The Corpus Callosum

Psychotherapy and Brain Chemistry

One of the articles that I read, early in my career, that influenced
the way I think about neuroscience, was this one:

glucose metabolic rate changes with both drug and behavior therapy for
obsessive-compulsive disorder

L. R. Baxter Jr, et. al., Arch Gen Psychiatry.

We used positron emission tomography to investigate local cerebral
metabolic rates for glucose (LCMRG1c) in patients with
obsessive-compulsive disorder before and after treatment with either
fluoxetine hydrochloride or behavior therapy. After treatment, LCMRG1c
in the head of the right caudate nucleus, divided by that in the
ipsilateral hemisphere (Cd/hem), was decreased significantly compared
with pretreatment values in responders to both drug and behavior
therapy. These decreases in responders were also significantly greater
than right Cd/hem changes in nonresponders and normal controls, in both
of whom values did not change from baseline. Percentage change in
obsessive-compulsive disorder symptom ratings correlated significantly
with the percent of right Cd/hem change with drug therapy and there was
a trend to significance for this same correlation with behavior
therapy. By lumping all responders to either treatment, right orbital
cortex/hem was significantly correlated with ipsilateral Cd/hem and
thalamus/hem before treatment but not after, and the differences before
and after treatment were significant. A similar pattern was noted in
the left hemisphere. A brain circuit involving these brain regions may
mediate obsessive-compulsive disorder symptoms.

For those too impatient to read the abstract, what it shows is that
treatment with either medication or psychotherapy can produce the same
changes in brain chemistry.  The changes demonstrated with
psychotherapy were quantitatively smaller than those with medication,
but there were in the same brain regions, and in the same direction.
 The changes in the psychotherapy treatment group did not
quite attain statistical significance.  However, in 1992, I
was pretty sure that subsequent studies would confirm the original

Because of recent discussions amongst ScienceBloggers, I decided to go
back and see if this has been replicated or expanded upon.  

Of course, the findings were simply too tantalizing to be left alone.
 Others have indeed followed up on this.  It turns
out that the findings are easiest to replicate in OCD and simple
phobias, but much more challenging in other conditions.  

A more up-to-date review was published in Nature
Molecular Psychiatry
earlier this year:

psychotherapy changes the brain – the contribution of
functional neuroimaging

D E J Linden, Molecular Psychiatry
(2006) 11, 528–538.

A thorough investigation of the neural effects of psychotherapy is
needed in order to provide a neurobiological foundation for widely used
treatment protocols. This paper reviews functional neuroimaging studies
on psychotherapy effects and their methodological background, including
the development of symptom provocation techniques. Studies of cognitive
behavioural therapy (CBT) effects in obsessive-compulsive disorder
(OCD) were consistent in showing decreased metabolism in the right
caudate nucleus. Cognitive behavioural therapy in phobia resulted in
decreased activity in limbic and paralimbic areas. Interestingly,
similar effects were observed after successful intervention with
selective serotonin reuptake inhibitors (SSRI) in both diseases,
indicating commonalities in the biological mechanisms of psycho- and
pharmacotherapy. These findings are discussed in the context of current
neurobiological models of anxiety disorders. Findings in depression,
where both decreases and increases in prefrontal metabolism after
treatment and considerable differences between pharmacological and
psychological interventions were reported, seem still too heterogeneous
to allow for an integrative account, but point to important differences
between the mechanisms through which these interventions attain their
clinical effects. Further studies with larger patient numbers, use of
standardised imaging protocols across studies, and ideally integration
with molecular imaging are needed to clarify the remaining
contradictions. This effort is worthwhile because functional imaging
can then be potentially used to monitor treatment effects and aid in
the choice of the optimal therapy. Finally, recent advances in the
functional imaging of hypnosis and the application of neurofeedback are
evaluated for their potential use in the development of psychotherapy
protocols that use the direct modulation of brain activity as a way of
improving symptoms.

This shows that so far, no one has been able to find robust, replicable
changes in the brains of persons being treated for depression.
 What the author says about it, in the full text of the
article, probably indicates that we have not yet learned to subdivide
depressed patients into neurobiologically distinct groups.

At present, the available evidence suggests that any
model that relies on global frontal hypometabolism to explain symptoms
of depression and its reversal to account for treatment effects would
be oversimplifying the complex nature of cortico-cortical and
subcortical interactions in affective disorders.  The
difference between the neural correlates of clinical improvement after
pharmacological and psychological interventions 37,
is a case in point. These differences were
particularly pronounced in the study by Goldapple et al.,38
where opposite changes were observed in PFC (decrease after CBT,
increase after paroxetine) and limbic areas (increase after CBT,
decrease after paroxetine).

There is little doubt, that there are many different causes for
depression, as there probably are for OCD.  However, OCD seems
to have a common pathway that is more uniform from patient to patient.
 That makes it easier to find systematic changes.  

I am not quite ready to say that we have a full synthesis between
psychotherapy and neurobiology.  However, it is safe to safe
that, as of 2006, we no longer have to worry about the philosophical
mind-body problem.  There is no problem.
 They are just two different ways of looking at the same thing.


  1. #1 katherine
    August 30, 2006

    Joseph, when you say that “no one has been able to find robust, replicable changes in the brains of persons being treated for depression,” do you mean that no one has been able to find changes resulting from psychotherapy, pharmacotherapy, or both?

    And what’s the upshot? Does it mean that the symptoms we call “depression” can be caused by a variety of different neural mechanisms? I.e., depression might not be “just one thing”?

  2. #2 Mixter
    August 30, 2006

    My daughter was diagnosed with severe OCD in 2003. While medication (Lexapro) helped a little, I really think CBT is what made her OCD much less severe. Not only did she learn how to manage her anxiety during partial hospitalization, but exposure/ritual prevention and other CBT gave her the tools to work through stress-related flare-ups.

    It would be interesting to see if CBT could work in a similar way for depression or bipolar disorder.


  3. #3 Joseph j7uy5
    August 30, 2006

    Katherine: the situation with depression is not as clear as it is with OCD. There is a table in the Nature Molecular Psychiatry article that describes the findings of three studies, and they are all different. So it is not that people have not demonstrated changes between depressed people and nondepressed people; rather, that the changes that have been demonstrated have not been consistent. One reasonable conclusion, which is the one that I think is most likely, is what you asked about: there are likely to be different causes of depression.

    Mixter: partial response to medication is commmon in OCD. Also, it is common for it to take months (up to six months) for the full effect of medication to be seen. Some people do not respond to medication unless CBT is done also. Likewise, some people do not respond to CBT very well until medication is added.

    It is important to recognize that only one specific kind of CBT –exposure therapy with response prevention (ETRP) — is likely to be effective. The more commonly employed variety of CBT is that which emphasizes correcting irrational thoughts. That alone is very unlikely to help. So patients with OCD need to find a therapist with specific training in ETRP, not just any therapist who does CBT.

  4. #4 Greg P
    August 30, 2006

    Years ago I had a patient who had a very focal stroke, in the left anteriolateral nucleus of the thalamus (which has a lot of frontal projections, by the way). I originally saw her on a psych unit, where she was because she was upset, she knew something was wrong. I could tell be her speech pattern that something wasn’t right, ordered an MRI, and there it was.

    Later she developed some interesting behavioral changes:
    She was a chainsmoker, but suddenly had no interest in cigarettes.
    She was someone who drank the “same” cup of coffee all day long, just adding to it as the day went on, but after the stroke, the cup had to be filled to a very particular place and the coffee a certain temperature.
    She developed a compulsion to go to Kroger every day, but at the same time had lost her appetite, so her home was filling up with all this food she was buying.
    She was an avid crossword puzzle solver, but even though conversationally her speech was quite normal, she could never get back to being able to do them again.

    I put her on Prozac, which had just come out not too long before that, and the compulsive behaviors went away. Alas, the crossword vocabulary never returned.

  5. #5 Mixter
    August 30, 2006

    Exposure therapy is exactly what she got: They called it exposure/ritual prevention, but it’s exactly what you’re speaking of. They also did “thought-challenging,” which is probably the other type of CBT you’re referring to?

    She was an in-patient at Rogers Memorial Hospital in Milwaukee for six days, and went to the partial hospitalization program at Rogers Memorial in Oconomowoc, WI for eleven weeks. Follow up therapy went for a few months. She’s on a low does of Lexapro (15 mg/day) and does exposures when she’s feeling like she’s flaring up.

    Now she has her life back! (And I have a healthy beautiful daughter again!)

    It’s amazing to this lay person how well treatment went for her. Lots of people in her program seemed to need to go back for treatment again and again. Knock on wood, I haven’t had to take her back to the hospital program, and she only needed a brief round of therapy in early 2005.


  6. #6 Hyperion
    August 30, 2006

    The data for ADHD is similar, if more strongly in favor of pharmacotherapy over CBT. At least, between Zametkin’s (and others) PET scans and the MTA. Actually, come to think of it, I don’t remember reading any PET scan studies of CBT for that, although the MTA pretty much put any controversy there to rest.

    On the other hand, I was reading an article today on the treatment of neuropsychiatric symptoms comorbid with dementia in geriatric patients in long-term care. Not peer reviewed, just an op/ed type piece. The author was certainly in favor of using various types of cognitive therapy over medications, but I wasn’t overly certain that she was correct. For starters, the evidence they had showed that only a few of the many options for cognitive therapy were actually useful in any way. Secondly, the symptoms described (“affective disturbances such as depression, anxiety and irritability; psychotic disturbances such as delusions and hallucinations; specific behaviors such as wandering and aggression/agitation; and disturbances of drives related to sleep, eating, and sexuality.”) seemed to scream out that this was a dopaminergic problem. Especially the psychosis, aggression, and changes in appetite and sex drive. They reported on a paper showing Risperidone to be effective, which would make sense. Then she discussed the side effects involved and from there immediately disregarded it as a possible treatment.

    I don’t know, everything I’ve seen on the issue of cognitive therapy (such as CBT) and pharmacotherapy seems to point in the direction that pharmacotherapy is going to be more effective. This makes a certain amount of sense, as (contrary to popular belief, unfortunately) pharmacotherapy actually deals with the underlying neurological causes, while cognitive therapy is dealing with behavioral symptoms.

    Unfortunately, risperidone is known to have some pretty bad side effects, but it’d be nice if they could find something else. Maybe it’s a pre-Parkinsonian effect, the brain attempting to compensate for the substantia nigra’s deficit by pumping out massive amounts of dopamine and flooding everything else…but I wouldn’t want to be the one to give l-DOPA to a psychotic patient. Anyways, the article can be found here:


  7. #7 Joseph j7uy5
    August 30, 2006

    I am glad to hear that your daughter is doing well. It seems that people who have struggles with OCD for a long time find it more difficult to get the symptoms under control. It’s possible that she got good treatment quickly after the onset of symptoms, which probably is when it is most likely to have an enduring effect.

    Unfortunately, that is not usually the case. Most people take years to even start looking for treatment, then more years before they get referred to someone who actually can help.

  8. #8 Joseph j7uy5
    August 30, 2006

    One more thing. One of the really interesting aspects of OCD is its correlation with neurological conditions. It is statistically associated with tics and with Tourette syndrome. It also is associated with PANDAS. (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Strep).

  9. #9 Mixter
    August 31, 2006

    When she was first diagnosed with OCD, we had a strep test done since we had read about PANDAS on the internet. (Mary and I actually came up with an OCD diagnosis before her first therapist did.) Mary is also afflicted with fibromyalgia, which some think is an autoimmune disorder and others think is a sleep disorder.

    I wonder if there’s a connection between anxiety and immune system: My mother has general anxiety disorder and social anxiety disorder with a severe case of RA. She’s almost 76, and finally has a social life after all these years after starting treatment with Lexapro.


  10. #10 Jenna
    September 2, 2006

    This post is a great idea: writing about articles that have wowed, or changed, my thinking/learning. And your last two sentences:

    “I am not quite ready to say that we have a full synthesis between psychotherapy and neurobiology. However, it is safe to safe that, as of 2006, we no longer have to worry about the philosophical mind-body problem. There is no problem. They are just two different ways of looking at the same thing.”

    really struck a chord with me as I’ve been thinking the exact same thing for months now. It’s frustrating when there are many people who still think it’s a problem.

  11. #11 logtar
    September 5, 2006

    I am almost scared to comment here (you people are way more knowledgeable). I believe that if you miss the conclusion of the post you miss the point. One is not being said to be better or replace the other, I belive a combination is the best treatment for any problem. The more solution trains you get in motion the mist likely it is that one will get there on time 🙂

  12. #12 ramy
    September 9, 2006

    it is very interesting that ocd, of all the mental disorders, should lend itself with relative ease to the probings of neuroimaging. more so inspite of its high comorbid rates with other disorders. i suppose it may be that ocd is naturally a categorically “pure” disorder, rather unlike personality disorders for example. i don’t know how the authors of the dsm4 or icd10 selected the criteria, but maybe they just hit on something there. it seems to “fit” well with behavioural as well as biological theories. and the elegance of it is winning.

    but you spoke of depression too, and i suspect as with most other disorders besides ocd, these are better looked at dimensionally. i think many “neuroimagists” have been approaching it from that perspective for some time now. you point out that depression is probably a far more heterogenous disorder, and we probably are not comparing like for like. it is a problem of defintions, again. i think what neuroimaging has to offer is drawing out symptom dimensions _across_ categories, then validating them. we may then end up with a better, revised dsm/icd that more closely approximates how the mind works. and i should think it would aid psychiatrists to think better clinically too. bringing their minds closer to their patients’ minds, and bodies.

  13. #13 Joseph Bude
    June 16, 2009

    Thank you for the information.

    Can you please try and explain the bioSychoSocial causes of schizophrenia clearly? Because your explanation is not very clear in terms of the terminology you are using.

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