Monday, December 28, 2009
"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).
Tuesday, December 15, 2009
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
Monday, December 14, 2009
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).
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.
Thursday, December 3, 2009
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.
Tuesday, December 1, 2009
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.
Friday, November 20, 2009
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
Wednesday, October 28, 2009
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).
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.
-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.
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
Tuesday, October 27, 2009
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.
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
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.
Monday, October 19, 2009
Monday, October 12, 2009
Thursday, October 8, 2009
Thursday, September 24, 2009
Here's a link to the federal constitution (2)
Indulge me here. Click the link to the federal constitution. Hit ctrl-f on your key pad. Type in the word "democratic" or "democracy." How many hits? Zero! As it turns out, this country and the individual states that comprise it, are guaranteed a REPUBLICAN form of government. The structure of our government was based on Rome (a republic), not Athens (a democracy).
What's the difference? A republic protects minority rights, a democracy doesn't. A republic (per our declaration of independence) states that all citizens have "inalienable rights" (except for that whole 'slavery' thing). In a democracy you have "civil liberties" bestowed upon you by the majority. The constitutions that form the various state governments and the federal government put restrictions on what those governments (and thus "the people") can and cannot do (e.g., "congress shall pass no law..."). People are allowed to do what they want, as long as they don't harm another person or violate the rights of another.
I don't want majority rule in this country. The majority of people are idiots. The idiot quoted above used the phrase "tyranny of the minority" However, it is the current tyranny of the majority that prevents many minority groups from having equal protection under the law.
Since when has "majority rule" been equal to "morally right." The majority of people in California voted to prevent homosexuals from having legal marriages; "what the majority of citizens want, a majority of elected representatives will enact" is a bad way to run a government.
There is only suppose to be a finite set of laws that apply to everyone equally. Outside of that, we are responsible for our own actions. The problem as I see it, is that there is too much democracy in this country.
Shortly after the forming of this republic, Benjamin Franklin was asked, "Well Doctor, what have we got? a Republic or a Monarchy?" to which he replied, "A Republic, if you can keep it." Sadly, we lost it (3).
The states lost their suffrage with the passage of the 17th amendment. Also during the progressive era was the "initiative and referendum" movement in many states (damn you South Dakota!). Ballot propositions now allow "the people" to alter their state constitutions by a simple majority (50% +1). Constitutions are the backbone of our governing system. An amendment can have far reaching consequences; thus, constitutions are suppose to be difficult to amend (hence the 2/3 majority required to amend the federal constitution).
The less power "the people" have to affect others, the better.
Here's why it's a good idea to have a 2/3 majority required for tax increases (4).
* The douche bag in question is George Lakoff, a professor at UC Berkeley. Since his specialty is cognitive science, he is eligible to receive the coveted Silver Douche Award (The Douchey), for his excellence in douche baggery.
Congrats George Lakoff! You're a douche!
Wednesday, September 23, 2009
The government (local, state, and federal) are never apart of the solution, only the problem.
Friday, September 11, 2009
"The asenapine FDA reviews are currently available but I don't know for how much longer. When FDA approved asenapine they did not include the reviews in the usual database for released reviews. Even if they are available in the future the way they published them is going to be very very difficult for anyone to find in the future. This looks very suspicious to me." -Salmon
"I've been going through the FDA reviews the last few days. It looks like this drug induces psychosis in a substantial fraction of patients resulting in a lot of problems in getting clean efficacy data in the phase III trials. Also it appears to be causing all kinds of precancerous lesions in a variety of tissues as well as blocking pGP resulting in testicular and uterine atrophy and dilation of the cerebral ventricles. Consequently Novartis dropped it. The 4th phase III study used to justify approval used a MMRM approach rather than LOCF this way they could combine the patients who dropped out due to drug induced psychosis with those who dropped out due to lack of efficacy and fudge a statistically significant result on the patients remaining in the study.
The medical officer recommended they turn it down so they had to but then it appears they forced her out had a meeting with Vanda 6 weeks later and magically found a way to accept previously unacceptable data. (They also lowered the dose range to 12 mg so they could claim they met regulatory requirements for numbers of patients studied for safety reasons even though there is insufficient data to support this dose." -Salmon
Here is some more (1, 2). Be sure to read the comments section of both posts.
And be sure to read his thorough analyses here (3, 4).
Thursday, September 10, 2009
Well that's not entirely true. I did come across this study titled, "公司已在美国启动供给N0的前列腺素" (2), and this one, "使用静脉注射免疫球蛋白" (3). At least, I think those are research articles..., I'm not quite sure.
Anyway, the great news is that there are plenty of press releases (4, 5) to extol the virtues of this drug prior to it being reviewed by the FDA and the psychiatric community (I just made myself laugh, that never happens 6).
Here are some quotes from this press releases:
"lurasidone was well-tolerated and had a relatively low discontinuation rate."
"Lurasidone's effect on weight was similar to placebo (median change 0.3 kg for overall lurasidone group vs. 0 kg for placebo) as was its effect on lipid and glucose measures. Lurasidone was also well tolerated with a lower overall discontinuation rate (31%) compared to placebo (43%) and few adverse event-related discontinuations (6% and 2% for the overall lurasidone group and placebo, respectively)."
"Adverse events seen in the trial were generally mild. The most commonly reported adverse events for lurasidone (greater than 5% and at least twice the rate of placebo) were akathisia (17.6% vs. 3.1% placebo), somnolence (11.7% vs. 5.5%), parkinsonism (6.8% vs. 0), and increased weight (5.1% vs. 2.4%)."
"The development program for lurasidone is intended to establish efficacy for the core symptoms of schizophrenia, characterize its safety profile and explore its effects in the treatment of cognitive impairment and other areas not adequately addressed by current therapies"
"If you look at the weight gain, the lipid changes, it's among the most benign of any antipsychotic drugs, clearly better than olanzapine, clozapine and Seroquel"
"From the point of view of efficacy and side effect profile, once a day administration, the fact that the lower dose works as well as the higher dose, I think this is going to have a very good chance of major acceptance among my colleagues"Douche bag.
That last quote is from this press release (5), and that lower dose he is referring to is 40mg. I guess he didn't read this press release (4), which reported this, "also evaluated two other fixed doses of lurasidone, 40 mg/day and 120 mg/day, which did not demonstrate separation from placebo on the PANSS or CGI-S at study endpoint."
Here are the reported adverse events from this article (1):
From the press releases, "The most commonly reported adverse events for lurasidone (greater than 5% and at least twice the rate of placebo) were akathisia (17.6% vs. 3.1% placebo), somnolence (11.7% vs. 5.5%), parkinsonism (6.8% vs. 0), and increased weight (5.1% vs. 2.4%)."
"The most common adverse events reported at a frequency of at least 5% and at least twice the rate of placebo among the combined lurasidone doses in these trials were akathisia (11.6% vs. 4.7% placebo), somnolence (14.3% vs. 7.1%) and nausea (14.8% vs. 6.1%)."
Then there is this beauty, "the adverse events were generally mild, such as restlessness and sleepiness." That last statement just made my third testicle descend.
All side effects are from the 80mg dose.The above-referenced study had a relatively small sample size (n=90), which I think downplays the akathisia (8.9%), while the summarized studies in the press releases are larger (n=500 & n=392) and have the high rates of akathisia.
Important Point: Akathisia is not a MILD side effect. Just asked anyone who has ever experienced it.
"These data showed that lurasidone was well tolerated with a low propensity for EPS."
More Important Point: Akathisia and parkinsonism ARE extrapyramidal symptoms.
Here are the side effect profiles from two other antipsychotic drugs:
asenapine & risperidone
iloperidone & haloperidol
Wow, lurasidone has a higher report rate of akathisia than haloperidol! (17.6% versus 13.6%). Correction, that's high (really high) dose haloperidol (15mg) . Taken together, lurasidone does not look any different, just more of the same.
"Zyprexa and similar drugs can cause significant weight gain and have been linked to increased risk of diabetes...Lurasidone was well tolerated with a discontinuation rate nearly identical to placebo -- 40 percent versus 39 percent." Have they forgotten that there already is a class of drugs that do not cause those severe metabolic changes? They're the first generation antipsychotics.
"...but this class of drugs as a whole is so superior to the first generation drugs said Meltzer." In what way is that Dr. Meltzer? Efficacy? No. Side effects? Nope. Patient tolerance? No again.
I'm feeling the need to be sued for defamation: Dr. Meltzer is a flabby bag of douche!
There's no point in reviewing the efficacy results here. Just read any random antipsychotic clinical trial. The numbers are all the same. No new psychiatric drug, antidepresant, antipsychotic, mood stabilizer, whatever, has been shown to be more effective than its predecessors in a clinically meaningful way.
Key points to remember:
1. This drug is being pushed as safer. So is asenapine and iloperidone. So will any new drug on the horizon. It's marketing. You don't manipulate the identical set of brain receptors and get less side effects. You only get different side effects.
2. The majority of the authors on these study are employees of the pharma company sponsoring the trial. The same is true for the asenapine and iloperidone studies. That's called bias. Double blind does not mean a damn thing.
3. The remainder of the second generation antipsychotics are becoming generic. That means they will be prescribed less. That means there will be a void, which can be filled by newer more expensive drugs. Since these drugs are more of the same, patients don't necessarily receive a lower quality of care, while at the same time drug pimps can continue to rake in the cash (7).
I was right. This was a waste of time (8, 9). I'm through reviewing drug research.
* Special thanks to Neuroskeptic and Cypher for teaching me how to lift images from secured files =)
Nakamura M, Ogasa M, Guarino J, Phillips D, Severs J, Cucchiaro J, & Loebel A (2009). Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. The Journal of clinical psychiatry, 70 (6), 829-36 PMID: 19497249
Thursday, September 3, 2009
Question: Should I, at all be concerned that there are more actual published peer-reviewed articles of this drug being tested in rats (2, 3, 4, 5, 6 ) than in humans (7; seriously, this is the only published peer-reviewed article I can find)?
I'm not going to discuss the controversy surrounding this drug (interested persons go here: 8, 9).
Here are the various receptor affinities for the drug:
What does this mean? "Asenapine has high affinity for an ensemble of receptors, including the 5-HT receptor subtypes 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7; adrenoceptor subtypes alpha1A, alpha2A, alpha2B and alpha2C and dopamine D3 and D4 receptors. The interaction of asenapine with each of these receptors occurred at a higher affinity than that for any of the other drugs tested" (10). In other words, Clozapine is for pussies, Asenapine is hung like horse!
The skinny of this article is that each of these receptors, when blocked by this drug, may confer improvement in emotional and cognitive functioning.
Oh you didn't know? Apparently other antipsychotics don't improve the negative and cognitive symptoms of schizophrenia, which was pointed out ad nauseum in the only published peer-reviewed study I could find (7): "Although all antipsychotics ameliorate such symptoms to varying degrees, none are completely effective in all symptoms domains. Thus, there is a need for newer, more effective agents to treat the the full range of symptoms expressed in schizophrenia." Two paragraphs later, "Current pharmacotherapy for schizophrenia is limited by inconsistent or inadequate control of negative, affective, and cognitive symptoms, as well as by distressing side effects." In case you're retarded, they reiterate, "Antipsychotic pharmacotherapy offering improved effectiveness in treating the full range of positive, negative, affective, and cognitive symptoms associated with schizophrenia, plus improved tolerability, therefore remains an important unmet clinical need."
It's common in these types of articles to state the same message throughout the paper (i.e., abstract, introduction, discussion); however, all this was in the introduction only, and in adjacent paragraphs.
The manufacturer is pushing the drug on the premise that it improves the negative and cognitive symptoms of schizophrenia better than other drugs, in addition to having a better safety profile.
The safety profile angle has been used before (11). While the drug demonstrated less weight gain compared to risperidone or olanzapine, it has an elevated level (18%) of extrapyramidal symptoms (EPS) comparable to first generation antipsychotics (12).
Don't worry folks, there's a way to obscure that little fact. All you have to do is generate a drug trial where you compare the drug to the very potent D2 blocker, haloperidol, thus making any incidence of EPS seem minuscule (13).
The sample size of this study (7) is quite small compared other clinical trials (n=174). At the end of 6 weeks, only 73 subjects completed the study. That high rate of attrition is common for schizophrenia trials, keeping in mind that the patients included in these types of studies are pretty high functioning (no co-morbid medical or psychiatric illnesses, able to provide consent).
Normally, this is the part where I copy the result charts for you visual learners out there, but the cocksuckers secured the PDF file, thus preventing me from copying the data. Anyway, "at end point, mean changes from baseline were -15.9 with asenapine versus -5.3 with placebo (p<.005); the change with risperidone (-10.9) was nonsignficant versus placebo." No statistical comparison was conducted between the two active treatments, but a 5 point difference most likely is not signficant.
What about those pesky positive symptoms? "At end point, mean change from baseline were -5.5 for asenapine versus -2.5 for placebo (p=.01); change with risperidone (-5.1) was also signficant versus placebo (P<.05)."
And the negative symptoms? "At end point, mean changes from baseline were -3.2 for asenapine versus -0.6 for placebo (p=.01); change with risperidone (-1.05) was nonsignificant versus placebo." It appears that the drug is actually better at improving the negative symptoms of schizophrenia. Not quite, "Mean baseline scores were 24.1, 23.1 and 21.9 for the asenapine, placebo, and risperidone groups, respectively." If you subtract the changes, total mean scores are 20.9 and 20.85 for the asenapine and risperidone groups, respectively. The asenapine group was more severe to start with, thus allowing more room for improvement. Moreover, the asenapine mean changes were no greater than the changes produced by iloperidone, haloperidone, and risperidone in this study (14). In other words, asenapine is more of the same.
Next comes the faulty logic and far reaching conclusions of the discussion section. In reference to the drug's "unique human receptor signature" the authors state that "this pharmacologic profile may explain, at least in part, the effectiveness and toelrability of asenapine in controlling a wide range of schizophrenia symptoms." If one reads a lot of research, then you'll know that these results are no different than any other drug on the market. This is pure advertising. Personally, I cannot wait for the next conference I attend. I can't wait to see the pharma puppet actually try to push this "unique human receptor signature" shit on his audience.
"In conclusion, this double-blind, placebo-and risperidone-controlled 6-week study showed that asenapine 5mg b.i.d. was effective and well tolerated in the treatment of acute schizophrenia and may be a useful option in patietns with negative symptoms." If you say it enough times, eventually it becomes true...
This study plus one more were what the FDA use to approve this drug for use in schizophrenia. All other research for this drug can be found in a single issue of Schizophrenia Research (Volume 98), which is a supplement issue, and it includes only abstracts that were presented at a conference (XIVth Biennial Winter Workshop on Schizophrenia and Bipolar Disorders). Stingy douchebags!
That second study (13), had a larger sample size (n=458) and compared asenapine to placebo and haloperidol. Haloperidol match asenapine on the primary measure, but for some reason, haloperidol's effect on negative symptoms were not reported, only asenapine's were (mutherfuckers!).
Saphris is going to be pushed as being good for negative symptoms. That's what I took away from these advertise, err, research articles. I tried to find more data at clinicaltrials.gov (15), but that was fucking pointless (Usually, when I jerk off I have something to show for it).
Another drug (lurasidone) is also ready for an FDA indication for schizophrenai as well (16). Guess what angle they're going with? "It's among the most benign of any antipsychotic drugs, clearly better than olanzapine, clozapine and Seroquel," Should I even waste my time with this drug?
Potkin SG, Cohen M, & Panagides J (2007). Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. The Journal of clinical psychiatry, 68 (10), 1492-500 PMID: 17960962
Update: (February 8, 2010) . The February 8th issue of the medial letter (Vol 52, Iss. 1331) they have a piece on Saphris