.  Ambiguous muddy diagnoses prevent someone who clearly has something wrong from falling through the cracks because they don't fit in a specific box.

But, the lack of coherence in the category does illustrate that the modern psychiatric medical establishment isn't really sure what is wrong and doesn't really know what to do about it.

Second, the label has pejorative connotations, seems to be applied to women when men with the same symptoms would be given another diagnosis (often "psychopathy" or in DSM-IV language, a particular subtype of "anti-social personality disorder"), may capture clinician bias about a particular patient rather than objective symptoms, and  it isn't really clear what metaphor is being invoked when the "borderline" label is used - borderline between what and what?  Critics argue that the label essentially consists of being both crazy and difficult, rather than merely crazy, or merely difficult.

Now one can argue that any classification that carries as diagnostic criteria more of the folk definitions of "evil" than all but one or two other diagnoses is inevitably going to develop prejorative connotations, just as labels for people with low IQ have to be re-invented every decade or two because they inevitably develop those connotations and cease to have exclusively clinical meaning.

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Neuroscience of Binge Drinking Better Understood

[M]anipulating two receptors in the brain, GABA receptors and toll-like receptor 4 (TLR4), "caused profound reduction" of binge drinking for two weeks in rodents that had been bred and trained to drink excessively." The study was published online the week of Feb. 28 in the journal the Proceedings of the National Academy of Sciences.

About 30 percent of Americans who drink do so excessively, and about 75,000 people die each year from the effects of excessive drinking. Current treatments for excessive alcohol drinking include prescription drugs Revia and Campral for controlling cravings. To ease withdrawal symptoms, doctors often prescribe medications such as Valium and Librium that carry their own risks of addiction. Valium and Librium reduce the anxiety alcoholics feel when they stop drinking but do not reduce cravings for alcohol.

The new study found that treatments that manipulate both the GABA receptor and toll-like receptor 4 have the potential to reduce anxiety and control cravings, with little to no risk for addiction[.] . . .

GABA receptors are a class of receptors in the brain that react to the neurotransmitter GABA and act as inhibitory receptors, calming down or inhibiting the activity of neurons in the brain. GABA receptors react to alcohol, giving drinkers a calm and euphoric feeling and reinforcing excessive drinking behavior. . . . This is the first scientific study to document GABA receptors' key involvement in binge drinking specifically, though scientists already believed that the receptors had a role in excessive drinking in general. . . .

Science has traditionally considered TLR4 to be an innate immunity receptor involved with neuroinflammation in the brain. Scientists associated TLR4 with microglia, cells that support inflammatory responses in the brain. "What makes this finding particularly important for the field of neuroscience is that we're showing that TLR4 plays a significant role in neurons, specifically, the neurons that are connected to the GABA receptor," . . . . To establish the connection between the GABA receptors, TLR4 and alcohol, the scientists manipulated this pathway in the binge drinking rodents . . . [with] a herpes viral vector . . . to deliver a gene-modifying agent directly to the neurons in the brain, to target TLR4 and GABA receptors. The scientists found that when they artificially stimulated the GABA receptors and TLR4 in order to simulate the good feelings binge drinkers feel when drinking alcohol, the rats lost interest in alcohol for two weeks after the procedure.

Compounds exist that would stimulate the receptors in the same way the scientists did in the study. "It's very likely that, down the road, these compounds could become new therapies for binge drinking . . . These compounds would act like a substitute for alcohol, much like methadone acts as a substitute for heroin. They would help alcoholics stop drinking, giving them relief from their cravings and from the anxiety that they try to alleviate with drinking."

From here.

So, drugs to end a predisposition to binge drink may be on the horizon in our near future, and there is a methodological precedent for determining a cause and developing a treatment for other kinds of substance addictions.

Given the strong connection between alcoholism and other kinds of substance abuse, and a wide range of socially unacceptable behavior and crimes, the next question is whether these treatments promise a world in which those social ills are dramatically less of problem.

Also, if such drugs existed, what would it take to get binge drinkers to take it? Will drug testing for probationers cease to become a matter of seeing that they aren't taking illegal drugs and become a matter of confirming that they are taking drugs that treat their vulnerabilities?

Given the poor track record of science at observing ethical standards with vulnerable or institutionalized populations, there is also good reason to fear abuses along the same lines in the future.

There may also be an upside to the complexity of many polygenetic mental health traits. While it may take just a single disruption of one of thousands of genes that go into a health functioning brain, if dysfunctional processes are equally complex, a single way to disrupt that process may deal with problems that have a wide variety of causes. This seems to be the story of modern psychiatry. We have found drugs that can manipulate a handful of neurochemicals in the brain, but those drugs treat a large number of patients with neurochemical imbalances in the neurochemical systems that most commonly go awry.

Drugs that act on neurochemical receptors and reuptake channels seems to address a great many mental health conditions. This part of the brain seems particularly succeptable to treatment with drugs. There may be other parts of the brain that are equally important, perhaps miswired neurons, for example, but we don't understand how to treat them as well.

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