Brodmann's Map 100 Years Later

Brodmann's map. Anyone who has taken a course in basic neuroanatomy has been exposed to his roadmap of the cerebral cortex.

In this month's Nature Reviews Neuroscience, Zilles and Amunts (1) dedicated an article to Korbinian Brodmann and his map, celebrating its 100th anniversary (Brodmann's original work was published in 1909).

First, a little background. Brodmann's original map contains 52 areas; however, areas 12-16 and 48-51 are only found in nonhuman primate brains, so only 43 areas are actually labeled. How Brodmann constructed his "map" is quite complicated. He made numerous razor thin, horizontal slices of human brains. He then stained the cell bodies within those slices and attributed a number to an area if it was cytoarchitectonically distinct from its neighboring areas of the cortex.

Many others followed Brodmann's work with maps of their own. According to the article,

"During the next three decades, Otfried Foerster, Alfred Walter Campbell, Grafton Elliott Smith, Constantin Freiherr von Economo and Georg N. Koskinas argued for localizable anatomical and functional correlation and the segregation of cortical entities"

Many of those names may be new to you, which highlight how influential Brodmann's work has been. The reason there are many different "maps" is because brain mapping is not an exact science. Trying to differentiate the cortex based on brain architecture can produce profoundly different results, depending on the staining technique that is used and on the researcher's subjectivity.

"The Vogts used myelin-stained histological sections to study brain architecture (that is, myeloarchitecture). Their myeloarchitectonic map has many more areas (a total of 200) than that of Brodmann, because the Vogts further subdivided the Brodmann areas on the basis of the regionally more differentiated architecture of intracortical nerve fibres."

Below is a comparison of the various "maps" that have been produced since Brodmann's work in 1909.

(click to enlarge)

Differences between all these brain maps are apparent. However, there is also considerable overlap, suggesting that there is some degree of observer independence, reproducibility, and objectivity to the process.

A little historical note for anyone who was forced to memorize all those Brodmann areas, but was hampered by its apparent lack of logic (areas 1,2,3, start in the mid-lateral areas, while the remaining numbers are distributed in a quasi-random order). Each area number was assigned based on the order in which he prepared a slide, hence the apparent randomness of number assignment.

In his time, testing whether each "area" was correlated to a specific function was quite difficult. Over time, as other "maps" were published and his original became criticized for lack of objectivity, his map fell out of fashion. That is until the 1980's, when various brain imaging techniques were developed. Being able to image a live human during the performance of a specific task, it became possible to associate functional data with cytoarchitectual data. It was Brodmann's map that become apart of many of the first software and sterotaxic atlases for these machines.

Brodmann's work helped to revolutionize modern neuroscience. While many other maps have followed Brodmann's, and even though contemporary research has shown that "his map is incomplete or even wrong in some of the brain regions," many of the areas do correlate very well with various functional areas of the cortex, which is why his work still has relevance 100 years later.



Zilles K, & Amunts K (2010). Centenary of Brodmann's map - conception and fate. Nature reviews. Neuroscience, 11 (2), 139-45 PMID: 20046193

Cognitive Impairment and Schizophrenia

Time to act like a big boy again...

When you hear the word "schizophrenia," what comes to mind? Frequently, people imagine someone who has auditory hallucinations (e.g., a voice keeping a running commentary on the person's behavior) or bizarre delusions, such as having thoughts broadcasted to others.

When mental health professionals discuss the disorder, the most common phrases used are "positive symptoms" (e.g., hallucinations, delusions) and "negative symptoms" (e.g., flat affect, alogia). Current medical treatments almost exclusively focus on treating the positive symptoms. Increasingly, there is more discussion about medications treating the negative symptoms as well; however, most medications do a piss poor job of this (1).

What is also "known" about this disorder, is that individuals who have it often have pervasive cognitive deficits as well. There are some who argue that it is the cognitive symptoms that are a main reason for disability and dysfunction (2).

In this month's American Journal of Psychiatry (3), a group of researchers reported on a 30-year longitudinal study of cognition in individuals who eventually go on to develop schizophrenia.

What they wanted to know, is if cognitive impairment is present from early childhood and if those impairments remain stable throughout a lifetime (the developmental deficit hypothesis); whether future schizophrenia subjects lag behind healthy people in their cognitive development (developmental lag hypothesis); or whether they have a decline in cognitive functioning just prior to illness onset or as a result of psychosis (developmental deterioration hypothesis).

The authors of this study followed a cohort from birth to age 32. The children were initially assessed at age 2, with follow-up assessments occurring at ages 5, 7, 9, 11, and 13.

The children's cognitive abilities were assessed with the Wechsler Intelligence Scale for Children - Revised (WISC-R), which was originally published in 1974 (the WISC is currently in its 4 edition).

Scores are generated from this battery by taking the raw score and converting it to an age-match scaled score (SS). In lay terms, an individual's performance is compared to other individuals who are of a similar age cohort. This way, you can tell how someone's performance compares to other people of the same age. The primary score generated by the WISC is a full-scale IQ. If you read my older post on IQ scores (4), you'll recall that IQ can be a meaningless number as it obscures the variability in an individual's performance. In order to compensate for this, the researchers mainly focused on the composite scores of the WISC: verbal comprehension (information, vocabulary, and similarities; see subtest descriptions below), perceptual organization (block design, picture completion, and object assembly), and freedom from distractibility (arithmetic and digit symbol coding).

(click the below image to enlarge)

  The researchers found support for both the developmental deficit and lag hypotheses but not the developmental deterioration hypothesis. This is consistent with other research, which suggests that cognitive deficits in people diagnosed with schizophrenia remain stable over time (5, 6, 7). As the authors described,

"For all eight cognitive tests, the linear slopes of the growth curves were positive and significant (all p values <0.001), indicating that on average, future case subjects, similar to healthy comparison subjects, showed developmental increases in their cognitive functions between ages 7 and 13 years."

For the developmental deficit hypothesis, the authors noted,

"future schizophrenic case subjects exhibited early and static cognitive deficits on the following four cognitive tests: information, similarities, vocabulary, and picture completion...future schizophrenia subjects had significantly lower [performance] values than healthy comparison subjects." 

And for the developmental lag hypothesis,

"on three cognitive tests (block design, arithmetic, and digit symbol)...future schizophrenia case subjects had lower linear slope values than healthy comparison subjects, indicating that their growth on tests measure freedome from distractibility and visual-spatial problem solving skills was developmentally slower."

(click to enlarge)

The researchers concluded,

"The neurodevelopmental model of schizophrenia posits the existence of deviations in cognitive development many years prior to the emergence of overt clinical symptoms of adult schizophrenia. Findings from this study add to what is known about the neurodevelopmental model in three ways. First, our findings point to both cognitive developmental deficits and cognitive developmental lags during childhood in individuals who will go on to develop schizophrenia as an adult. Second, different cognitive functions appear to follow different developmental courses from childhood to early adolescence. The developmental deficit model appears to apply to verbal and visual knowledge acquisition, reasoning, and conceptualization abilities. The developmental lag model appears to apply to freedom from distractibility and visual-spatial problem solving abilities. Third, these patterns of cognitive deviations from childhood to early adolescence in schizophrenia are not shared in recurrent depression."

By this point you may be asking yourself, "what the hell does all this psychobabble mean?"

In short, these results don't mean much for clinical practice. They've reconfirmed that future schizophrenia subjects have baseline cognitive deficits, and their neurodevelopment is slower than healthy people.

Here are the average IQs of the different groups pooled together:

The authors of this study made it sound as if all future schizophrenia subjects had cognitive deficits. They didn't. Future schizophrenia subjects had an average IQ score of 94, while healthy subjects had an IQ of 101. Both of these scores fall in the average range (90-110). 7 points is not a big difference.

Above, are two bell curves I constructed to illustrate my point. IQ is a normally distributed score. The purple curve represents normal subjects (mean IQ 101) and the pink curve represents the future schizophrenia subjects (mean IQ 94).

A standard deviation (i.e., a measure of performance variability) for IQ scores is 15 points. A score of 85 (1 SD below the mean) is considered impaired. As you can see, there is considerable overlap between the schizophrenia bell curve and the normal subject bell curve. Nearly two/thirds of the schizophrenia population will have an IQ in the normal range or better; however, the maximum IQ for most schizophrenia subjects will be caped (i.e., rarely above 115), although there are notable exceptions (e.g., John Nash).

Another important point to note is that while a difference in IQ of 7 points (94 versus 101) is statistically significant, it is not clinically significant. You need a difference between 1 to 1-1/2 standard deviations to achieve clinical significance. Based on the bell curve, only 15% of future schizophrenia subjects will have an IQ that low.

The second problem with this study is that the cognitive assessments were not neurodiagnostic.

"the model posits that there is insult to the brain acquired or inherited in early development" and therefore "the developmental deficit model for the etiology of schizophrenia is supported by our data." 

What the data indicate is that some, but not all, future schizophrenia subjects had difficulty on some, but not all, of these tests (remember, performance was lower on average). One of the major criticisms of cognitive tests is that performance is influenced by factors outside of the individual. The only factor that is controlled for by the WISC-R is age. But other factors, such as quality of education, region of habitation, ethnicity, medications, and gender are not controlled. In order to determine if a problem is brain based, one needs to control for those other variables, which is why neuropsychologists should use demographically correct norms when possible.

Here's an example: Future schizophrenia subjects tend to be isolated, are viewed by others as weird, and are stigmatized by their peers. These factors can contribute to poor self esteem, stereotype threat, poor school performance, and most importantly, poor motivation to perform well. Of course a person with this social history will perform poorly on cognitive tests (people with recurrent depression also have lower IQ scores on average, see above).

Here's another problem: let's assume that differences in IQ are brain based. The IQ test results do not pinpoint were the problem actually is. Below is a pyramid that illustrates what brain/neurocognitive functions need to be intact in order for the higher order functions (e.g., IQ) to be accurately assessed.

For example, if a person performs poorly on the WISC-R Vocabulary subtest, you then want to know why that person performed poorly. He or she could of had a poor educational background, the person could have a memory retrieval problem, or an expressive speech problem, or a hearing problem.

For anyone who has undergone neuropsychological testing, you'll recall that we administer a butt-load of tests (between 20-30), which takes between 3-6 hours to complete. We do this so we can accurately pinpoint why a person performed poorly and so we can make useful recommendations. If the problem was educational, a tutor will help, if the problem was memory retrieval, cueing will be helpful, if the problem was hearing, a aid will be helpful.

There are many other problems with this study. However, the take home message is that future schizophrenia subjects, on average, perform poorly on some cognitive tests, but that poor performance difference is not huge. Why some perform poorly while others do not is still unknown. This study and its press release (8) do not help resolve this debate, it only muddies the waters. 



Reichenberg, A., Caspi, A., Harrington, H., Houts, R., Keefe, R., Murray, R., Poulton, R., & Moffitt, T. (2010). Static and Dynamic Cognitive Deficits in Childhood Preceding Adult Schizophrenia: A 30-Year Study American Journal of Psychiatry, 167 (2), 160-169 DOI: 10.1176/appi.ajp.2009.09040574

Cock Goes Here...

and here...

I expect to lose readers over this...

Does Schizophrenia Need to Be Treated?

The short answer is "Yes."

However, the dogma about the illness is one of chronicity, that is, schizophrenia is an illness of unremitting symptoms even with the best of treatments.

Is this depiction accurate?

Not entirely, according to Harrow et. al, who set out to answer this question (and many more) in the Schizophrenia Bulletin article "Do Patients with Schizophrenia Ever Show Periods of Recovery? A 15-year Multifollow-Up Study."

The authors wanted to answer 4 questions:

1. Do some or even a large percentage of patients with schizophrenia show periods of recovery? If so, what percentage?

2. Do patients with schizophreniform disorders show more favorable courses and outcomes than patients with schizophrenia? (Yes)

3. Is schizophrenia associated with slower recovery than other psychotic disorders? (Yes)

4. Is psychosis in nonschizophrenia patients a risk factor for subsequent poor outcome? (Maybe)

Since the focus of this post is on the answer to that first question, I've provided the answers to the other questions for brevity (the article is available for free).

Methodology and Study Outcomes:
The study consisted of 274 DSM-III diagnosed patients (64 of whom had schizophrenia) who were studied at 5 different intervals over 15 years. The total diagnostic breakdown and numbers of patients within each diagnosis assessed during each follow-up period are listed below:

Patients were assessed at 2 years, 4.5 years, 7.5 years, 10 years, and 15 years post-initial hospitalization. 

Other schizophrenia patient demographics are listed below:

Recovery was defined rather strictly:

1. the absence of major symptoms throughout the follow-up year (i.e., absence of psychotic activity and absence of negative symptoms).

2. adequate psychosocial functioning, including instrumental (or paid) work half-time or more during the follow-up year.

3. the absence of a very poor social activity level.

4. no psychiatric rehospitalizations during the follow-up year.

The data provided include, "(a) percentage of patients with schizophrenia in recovery at any follow-up year and (b) the cumulative percentage of schizophrenia patients who, over 15 years, ever show the potential for an interval or period of recovery." In other words,the number of patients with schizophrenia who had at least one interval of recovery during the 15 year period.

Results:
Here are the percentages of patients that were in recovery during each follow-up interval for each diagnostic group:

On average, during any given follow-up period, approximately 19-22% of schizophrenia patients (out of 64 total) were in remission. All patients groups had their lowest period of recovery during the first two years after hospitalization. The schizophrenia group had the lowest frequency of patient recovery during all follow-up periods.

Here are the cumulative percentages of the patients that had at least one interval of recovery during the entire study period:

As time progressed, the number of patients who experienced at least 1 interval of recovery in each diagnostic group increased. Again, the schizophrenia group had the lowest cumulative number of patients who achieve recovery; 3 out of every 5 schizophrenia patients did not achieve remission.

Here is where it gets interesting:

The majority of the schizophrenia patients, who had at least one interval of recovery, were not being treated with any medications. In the authors' words, "very poor outcome patients with schizophrenia are more likely to be on antipsychotic medications."

One can generate many different hypotheses based on this result. For example, you could argue that psychotropic medications in general, and antipsychotic medications specifically, are dangerous drugs that cause more harm than good.

That's just how two individuals chose to spin this result:

Indeed, these findings indicate that not receiving treatment works better than pharmaceutical intervention. Similarly, University of Illinois researchers recently found that only 5 percent of medicated schizophrenia patients recover, but 40 percent of non-medicated patients recover (Harrow, Grossman, Jobe, and Herbener 2005; also see Harrow and Jobe 2007). In other words, schizophrenia patients are eight times more likely to recover if they are not on medications!(1)

Quick! Somebody notify the APA! We need to start revising all those treatment algorithms, STAT!.

Unfortunately, the authors of that piece, which appeared in the September/October 2008 edition of Skeptical Inquirer, are full of shit (excuse my French, but to call them liars would be considered libel).

Harrow and Thomas, with the same patient cohort, did another study: Factors Involved in Outcome and Recovery in Schizophrenia Patients Not on Antipsychotic Medications - A 15-Year Multifollow-Up Study.

One goal of this study was to examine the "clues on whether the better functioning of the subgroup of unmedicated patients with schizophrenia versus those on antipsychotics at the 15-year follow-up was a function of their current medication status" or "other long-term characteristics marked them off as different types of patients."

They answered this question by comparing the two groups on various premorbid and prognostic factors that were assessed near the beginning of the study.

 In the figure above, we see that unmedicated patients scored better on indices of "favorable prognosis." In the figure below, we also see that unmedicated patients had better scores on "premorbid achievement" measures as well. Keep in mind that these two factors (i.e., favorable prognosis and premorbid achievement) were assessed near the beginning of the study, and not afterward. This means that being on antipsychotics was not a major factor in patient outcomes, suggesting that the better overall recovery of the unmedicated patients was mainly due to long-term patient characteristics.

In the discussion section, the authors summarize their main findings:

"Looking at from a different viewpoint, the data suggests that schizophrenia patients with good prognostic features, with better premorbid developmental achievements and with more favorable personality characteristics are the subgroup more likely to stay off antipsychotics for a prolonged period."

What was identified is a small subset of patients who are able to experience episodes of recovery in the absence of antipsychotics. According to the authors, those patients "who go off antipsychotics are a different type of patient."

There are many things to keep in mind regarding these two research papers. First, the sample is rather small (64 cases of schizophrenia). Of those diagnosed, the majority never did achieved remission. At the end of the study, only 12/64 (19%) patients had been in remission the previous study year. Of those who did achieve remission, many eventually relapsed. And, overall, the schizophrenia patients had significantly poorer outcomes when compared to all other clinical groups...Oh screw it, who wants pie?



Harrow M, Grossman LS, Jobe TH, & Herbener ES (2005). Do patients with schizophrenia ever show periods of recovery? A 15-year multi-follow-up study. Schizophrenia bulletin, 31 (3), 723-34 PMID: 16020553

Harrow M, & Jobe TH (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. The Journal of nervous and mental disease, 195 (5), 406-14 PMID: 17502806

Now That's Change I Can Believe In!

In this week's issue of the Medical Letter (1), a brief review regarding medical marijuana is included, which concluded that,

"Medical marijuana may be effective for treatment of nausea, anorexia, pain and some other conditions, but published data supporting its efficacy for treating patients with intractable cancer pain are limited, dosage is not well standardized, and cannabis is often poorly tolerated, especially by older patients. " (Jan 25 issues, 2010)

This conclusion was based on a review of the three forms in which marijuana is usually consumed: botanical, oral synthetic, and oromucosal. As it relates to the botanical form (most popular among the 18-34 demographic), the Medical Letter stated that for nausea, pain, anorexia, asthma, glaucoma and spasticity,

"It appears to be modestly effective, depending on the dose, for some of these disorders, but well-controlled studies large enough to be convincing are lacking, and non-standardization of dosage makes the available data difficult to interpret." (my emphasis)

Let's forget about the controversy surrounding marijuana as a medicinal agent or as an illicit schedule I controlled substance (i.e., high abuse potential; no legitimate medical use). Just focus on the reason why, this drug, which is legal for medicinal use in 14 states, lacks "well-controlled studies large enough to be convincing" as a medicinal agent: the federal government has a monopoly on the supply of marijuana for large scale, FDA approved study:

"DEA's final ruling rejecting the application of UMass Amherst Professor Lyle Craker for a license to cultivate research marijuana for use by scientists in FDA-approved research. The ruling, which contradicts the recommendation of DEA Administrative Law Judge Mary Ellen Bittner, maintains the unique government monopoly over the supply of marijuana available for FDA-approved research." (2)

Here's the back story: Professor Craker and the Multidisciplinary Association for Psychedelic Studies (MAPS) applied for that license 7 years ago. A DEA administrative judge, Ms. Ellen, recommended the license because "competition with NIDA would be in the public interest." Still the DEA rejected the application.

Marijuana must be a very, very dangerous drug because every other Schedule I drug (e.g., cocaine) can be produced by government-licensed independent laboratories.

The only organization that conducts research on marijuana in large scale studies is the National Institute on Drug Abuse (NIDA). (3) As the name of the organization betrays, their interest lie in showing how bad marijuana can be. Since the Institute on Drug Abuse is a federal organization, the research produced there is used to produce legislation. (4) This lack of competition is what prevents real discoveries and innovations, which can be a benefit to the public, from being made.

The individual responsible for making this final DEA ruling is Michele Leonhart, whom Obama just nominated as the new head of the DEA. (5) I vaguely remember Obama promising some sort of Change as it relates to marijuana policy (i.e., no more raids). (6) However, raids on marijuana clinics still continued. In response to this apparent hypocrisy, Mr. Obama's White House said that,

"It expects those kinds of raids to end once Mr. Obama nominates someone to take charge of DEA, which is still run by Bush administration holdovers."

Mr. Leonhart is one of those Bush holdovers. Now that's Change!



Medical Letter, Inc. (2010). Medical Marijuana The Medical Letter, 52 (1330)

Schizophrenia Treatment: The Future

A reader request:

"I know you wrote that you're frustrated with reading clinical drug research but I was wondering if you could dedicate a post to explaining the barrier of entry for new antipsychotics that are *different* from the "new" antipsychotics. Also, I do not understand why you've stated the old antipsychotics are better (for whatever reasons) than the new antipsychotics. My husband has been on Risperdal for years and it works. I'm vigilant about exercise and diet so as to try to curb the potential diabetes side-effect. The fear on both our parts of psychotic episodes and the potential destruction that one could cause, is far outweighed by the benefits of risperidone. That is our choice, but I'm hopeful breakthroughs will occur in drug research that improve beyond the current "new" drugs that are simply more of the same.

I love your blog and plan to visit frequently."

I cannot say that there is just one "barrier of entry" for new drugs to treat psychosis. Many new chemicals go through a very lengthy developmental process that takes years of preparation before testing human subjects is possible. Only a minority of drugs make it that far, and an even smaller percentage actually make it to market. As I do not work in this particular field, I cannot comment beyond this.

Both the first and second generation antipsychotics are thought to treat psychosis through blockade of D2 dopamine receptors. This is know as the dopamine hypothesis of schizophrenia.

The third wave of antipsychotics that are currently under development are driven by the glutamate hypothesis of schizophrenia. In order to explain how these newer agents might work, I first need to give an overview of the glutamate system.

Organization of the Glutamatergic System: (Very BORING, but necessary to understand how these compounds work)

Glutamate is the primary excitatory neurotransmitter of the nervous system. It is composed of both metabotropic and  ionotropic receptors, the latter of which produce fast postsynaptic reactions. Because glutamate neurons are present throughout the brain (as opposed to specific, concentrated nuclei such as the median raphe and substantia nigra), its role in specific behaviors and other brain functions is difficult to determine. For sure, however, its major functions discovered so far include synaptic plasticity, and learning/new memory (especially long-term potentiation).

Glutamate Synthesis, Release, and Inactivation:
Glutamate can be synthesized by many different chemical processes. It is primarily made by the breakdown of glucose. The primary precursor to glutamate is known as glutamine (which is located in glial cells as well as glutamate neurons), which is converted into glutamate via an enzyme called glutaminase (located in glutamate neurons). The process works like this: after a neuron releases glutamate, in will be transported back either into the nerve terminal or into glial cells (astrocytes in this case) and is then converted into glutamine by the enzyme glutamine synthetase. Glutamaine can be later released again by astrocytes and taken up by neurons that converted it back into glutamate by the enzyme glutaminase.

Ionotropic Glutamate Receptors:
There are three subtypes of glutamate ionotropic receptors. The three receptors are AMPA, Kainate, and NMDA (see the image above). Most fast excitatory responses to glutamate are mediated by activation of the AMPA receptor (even though the NMDA receptors gets all the press these days).

For both the AMPA and kainate receptors, the effect of depolarization is mainly caused by the influx of sodium (Na+) ions into the cell. NMDA activation is very different. These receptors allow sodium AND calcium (Ca++) into the cell. Calcium is responsible for activation of various second messenger systems.

Similar to the nicotinic receptor described in this post, recall that the complete receptor contains five separate subunits that come together to form the receptor channel. The other feature that distinguishes the NMDA receptor from the AMPA and kainate receptors is that it requires TWO different neurotransmitters to cause depolarization. Glutamate is the first neurotransmitter required. The other neurotransmitter is the amino acid glycine (see below).

If glycine is not binding to its specific site along with glutamate, the receptor channel remains closed. Another amino acid, d-serine, can also bind to this site in place of glycine. Glycine and d-serine are considered co-agonists. There are two additional binding sites on the NMDA receptor that affects its function. One site is within the cell that binds to magnesium (Mg++) ions. The magnesium ions block the flow of sodium and calcium until it is released from the receptor. Here is where it gets complicated: the presence of both glutamate and glycine at their respective sites is not enough to release the magnesium ion from within the cell. The cell must be depolarized first by either the AMPA or kainate receptors, in addition to glutamate and glycine latching onto their NMDA receptors, which then frees the magnesium ion from within the cell allowing sodium and calcium to flow inside, thereby activating a second messenger system (phew!).

You'll also notice from the above image that there is a site for the illicit drug phencyclidine (PCP) and also ketamine (AKA special K). Both PCP and ketamine, when binding to their receptor site, act as an antagonist. As it turns out, the behavioral effects of both of these drugs produce a syndrome very similar to schizophrenia, which is why the NMDA receptor is a new target for treatment in schizophrenia.

Metabotropic Glutamate Receptors:
In all, there are eight metabotropic glutamate receptors. They have the designations of mGluR1-mGluR8 (metabotropic Glutamate Receptor #). Similar to other metabotropic receptors, some are excitatory while others are inhibitory. Some are also located on neuronal terminals, where they act as presynaptic autoreceptors that inhibit glutamate release.

Third Generation Antipsychotics:
Most of what you are about to read is from Essential Pharmacology by Stephen Stahl (1). There will not be the usual links to research studies for two reasons: I am too lazy to look them up, and Stephen Stahl doesn't cite shit (thus, making his opinions suspect).

Glutamate Antagonist and Agonist
Currently, there is a split in the field as to whether glutamate agonists or antagonists will be effective treatments. Some feel that excessive glutamate activity, which leads to excitotoxicity, occurs at the beginning of schizophrenia, thus making an antagonist a reasonable choice for treatment (by preventing cell death). However, if you recall from the above section, certain drugs that are glutamate antagonists (e.g., PCP) lead to a syndrome very similar to schizophrenia. Finding a drug that is "just right" will be difficult (memantine is a current candidate). Also proposed are drugs that stimulate the glutamate autoreceptors (see section below), which have the benefit of not causing psychosis. Lamotrigine has been proposed as a possible treatment option.

Others theorize that the glutamate system is hypofunctional and needs a little boost (the theory being that if glutamate blockade leads to psychotic symptoms, then reactivation will treat the illness). One class of drugs being researched to achieve this goal is glycine agonists. If you recall, glycine is a co-agonist that is integral for the depolarization of the NMDA cell. The amino acids which bind to this receptor site (i.e., glycine, d-serine, & d-cycloserine) all "have been tested in schizophrenia, with evidence that they can reduce negative and/or cognitive symptoms" (pg. 441).

GlyT1 inhibitors
This is a class of drugs that inhibit the reuptake of glycine into glial cells. The theory is that glycine levels in the brain are lower than normal. In this sense, they would work like SSRI antidepressants and increase the amount of glycine available. According to Stahl, "several GlyT1 inhibitors are now in testing" and have been "shown to improve negative, cognitive, and depressive symptoms, including symptoms such as alogia and blunted affect" (pg. 442). Possible agents include: sarcosine, SSR 504734, SSR 241586, JNJ17305600, and Org25935.

mGluR2/3 presynaptic agonist
These are the autoreceptors that I mentioned earlier. Current compounds include LY404039, LY35470, LY379268, and MSG0028. LY404039 has been tested through its prodrug version (allows for better absorption) LY2140023, which is eventually converted into LY404039. It has demonstrated "significant improvement of positive and negative symptoms of schizophrenia compared to placebo" possibly making it the "first example of an antipsychotic agent that does not directly block dopamine 2 receptors." These results should be viewed with caution (2). The Last Psychiatrist reviewed this study briefly:

"One side effect the authors did not discuss is the 4% rate of increased CPK.  CPK increases from antipsychotics indicate that excess muscle rigidity is causing muscle breakdown; muscle proteins then clog up your kidneys, leading to death, a disorder called, neuroleptic malignant syndrome (NMS).  In this study, placebo and Zyprexa did not cause increased CPK."

AMPA-kines
Recall that AMPA (or kainate) activation is required for the NMDA receptor to depolarize. This class of compound focuses on increasing activity at the AMPA receptor. One drug that has been tested, CX 516, produced results that have been characterized as "disappointing." Still, other similar compounds are being developed: CX 546, CX619/Org 24448, Org 25573, Org 24292, Org 25501, and LY 293558.

Other Compounds
Many other compounds are also being tested, which have nothing to do with glutamate. These include: 5HT2A antagonist/agonist, 5HT1A/2C/6/7 agonist/antagonists, D3 antagonists, D1 agonists, nicotinic agonists, muscarinic agonists, cannabinoid antagonits, and many, mamy more.

Conclusion:
Glutamate is currently the neurotransmitter du jour. Any novel antipsychotic that hits the market will likely manipulate this particular system. If you trust Stahl (which I don't) there is a lot of promise here. My opinion is that everything is still in the gestational phase, and a major break through could happen or it could not. Moreover, I believe that it is unlikely that any one drug alone will treat all the symptom domains of schizophrenia. More likely, a polypharmacoligic approach will be needed. However, side-effects are always additive, so finding the right combination of drugs will be difficult. But hopefully, with the advent of new classes of drugs, that combination will be more effective than currently available treatments.

P.S. I do not specifically recall stating that first generation antipsychotics are "better" than second generation antipsychotics. Both appear to be equal in efficacy. Where they differ is side-effect profile (e.g., tardive dyskinesia versus metabolic syndrome).

Great Acts of Stupidity or How Science Shouldn't Work

Has anyone read the book Freakonomics? I have. And by "have," I mean that I read the first page of the table of contents (1). What I learned from that brief, yet informative passage is that "conventional wisdom is so often wrong."

Here's an example. "Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder" (2).

For reasons of brevity, articles are worded so that certain assumptions are implied (implicit), while the main aim of the article can be stated explicitly.

What is the implicit assumption in this introduction?

It's this: Valproate (Depakote) and lithium are reasonably effective maintenance therapies. How do we know this? Because both drugs are recommended as monotherapy for the prevention of relapse in bipolar disorder.

Here is where it gets interesting (or pathetically sad). Lithium has over four decades of research supporting its efficacy. If we define a mood stabilizer as a drug that treats acute mania, acute depression, and prevents relapse into either mood episode, then lithium is the only drug on the market that meets those criteria (3). Valproate, on the other hand, has evidence to support its efficacy as an anti-manic agent. It meets only 1 out 3 criteria for a mood stabilizer.

"Then why is it recommended as a maintenance treatment?" Because of this study (4), which found that "divalproex...did not differ significantly from the placebo group in time to any mood episode."

If you are exceedingly sharp, you'll notice that it's a negative study. Yet valproate has managed to become a recommended monotherapy. To read more about this, check out this post (5).

This article, released online ahead of print, is known as the BALANCE study. (BALANCE is a backronym that stands for Bipolar Affective disorder Lithium/ANticonvulsant Evaluation). Here is the saddest fact of this study: Most of the mental effort that when into it was for creating the backronym. It goes down hill after that.

Here are the results: "For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy."

It other words, lithium monotherapy or lithium with valproate adjunctive therapy is more effective at preventing relapse than valproate alone. The difference between lithium and the combination treatment was not statistically significant.

Here is where it gets really sad (6): "Welcome back lithium. After losing its luster because of concerns over potentially serious adverse effects, this drug is drawing increasing respect...This study, along with other recent research, goes a long way toward putting lithium back on top as the preferred treatment for bipolar disorder, said lead study author John R. Geddes, MD...We’ve got more evidence purporting the lithium efficacy, safety, and its antisuicidal effects than we’ve ever had before," Dr. Geddes told Medscape Psychiatry. "So don’t throw lithium away; it’s a highly effective treatment, and if people can tolerate it, then it’s worth trying."

"don't throw lithium away!?" Exactly, what study suggested that? Some of you might be thinking that atypicals have replaced lithium since they too are effective as anti-manic and maintenance treatments, but lithium's efficacy was compared to valproate, not an atypical.

In other words, lithium was more effective than a drug that is no more effective than placebo. Why is this a major finding? Why was this study done?

"Although the study could not confirm a benefit of the valproate-lithium combination therapy over lithium alone, its findings should challenge current clinical guidelines that recommend valproate monotherapy as a first-line option for long-term treatment of bipolar disorder."

There is one study, ONE! on maintenance treatment. It's NEGATIVE! That alone should have prevented valproate from becoming a first-line option.

Here is a special kind of stupid: "In an accompanying editorial (7), Rasmus W. Licht, MD, Mood Disorders Research Unit, Aarhus University Hospital, Risskov, Denmark, praised the BALANCE study, describing it as 'outstanding work' and 'an impressive example of international collaboration.'

He said that even without a placebo group*, the study 'confirms the long-term efficacy of lithium, not only for the prevention of mania but also for prevention of depression.'

On the basis of the study’s results, 'the BALANCE group rightly challenges the recommendation by present clinical guidelines that valproate monotherapy is a first-line option for long-term treatment."

Make sure you read the above carefully. I highlighted the parts that celebrate acts of stupidity. This "outstanding work" took an "international collaboration" to "confirm the long-term efficacy of lithium," which "rightly challenge" clinical guidelines.

Lithium has been the most empirically supported bipolar drug to date. It's the only drug that meets all three defining criteria for a mood stabilizer. Valproate has proven efficacy as an anti-manic only. This study, along with the accompanying editorial, and subsequent press releases should not exist. This is just plain fucking stupid!

A few years ago, articles, based on data that has been around for 20 years, stated that that antidepressants were not as effective as initially stated.

Last year, research showed that vaccines didn't cause autism (even though no research showed that they did).

Now, research is showing us that lithium is effective (never disputed) when compared to a drug that was never shown to be effective.

This is science, telling us what we should already know!

* Just as a side note. The press releases for this study (8) are pushing the combination treatment as the preferred method of treatment. Here is my problem with that: I don't interpret these results as supporting polypharmacy as superior. Although there was a trend for the combination treatment over lithium alone, the difference was not statistically significant. Second, since valproate never had proven efficacy, I view it as an "active placebo," which could also explain the the better performance of the combination treatment. Sadly, the damage is done.



The BALANCE investigators and collaborators (2009). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial The Lancent : doi:10.1016/S0140-6736(09)61828-6

One of These Beasts is Lindsay Lohan's Sister.

Kanye West is still a Douche Bag

In an attempt to counter his image as a professional douche bag, Mr. West "got into the Christmas spirit by making a surprise appearance at the Los Angeles Mission Saturday (Dec. 26). The Grammy winner, alongside longtime girlfriend Amber Rose, joined other volunteers and served lunch to the homeless, who greeted the Chicago native and took pictures. 'It's just important [to give back] when you're very blessed.'" (1).

"West showed up ready to work. He went straight for the kitchen, put on a apron and got on serving duty."

What Mr. West did not do, however, was go straight for his wallet to donate a tiny fraction of his fortune to the very organization that has to raise money to feed this segment of the population (2).

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

Ben Stein is a Moron (O'Reilly is too)

This has been done to death, but I've been wanting to write about this for a long time. (Excerpt from the O'Reilly Factor back in October 2007, 1 .)

O'REILLY: In the unresolved problems segment tonight, how did life begin? Religious people believe a higher power created the universe; secular progressives say all kinds of things, but God is not in the equation. And some believe, those who subscribe to intelligent design; that is a deity created life; are being persecuted in America. Joining us now from Washington Ben Stein, who has put together a new documentary called “Expelled: No Intelligence Allowed.” The film set to open in theaters this February.

So, what's the issue in your mind?

STEIN: Well, the issue is that Darwinism, which was a brilliant theory and a great, great relic of the age of imperialism in the 19th century, basically said that mankind evolved from apes and monkeys and from cells and so forth. And that's a brilliant proposition; Darwin was a brilliant guy. But it didn't say how life began. It didn't say how the cell got to have hundreds of thousands of moving parts each of which has to work perfectly. It said maybe life was created by lightning striking a mud puddle. That has never struck me as convincing. And I thought there are a lot of gaps in Darwinism. Intelligent Design is an effort to try to fill in some of those gaps. It might be totally wrong, but at least it's an effort to try to fill in some very obvious gaps.

Amazingly, if you take half of O'Reilly's brain and half of Stein's brain and put them together, somehow, you end up with less than you started.

1. "how did life begin?" Evolution can not, does not, and will not explain how life began. Abiogenesis, a subfield of chemistry (not biology), is the study of how life on Earth could have arisen. Evolution is a mechanism of change. It does not explain the origins of life, it explains the diversity of life.

2. "those who subscribe to intelligent design; that is a deity created life" Intelligent design and creationism are not entirely interchangeable (actually they are, there are only semantic differences). Intelligent design holds that "certain features of the universe and of living things are best explained by an intelligent cause, not an undirected process such as natural selection" (2). For whatever reason, they refuse to define or operationalize that "intelligent cause" (i.e., God) and they seem to lack the curiosity to want to discover how this "intelligent cause" operates.

3. There is no such thing as "Darwinism." That's a term used by creationist to demean those who believe in the theory of evolution. What Mr. Stein should have said is that "Evolution is a brilliant theory" and then end the interview.

4. "mankind evolved from apes and monkeys and from cells and so forth." Apes are monkeys. Humans are apes. Humans are also monkeys. Humans did not evolve from apes and monkeys, humans share a common ancestor with apes and monkeys.

5. "But it didn't say how life began." Of course it doesn't. That's called abiogenesis.

6. "It didn't say how the cell got to have hundreds of thousands of moving parts each of which has to work perfectly." Once the cell was there (the living organism), evolution explains the diversity of those moving parts and how they function so well.

7. "life was created by lightning striking a mud puddle." No scientific theory that attempts to explain the origin of life on Earth postulates this. And again, evolution has nothing to do with this.

8. "Intelligent Design is an effort to try to fill in some of those gaps." Mr. Stein identified no gaps in evolution. He conflated two distinct theories from two different fields of science (chemistry and biology).

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.

Your IQ Means Nothing

"The teenager accused of murdering a 21-year-old man in 2005 has a below-average level of intelligence, making it more likely he could be influenced by an older gang member, a psychologist testified Monday.

Dr. Rahn Minagawa testified that he performed an IQ test on defendant Josue Orozco, 19, in October and found Orozco scored an 81, indicating a much-lower-than-average intelligence but not mental retardation.

Minagawa, a San Diego-based psychologist who testified for the defense Monday, said Orozco's low intelligence would likely make him 'more vulnerable' to the influence of an 'original gangster.'" (1).

IQ is an antiquated concept. Many people, included the above-mentioned douchebag Dr. Minagawa, believe that IQ is a unitary construct. It's not. The number is useless.

First the basics. IQ or full-scale IQ (FSIQ) is a composite of separate, smaller composites. For example, the WAIS FSIQ is made up of the Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and the Processing Speed Index (PSI). The sub-composite scales convey more information than the FSIQ, but they too also obscure a lot of clinical information tool.

Here's how useless an IQ score is. The article notes that Orozco's IQ is 81. I recently had a patient (young male with similar demographic characteristics as Orozco). His FSIQ was also 81.

If I only told my patient that his IQ was 81, what could he do with that information? Other than believe that he is stupid, nothing. If I made treatment recommendations based his IQ, what could I suggest? Nothing.

My patient's full profile breaks down to this when he is compared to people of a similar age (Orozco's IQ is age based):

FSIQ = 81 (mild-deficit)
VCI = 90 (low average)
PRI = 76 (mild deficit)
WMI = 86 (low average)
PSI = 84 (mild deficit)

On the surface, his scores seem pretty poor.

Here's the rub, test performance is influence by other factors other than age. Factors like ethnicity, level of education, and gender also affect test performance.

Instead of comparing my patient's results to people of a similar age, let's look at what happens when I compare his results to a population with similar age, education, gender, and ethnic background.

FSIQ = 86 (low average)
VCI = 97 (average)
PRI = 79 (mild deficit)
WMI = 91 (average)
PSI = 91 (average)

His scores improved! Only his PRI is still in the mild-deficit range (he had a right-parietal lesion). Does this alter my interpretation? What about our murderer? Let's pretended that these are his test scores. If his age-matched IQ of 81 means that he is "more likely" to be influenced by an OG, does that mean his demo-corrected IQ makes him less gullible? Not even close.

Why not? Because IQ has nothing to do with social psychology. IQ cannot predict one's ability to make decisions. Even tests designed to assess decision making cannot predict one's ability to make decisions.

In this case, it's Orozco's position within the gang that makes him more likely to be influence by an older gang member. His age at the time of the crime (14) better explains his gullibility than his lousy IQ score. Bottom line: This psychologist is an idiot!

I use to take a combination of Ambien CR, diazepam, Restoril, diphenhydramine, and bourbon to sleep at night. I have an IQ of 140. Like I said, it's a useless number.

Sorry Philip, This Study Won't Change Anything

This study (1) published in the British Journal of Psychiatry was first brought to my attention on the Furious Seasons blog (2).

This study recruited the following subjects, "Parents with bipolar disorder were identified from their involvement in a mood disorders subspecialty programme and/or genetic studies as previously described. Briefly, suitable families were identified through a proband who met DSM–IV criteria for bipolar disorder based on Schedule for Affective Disorders and Schizophrenia – Lifetime version (SADS–L) research interviews conducted by an experienced research psychiatrist. Final diagnosis was made on masked consensus review involving two additional research psychiatrists using all available clinical information

All consenting children (n = 207) from eligible families (n = 105) between the ages of 8–25 years were enrolled. The duration of the longitudinal study ranged from 1 to 15 years. Children completed Kiddie–SADS–PL (Present and Lifetime version) interviews conducted by a child and adolescent psychiatrist at enrolment, annually or at any time symptoms developed, up until their 30th birthday. DSM–IV diagnoses were made using all available clinical information on a masked consensus basis. 64% of all major episodes were prospectively captured. Any retrospective data used were based on participant and parent recall, and verified through a review of all available clinical documentation."

Here is a brief summary of the results: "Of the 207 participants, 67 met DSM-IV lifetime criteria for at least one major mood episode (i.e., depression, mania, hypomania, mixed). Their mean age at analysis was 24 (s.d.=5) years and 67% were females. in total, 16% had been admitted to hospital at least once in their lifetime and 18% had a lifetime history of psychotic symptoms in episodes. The mean age at onset of the first major mood episode was 17 (s.d.=4) years and no one experienced an onset prior to 12 years."

Overall, this study confirmed what is already known about bipolar disorder. Average age of onset was 17 (+/-4) years. First episode is typically depressive, as is the second episode. Average cycle length was 31 months. No mood episodes occurred before the age of 12. This is the typical information anyone can get by reading the DSM-IV.

Philip added this brief commentary on his site regarding these results, "Someone alert Joe "Agitation is Mania!" Biederman and CABF! Seriously, that's a pretty stunning finding and certainly confirms what other researchers elsewhere in the world have written."

Unfortunately, Joe Biederman probably didn't even read this study, since, from his point of view, it's completely wrong. It's wrong because these researchers were using the old rule book (i.e., DSM-IV). People like Biederman, Goodwin, and Akiskal et al have changed the official rule book (actually each one has their own rule book).

Biederman asserts that agitation is pathognomonic for pediatric bipolar. Others have created such ridiculous terms as "soft bipolar disorder," "subthreshold hymania," and the absurd "Bipolar III 1/2." Check out CLpsych's critique (3) of the "COBY-established criteria for BP-NOS" (4) for an example of how such rule changes can be misused.

Some say that we are simply adopting a dimensional paradigm of illness as opposed to the rigid traditional paradigm. What makes the dimensional view superior to the traditional paradigm? Is it because more people are eligible for a diagnosis? Is it that more people are eligible for prescription medications? The bipolar spectrum paradigm certainly allows more of the population to have mental health diagnoses, and it allows drug companies to get more bang for their advertising bucks.

Some mental health diagnoses seem undeniable (e.g., depression, bipolar I disorder). Come DSM-V, schizoaffective disorder, Apserger's, borderline personality disorder (which might be reduced to an axis I disorder), and narcissistic personality disorder might disappear from our vernacular all together.

Bottom line: We're making this shit up!



Duffy A, Alda M, Hajek T, & Grof P (2009). Early course of bipolar disorder in high-risk offspring: prospective study. The British journal of psychiatry : the journal of mental science, 195 (5), 457-8 PMID: 19880938

Valdoxan: The Ideal Anti-Depressant Part 3

You can read my previous posts on this drug here (1, 2).

The Research: Part 2

The second study published on the efficacy of agomelatine was by Kennedy and Emsley (2006, 3).

This was a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients. Dosage ranged from 25-50mg/day (dose adjustment at week 2 for poor responders). No other active comparator (e.g., paroxetine) was used in this study. Similar to the previous study (Loo et al, 2002), the efficacy of agomelatine on a severely depressed subpopulation was examine too.

Surprise, surprise, agomelatine was shown to be superior to placebo (HAM-D total score 14.1 +/- 7.7 versus 16.5+/- 7.4). Plot twist: "The proportion of patients who were in remission by the end of the acute treatment period was not statistically different between the two treatment groups." Of course, that could be due to the short duration (6-weeks) of the study.

Remember this quote from the previous study I reviewed: "25mg of agomelatine was significantly better than placebo at 2 weeks..., whereas this significant advantage for paroxetine...did not emerge until 4 weeks." Here is the survival analysis for this study:
The difference did not occur until week 4, the same as paroxetine in the previous study. So this study failed to replicate the result of the first study.

Common side-effects reported include: "dizziness, nasopharyngitis and influenza were more common in the agomelatine group that placebo." Again, no sexual side-effects were reported (sorry, no fancy chart to show).

Part 3:

The third published study was by Olie and Kasper (2005, 4). This study is similar in design as the study mentioned-above. At the end of 6-weeks, there was a superior response for agomelatine compared to placebo (3.44 point difference).

Here is the survival analysis curve for time to first response:
Here, you can see a difference was noted at week 2 (replicating the original result), but then they merge at week 4 (difference was still significant) and then separate again thereafter. What is interesting about placebo temporarily merging with the active drug at week four, is that there was a dose adjustment from 25mg to 50mg for poor responders at week 2. Probably not the robust result they were looking for, but a reaction non-the-less.
Reported side-effects are similar to the previous studies:
Comment: Both of these study are extremely short (6-weeks). 2/3 of depressed patients usually do not respond to their first anti-depressant. Moreover, while response rates (50% reduction in symptoms) are usually robust, remissions rates a paltry (usually 1/5-1/3 remission). No long-term information can be gathered from these two short-term studies. There is long-term data, but it's unpublished.

Side-effect do appear mild. However, many SSRI antidepressant trials show mild side-effects. It's not until the drug is widely prescribe do common side-effects become evident.

All three studies were biased against placebo (i.e., 1 week placebo wash-out period).

Keep in mind that these are published studies of positive trials. There are negative trials that are simply not published (I'm shocked!).

The European Medicines Agency, the parallel to the FDA, initially rejected the drug in 2006 (5).
Here is what they said:
In case you cannot read the image, it says, "The major concern of the CHMP was that the effectiveness of Valdoxan/Thymanax had not been sufficiently shown. The long-term study (the unpublished data I mentioned) did not show that the medicine was effective. The short-term studies shown that the medicine has an effect, but the extent of this did not allow the Committee to draw a firm conclusion on the medicine's effectiveness."

The drug was finally approved in 2008 (6). In their report they list all the submitted trials.

Some highlights:

-In study CL3-22, which included a fluoxetine comparator. This study, which was a short-term with a long-term (1 year) extension found that both agomelatine and fluoxetine were not statistically superior to placebo. (oops!).

-In study CL3-23 agomelatine and paroxetine were not statistically superior to placebo over the short-and-long term. (whoops!).

-CL3-24, the results were identical to CL3-33. (strike three, you're out!).

-Study CL3-21 was a relapse prevention study against placebo. At the end of the trial, agomelatine had a relapse rate of 26% versus 24% for the placebo group (strike four! wait that's not right). They did a post-hoc analysis (i.e., statistical masturbation) and found that only for severely depressed patients there was a statistical difference. The proper thing to do at this point is to run a NEW study to test that intriguing hypothesis since the analysis was done after the fact. (It didn't happen, obviously).

-Efficacy in the elderly was not demonstrated

-Because of concerns over liver toxicity, liver monitoring is required. (do they require that for SSRI's)

Versus other Antidepressants

Much of the hoopla around this drug has been it's supposed superiority against fluoxetine (Prozac). If you head over to the official website, they tout the findings of a recent study (7). But is it really superior? The data submitted to the EMEA showed agomelatine to be equal to SSRI's (2 paroxetine studies, 2 fluoxetine studies, & 2 venlafaxine studies). With the exception of one study where superiority to sertraline (submitted later) was shown. Here's is what the EMEA had to say about the matter:
"magnitude appears less than the active comparators."So that's 2 studies out of 8 that showed a superior effect. There are many studies in the literature that show one antidepressant being superior to another (8). However, results like theses are the exception, not the rule.

The Hype

Based on my review of the data, I'm not seeing much in the way of a wonderful new addition to the anti-depressant family. Aside from liver toxicity, side-effect profile does seem favorable, which is certainly an advantage compared to SSRI's. However, efficacy does not appear any greater than currently available treatments (maybe less effective overall). Just like SSRI's, there are a number of negative trials, so the effect is certainly not consistent.

Furthermore, during my review, I found 6 review articles (see my first post), which rehash the same 3 primary studies over and over again. What's worse, these 6 articles were published within a 3 year period and all in the journals for which Montgomery is the editor. They also read like the democratic party's "talking points" on health care reform, meaning, they all stay on message. That message being "need for better antidepressants" "safety and tolerability" "unique mechanism of action." This strikes me as familiar to the recent trend in second generation antipsychotic articles (9, 10, 11). What I truly enjoyed, though, is the SSRI bashing that was going on in these studies. Last Psychiatrist discussed quite well last year (12, 13).

My Final Verdict

Slightly better side-effect profile, actual clinical efficacy is uncertain.



KENNEDY, S., & EMSLEY, R. (2006). Placebo-controlled trial of agomelatine in the treatment of major depressive disorder European Neuropsychopharmacology, 16 (2), 93-100 DOI: 10.1016/j.euroneuro.2005.09.002

Pierre Olié, J., & Kasper, S. (2007). Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder The International Journal of Neuropsychopharmacology, 10 (05) DOI: 10.1017/S1461145707007766

Valdoxan: The Ideal Anti-Depressant Part 2

If you have not read my first post on agomelatine, do so now (1).

This is my usual shtick wherein I review research articles and crap all over them. The main questions I am seeking to answer through the next series of posts are:

Is agomelatine superior to SSRI anti-depressants? And,

Does it have a more tolerable side-effect profile?

Before I address those questions through the available literature, I want to bring a certain bias to everyone's attention. The bias is not mine, but rather Stuart A. Montgomery's bias.

"Who's that?"

Have you heard of the Montgomery-Asberg Depression Rating Scale (MADRS, 2)? It's that Montgomery. Here is a brief biography (3). Here is the important part: "Dr Montgomery is editor of International Clinical Psychopharmacology and editor of European Neuropsychopharmacology. He also serves on the editorial board of 18 other scientific journals." I point this out because much of the published research (including his own research) on this drug just happen to be in the two journals for which he is the editor (4, 5, 6, 7, 8, 9, 10). A siginifcant portion of these articles were published in supplement issues (i.e., pharma sponsored). He is also a "consultant" for the company (Servier) that manufactures the drug. For you lay readers, this is our much cherished "peer-review process" at work.

The Research: Part 1

The first published study demonstrating general efficacy for major depressive disorder (MDD) was in 2002 by Loo et al (10). In this study different doses of agomelatine (1, 5, and 25mg once a day) were compared to paroxetine (20mg) and placebo in people with MDD for 8 weeks.

Here are the results:
There were more patients in remission on agomelatine 25mg and on paroxetine compared to placebo. No statistical comparisons were done between the two active drugs. Here is a finding I saw quoted in almost every article I read hereafter, "25mg of agomelatine was significantly better than placebo at 2 weeks..., whereas this significant advantage for paroxetine...did not emerge until 4 weeks." I've circled the area on the graph this is in reference to:
Here are the results for severely depressed patients:
Here are the common side-effects:
Overall, both drugs were superior to placebo. Compared to severely depressed patients (i.e., HAM-D score >25), only agomelatine was superior to placebo. Patients on agomelatine 25mg responded sooner than paroxetine. Paroxetine had more side-effects when compared to agomelatine and placebo, with a significant difference for nausea. Neither drug was associated with a high incidence of sexual dysfunction.

Comment: I'm not seeing anything here that I would call a major breakthrough. The HAM-D standard deviations are pretty large (+/- 8 points or more) so there is a lot of variability in individual patient performance (common in AD clinical trials), which limits the generalizability of the study results. I wonder how both drugs would have compared to an active placebo (11). There are not too many differences in reported side-effects except for nausea. I would have expected a far worse side-effect profile for paroxetine given agomelatine's short-half life compared to paroxetine's 24hr half-life (agomelatine patients supposedly will sleep through any acute side-effects).

This study had a one-week placebo wash-out period (which they refer to as "placebo run-in"), which biases the study against placebo. The patients (including the severely depressed patients) were not actually that severely depression, "mean duration of current episode before inclusion was 4.8 months." I can't remember the last time I saw a depressed patient with an episode duration that short.

During the study, two participants committed suicide (congrats to the researchers for reporting these data!); one on paroxetine after 11 days and one on agomelatine 25mg after 10 days. There were 7 suicide attempts: 1 on agomelatine 1mg, 3 on agomelatine 5mg, 1 on agomelatine 25mg, 2 on paroxetine, and NONE on placebo (does that mean there's no risk of not treating with AD's?).

"Among these, one was an overdose with agomelatine. A patient ingested 18 capsules of 5 mg (90mg) with an unknown quantity of alcohol." This is very important: One major downfall of the tricyclic anti-depressants (TCA's) is that patients could use them to commit suicide. Doctors use to prescribe one weeks amount at a time to prevent suicides. Overdose with SSRI's is extremely difficult. A drug with hypnotic properties, when consumed with alcohol (which is commonly abused in depressed people) might suggest that this drug is contraindicated in suicidal patients; however, there was no mention of this in the article.

Part 3 coming soon.



Loo, H., Hale, A., & D'haenen, H. (2002). Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study International Clinical Psychopharmacology, 17 (5), 239-247 DOI: 10.1097/00004850-200209000-00004

Valdoxan: The Ideal Anti-Depressant Part 1

Have you heard the news? Not only is there a novel anti-depressant with a "unique" mechanism of action on the horizon, it is also more effective than Prozac and with none of the side-effects! (1) What is this new wonder drug? Is it truly the ideal anti-depressant? (2) The new drug is agomelatine (Valdoxan, 3). The questions that should be asked are, does it really live up to the hype? Or is the hype just a marketing ploy?

Pharmacology

First, the boring stuff.

Agomelatine is a potent agonist of melatonin receptors MT1 and MT2 (same as Rozerem). Moreover, it is an antagonist (i.e., blocker) of the serotonin 5HT-2c receptor. Agomelatine is metabolised by the liver and excreted mainly in urine. The drug's half-life (i.e., time it takes to eliminate half of the compound) is 2.3 hours.

The drug is theorized to work in two ways. First, its actions at the MT1 and MT2 receptors are supposed to help "reset" circadian rhythms and improve sleep architecture. That seems simple enough, as melatonin is freely bought at any drug store; however, whether people with depression have a true circadian rhythm disorder (e.g., delayed sleep phase syndrome) or if their insomnia (or hypersomnia) is connected to another biological mechanism (hyper-or-hypo-cortisolism) is a matter of debate (My bias is with the latter theory).

The second mechanism is antagonism of the 5HT-2c receptor. This particular serotonin receptor is a post-synaptic receptor that is mainly found in the choroid plexus (4), cerebral cortex (5), globus pallidus (6), substantia nigra (7), and spinal cord (8). Drugs that affect the 5HT-2c receptor represent a subclass of anti-depressant known as norepinephrine/dopamine disinhibitors (NDDI).

According to psychopharmacology god Stephen Stahl, "Serotonin action at 5HT-2c receptors inhibits both NE and DA release...Drugs that block 5HT-2c receptors have the opposite action and thus disinhibit both NE and DA release." Keep in mind that is has only been demonstrated in rats. It is much harder to prove in humans. Stahl also notes that, "...this action is generally activating and may be why many patients, even from the first dose, detect an energizing and fatigue-reducing effect."

Did anyone pick-up on the drug's paradoxical mechanism of action? It is both a sedative-hypnotic and activating-energizing. I'm not sure how that works out when the drug is supposed to be taken at night (Any patient testimonials?). Also, as Neuroskeptic pointed out to me, "it is also very rapidly metabolised so if you take it at night there's probably none left by the next day..." With a half-life of 2.3 hours, most (but not all of the drug) will have been excreted by the time you wake-up in the morning and almost completely gone by next dosing time.

All anti-depressants have pretty lengthy half-lives (minus paroxetine), and a steady-state blood level is required for the drug to have a consistent effect. Usually it is the rapid shift in blood levels that contribute to side-effect severity (hence paroxetine's problems). With such a short half-life, can this drug truly be more effective? Is our current paradigm of how previous anti-depressants work just plain wrong?

Sleep and Depression

Now, more boring stuff.

Will this drug's action at the MT1 and MT2 receptors contribute to its overall efficacy? I have not been able to find any published studies utilizing polysomnography to measure its effects. Why is it important to test this drug with a polysomnograph? Here are some of the sleep findings in pateints with depression:

Depression is associated with a relative increase in central cholinergic activity compared with monoaminergic activity (i.e., serotonin); cholinergic systems reduce short-wave sleep (SWS) and increase REM sleep.

Initial insomnia is inversely proportional to age: the young do not fall asleep easily and complain of initial insomnia; older adults have trouble with sleep maintenance and complain of early morning awakening.

REM sleep abnormalities may persist after successful treatment of depression; short REM latency and SWS deficits can be familial and are found in relatives of depressed patients who do not have depression. Also, depressed individuals have increased sleep fragmentation; their sleep is unstable.

You might think it wise to discover if the drug actually benefits depressed people by resolving at least some of these problems. We'll see if any of the research addresses these issues.

Another MT1 and MT2 agonist drug on the market, Rozerem (ramelteon) is not very effective. According to the medical letter: "Ramelteon (Rozerem), a melatonin receptor agonist, is not a controlled substance and apparently has no potential for abuse, but its hypnotic effect is not impressive. In clinical trials, it produced small, statistically significant improvements in sleep latency, but had little effect on sleep maintenance." The two drugs have similar melotonin properties and half-lives (2.3 hours versus 2.6 hours) Also, it should be noted that depression associated insomnia is distinct from primary insomnia (i.e., psychophysiological insomnia). Typically, people who have insomnia that is a manifestation of a primary psychiatric illness tend not to respond well to the hypnotic class of drugs. As mentioned-above, the drug is somehow both sedating and activating. It's hard to tell how that will affect sleep quality as well.

In the real world, it is unlikely this property (i.e., MT1 & MT2 agonism) will have a clinically meaningful effect.

Part 2.

"White House advisers say Fox News is not news"

News flash: If this is you're leading news story (CNN, 1), (MSNBC, 2), it's not a news organization either.

Six Biggest Myths about Psychology that Everyone Believes

This is by Angela Peterson (No idea who she is). She requested a plug. So here it is (1).