Stress Now, Mental Illness Later

Routinely, I enjoy crapping on the common biological explanations of various mental illnesses (e.g., monoamine hypothesis). However, this does not mean that I do not believe in the importance biology plays in the development of mental illness.

To say that a specific mental illness is the result of a "chemical imbalance" or one "bad gene" is ridiculous. The problem with biological explanations of mental illness is that they neglect the psycho/social aspects of illness development (they are also poorly support by research too!).

Since I'm a psychologist, I pay attention to stress. I believe stress to the be the glue that binds biology and psychology together. This is because stress or more importantly, psychological stress, has a biological mechanism that has both short-term and long-term effects on the body and brain. Certain aspects of the physiology of stress act as "transcription factors," that is, they regulate gene expression. This means the effects of stress can be felt acutely (i.e., in the short-term) or many years later (e.g., the average time span between onset of sexual abuse and the development of clinical depression is 11.5 years, 1).

This poses an interesting question: can the age at which one experience "stress" predict both the onset and type of mental illness? That's what Lupien et al. (2) wanted to answer in an interesting paper that was published in Nature Reviews Neuroscience earlier this year.

Before I delve into their hypothesis, I am required by law to describe the hypothalamus-pituitary-adrenal (HPA) axis (see below).

This is how it works. You perceive a stressor (e.g., all the women with whom you were having extra-marital affairs, suddenly decide to tell their "stories" to TMZ), your hypothalamus releases corticotropin release hormone (CRH). CRH stimulates its neighbor, the pituitary gland, to release adrenocorticotropic hormone (ACTH), which finds its way down your blood stream and stimulates the adrenal glands to release glucocorticoids (steroids) as well as catecholamines (epinephrine and norepinephrine).

After this, many wonderful things occur: your wife attacks you with a golf club; your blood sugar spikes, blood pressure and heart rate increase, which delivers a rush of blood and oxygen to your thigh muscles. This enables you to run to your SUV, which you crash 5 feet from your drive way. Now the stressor is gone (i.e., you release a statement on your website indicating that you need to do some "soul searching"); the glucocorticoids bind to certain receptors (i.e., GRs & MRs), and the system shuts down and returns back to its homeostatic baseline.

Lupien et al. reviewed the relevant literature on the effects of stress (e.g., chronic stress, abuse, etc) and neurological development during the following life phases: prenatal, postnatal, adolescence, and adulthood. What they found is summarized below.

"How the effects of chronic or repeated exposure to stress (or a single exposure to severe stress) at different stages in life depend on the brain areas that are developing or declining at the time of the exposure."

(Paraphrased for simplicity) prenatal stress (defined as maternal stress or exogenous steroids during pregnancy) affects the development of many of the brain regions that are involved in regulating the HPA axis (i.e., hippocampus, frontal cortex, and amygdala).

"Postnatal stress has varying effects: exposure to maternal separation during childhood leads to increased secretion of glucocorticoids, whereas exposure to severe abuse is associated with decreased levels of glucocorticoids. Thus, glucocorticoid production during childhood differentiates as a function of the environment."

"From the prenatal period onwards...some areas undergo rapid growth during a particular period. From birth to 2 years of age the hippocampus is developing; it might therefore be the brain area that is most vulnerable to the effects of stress at this time. By contrast, exposure to stress from birth to late childhood might lead to changes in amygdala volume, as this brain region continues to develop until the late 20s. During adolescence...there is an important increase in frontal volume. Consequently, stress exposure during this period should have major effects on the frontal cortex."

"In adulthood and during aging the brain regions that undergo the most rapid decline as a result of aging (amygdala, frontal cortex, hippocampus) are highly vulnerable to the effects of stress hormones. Stress during these periods can lead to the manifestation of incubated effects of early adversity on the brain or to maintenance of chronic effects of stress."

What all that psychobabble means is this: certain brain regions (i.e., amygdala, hippocampus, & frontal cortex) are more vulnerable to stress during certain developmental stages (e.g., the hippocampus is most vulnerable before age two). What the authors are postulating is that these areas, when affected by stress, can be use to predict the nature of the psychopathology that will result from exposure to stress at different ages. Or in their words:

"Exposure to adversity at the time of hippocampal development could lead to hippocampus dependent emotional disorders, which would be different from disorders arising from exposure to adversity a times of frontal cortex development."

This sounds very interesting! Is there any evidence to support it? They list two studies (3, 4). "The first reported that women who experienced trauma before the age of 12 years had increased risk for major depression, whereas women who experienced trauma between 12 and 18 years of age more frequently developed PTSD. The second study reported that repeated episodes of sexual abuse were associated with reduced hippocampal volume if the abuse occurred early in childhood, but with reduced prefrontal cortex volume if the abuse occurred during adolescence."

This does seem to support their hypothesis. However, if you read those two studies, you'll find that it is not as clean cut as these authors suggest. Also, other variables were not discussed such as temperament and genetics, sex and gender, SES, and culture. The research is also murky on what constitutes a "prefrontal" disorder versus a "hippocampal" disorder (not to mention the many anatomical overlaps between psychiatric diagnoses). In spite of those limitations, it is an interesting hypothesis that is worth exploring.

To read an excellent book on this subject, check out Robert Sapolsky's Why Zebras Don't Get Ulcers.



Lupien, S., McEwen, B., Gunnar, M., & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition Nature Reviews Neuroscience, 10 (6), 434-445 DOI: 10.1038/nrn2639

The Devolution of Psychotherapy

Devolution: noun; retrograde evolution, degeneration.

I recently returned from the 6th Evolution of Psychotherapy Conference (1), the "world's largest psychotherapy conference!"

This conference is supposedly a who's who of the world of psychology and psychotherapy. The list of "keynote speakers" included luminaries such as Robert Sapolsky, Aaron Beck, and Philip Zimbardo. However, other people of questionable credentials (e.g., Daniel Amen and Francine Shapiro) and of questionable relevance (e.g., Andrew Weil and Deepak Chopra) were also featured.

Similar to all major conferences, it was expensive (2):$699 for the main conference, plus an additional $249 for the pre-conference, and $199 for the post-conference. In all there were over40 "prominent" people featured and over 200 presentations and workshops. With over 7,000 people in attendance, what where we paying for?

According to the syllabus it was this: "attendees will increase their therapeutic skills by learning: 1. the basic principles and techniques of contemporary schools of psychotherapy, 2. the commonalities that underlie successful clinical work, and 3. the historical development and future projections of psychotherapeutic disciplines."

Unfortunately, those goals were not accomplished.

What the fuck was that purveyors of pseudoscience, Daniel Amen, doing at this conference? And why was he reserved for $249 pre-conference? Jeffrey "I whistle when I talk" Zeig, the person who produces these conferences, is a star fucker. Here is why Amen should not have been there (3, 4, 5).

I will admit that I have never familiarized myself with the work of either Andrew Weil or Deepak Chopra. My bias automatically lumped them in with quacks (e.g., Amen). However, after viewing their addresses, I have a difference opinion of them. Both are vary good public speakers (especially Deepak). Weil has a fairly good conceptualization of the current state of health care, but his prescriptions involved way too much government intervention for my libertarian soul. Deepak prefers to stay in the realm of metaphysics (i.e., philosophy, logic), rather than hard science. There is nothing wrong with that, but the relevance of his speech (and Weil's) to psychotherapy is questionable.

Although she was not a keynote speaker, I have to mention my hatred for the work of Francine Shapiro. I know this will be unpopular, but eye movement desensitization and reprocessing (EMDR) is bunk (6) . Let me clarify that, the theory behind EMDR is bunk (7). I have wanted to dedicate a series of posts to Shapiro and her "therapy," but every time I begin reading the relevant literature, I get so over come with rage that all I want to do is travel to Rwanda and club a Tutsi to death.

In the main auditorium there were various booths promoting various high-tech fancy pants technology such as EEG Spectrum International's "neuro feedback" (8) for clinical practice (An over zealous rep claimed that neuro feedback can "cure" ADHD in just 6 short sessions!).

Sadly, many of the other great names (Barlow, Bandura, Kernberg) had poorly done presentations and workshops.

Now for the good: Robert Sapolsky is amazing. Unfortunately, I am so intimately familiar with his research that I didn't learn anything.

Aaron Beck was amazing. For someone who is pushing 90, he was sharp, spry, articulate, funny, and up-to-date with all the current research.

Zimbardo also gave a great speech. I have never been much of a fan of his, but his presentation altered my perception of him and his work (though I still question the validity of his prison study).

Overall, the conference was not as great as I had hoped. Many of the workshops were a let down. Very little evidence based material was presented (I didn't spend over $800 to meditate in a room full of strangers or express my needs through dance). This conference reminded me of a late night talk show. A lot of bad jokes (told primarily by host Jeff Zeig) and the guests were there only to push their latest products (new books, etc).

If this is the evolution of psychotherapy, I just might change my mind about biological psychiatry.

The Cholinergic Hypothesis of Depression?

Come the year 2012 there could be a new antidepressant with a novel mechanism of action on the market in these United States (1). As the drug is still in development, it is known as "TC-5214."

According the the press release, TC-5214 is a "nicotinic channel blocker that is thought to treat depression by acting on neuronal nicotinic receptors, or NNRs, according to Targacept. Targacept says NNRs are found on nerve cells throughout the nervous system and regulate nervous system activity."

This is the first I've heard the term "neuronal nicotinic receptors." In all my texts they are referred to as nicotinic cholinergic receptors (nAChRs). In common parlance, they are simply referred to as "nicotinic receptors." My bias leads me to believe that this is the term that polled best in a focus group as being both "sciency" sounding and "catchy." But I digress...

In this abstract (2), this rationale is put forward, "based on the notion that the depressive states involve hypercholinergic tone, we have examined the potential palliative role of NNR antagonism in these disorders, using TC-5214" (my emphasis).

I have never heard this "cholinergic" hypothese of depression before.

They add, "TC-5214 demonstrated positive effects in a number of animal models of depression and anxiety... forced swim test, a classical depression model....behavioral despair test ... the social interaction paradigm, a model of generalized anxiety disorder...the light/dark chamber paradigm , a model of GAD and phobia."

Take this for what it is worth. I hold almost no faith in animal studies (3) since the animal models simply cannot mimic the complexities of human mental illness and that the majority of drugs that pass animal trials fail to generate positive result in humans.

And just like many other theories of depression, a complex mental illness can be boiled down to a single receptor, "the antidepressant and anxiolytic effects seen in these studies are likely attributable to antagonist effects at the α4β2."

Since so much has been written about serotonin, norepinephrine, and dopamine, I've decided to dedicate the rest of post to acetylcholilne, the proposed "cause" of depression that this new drug will treat. (NERD ALERT: If you find this kind of stuff boring, stop reading now!)

Acetylcholine (ACh) is synthesized in one step (as opposed to the multiple steps required for the catecholamines). As you can see in the above image, there are two precursors: choline and acetyl coenyzme A (acetyl CoA). Choline is primarily derived from the fat in our daily diets. Acetyl CoA is produced within the cell by way of fat and sugar metabolism. The synthesis of ACh is catalyzed by the enzyme choline acetyltransferase (ChAT), which does as the name implies, it transfers the acetyl from CoA to choline to form ACh. ChAT is present in the cytoplasm of neurons that use ACh as their neurotransmitter.

Acetylcholinesterase (pictured above) breaks down ACh into choline and acetic acid (the acid that gives vinegar its smell and taste, 4). AChE is found within the presynaptic cell to metabolize excess ACh, on the membrane of the postsynaptic cell to break down ACh released into the synaptic cleft. It's also found in the neuromuscular junction (where PNS nerves stimulate muscles).

Cholinergic neurons play important roles in both the central and peripheral nervous systems (CNS & PNS). ACh neurons modulate both the sympathetic branch and the parasympathetic branches of the PNS. In the brain, the main neuclei that produce ACh are clustered in only a few areas. The first major pathway originates in the dorsal tegmental areas and projects to the thalamus. This pathway is part of the "reticular activating system," which govern the arousal level and alertness. Next is the septal nucleus that projects to the fornix and terminates in the hippocampus (ACh plays a prominent role in long-term memory formation). Next is the "ACh forebrain complex," which includes three "bands," the largest being the nucleus basalis of Meynert. These projections go all through the cortex and amygdala, the olfactory bulbs and the vestibular-cochlear nerve (important in balance).

There are two acetylcholine receptor subtypes, muscarinic and nicotinic.

Nicotinic receptors are highly concentrated on muscle cells, ganglionic neurons in the PNS, and on certain brain neurons. They are ionotropic (made up of an ion channel). When ACh binds to this receptor, sodium (Na+) and calcium (Ca2+) rush into the cell, causing depolorization, and increasing the cell's excitability. These receptors also enhance the release of other neurotransmitters.

The nicotinic receptor (above) is comprised of five proteins that form a channel. The subunits are label with Greek letters: beta, gamma, sigma, and two alpha subunits (ACh needs to bind to both of these to open the channel up). The structure, however, of the brain nicotinic neurons and muscles neurons are different, leading to different pharmacological difference between the two (see below).

The drug TC-5214 reportedly binds to neuron type three at the alpha4, beta2 subunit. (Contrary to what Wikipedia says, 5, this drug has NOT been tested in MDD patients).

Muscarinic receptors, conversely, are metabotropic (similar to monoamine NTs). So far, 5 muscarinic receptors have been discovered (M1 to M5), with some being excitatory and others inhibitory. Receptors are widely distributed throughout the brain including the neocortex, hippocampus, thalamus, striatum, and the basal forebrain. Outside of the brain muscarinic receptors are found mainly in cardiac muscle and smooth muscle (such as those found in the bladder). This is the receptor system associated with "anticholinergic syndrome" (6).

ACh's exact role in mood and cognition is still not known. It's associated with long-term memory formation (e.g., Alzheimer's disease) and attention and arousal (e.g., focused attention). Will TC-5214 actually treat depression? I doubt it. It seems to me, as a nicotinic receptor antagonist, it is better suited for smoking cessation (Chantix loses patent protection in 2012). Either way, it will be interesting to see how this one develops.