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Saturday, July 15, 2006

Finally, some insight on how antipsychotics cause weight gain and metabolic syndrome

Second Generation Antipsychotics (such as olanzapine, quetiapine, etc) are a mixed bag. On one hand, some physicians view them as a god-send for the treatment of schizophrenia, bipolar disorder, and even as augmentation strategies for antidepressants. Quite a few studies show that they can upregulate neurogenesis in key areas of the brain similar to antidepressants. Their main selling point over the older antipsychotic drugs is a lower prevalence of extrapyrmidal side-effects (parkinson symptoms). But the big issue with these drugs is their ability to cause massive weight gain and insulin resistance. And in our overweight society of fast food, drugs that cause weight gain is possibly the last thing we need. This can be a particular draw back for mental health patients who probably already have issues with self-esteem (and overall health).

The following abstract provides some ideas on how these drugs might cause such weight gain. It looks like they directly affect fat cells, decreasing fat breakdown and favoring fat cell growth in addition to making the fat cells insulin resistant:

Neuropsychopharmacology. 2006 Jun 28; [Epub ahead of print]
Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis.

Vestri HS, Maianu L, Moellering DR, Garvey WT.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.

Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 muM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 muM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by approximately 40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by approximately 50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes.Neuropsychopharmacology advance online publication, 28 June 2006; doi:10.1038/sj.npp.1301142.

PMID: 16823387 [PubMed - as supplied by publisher]

Sunday, May 14, 2006

Effexor Confusion in the healthy vs. depressed

I've always seen effexor as a controversial drug. With chemical and pharmacological properties distinct from the SSRI's, there's no doubt that it's effective. Much of the research even demonstrates that it's more effective and faster acting than many other antidepressants. However, a foggy mechanism of action and withdrawal complications have surrounded effexor with a sketchy veil.

Perhaps the biggest controversy regarding Effexor's mechanism of action is its capability to inhibit norepinephrine re-uptake. There's quite a gap in effexor's affinity for the serotonin and norepinephrine re-uptake pump, so its been commonly believed that its norepineprhine action doesn't kick in until the higher dosages. Clinically, most psychiatrists agree with this assessment, citing increased clinical responses as the dose gets above 150mg. Rat studies seem to support effexor's ability to inhibit NE uptake at higher dosages, but the human studies have been lacking.

Just recently a group at McGill published two seperate studies, one on healthy individuals and one on depressed individuals. In depressed individuals, doses of effexor above 225mg showed clear NE uptake inhibition by means of the tyramine pressor test. But in normal individuals, neither a 150mg nor a 300mg dose demonstrated NE uptake inhibition. On the other hand, the relatively selective NE uptake inhibitor desipramine had potent effects in healthy individuals.

So what's going on? Why can high doses of effexor act as an NE re-uptake inhibitor in depressed but not in healthy individuals? Does it have to do with actual physical differences/genetic differences in the NE transporter? Could it have to do with the testing method used and differential blood pressure regulation in the healthy vs. depressed?

Perhaps only time will tell. Until then, the nature of effexor remains quite curious.
Pubmed references: 16690005 and 16690006

Friday, April 28, 2006

Can there be a 'cosmetic' psychopharmacology?

Can there be a 'cosmetic' psychopharmacology? Prozac unplugged: the search for an ontologically distinct cosmetic psychopharmacology.

'Cosmetic psychopharmacology' is a term coined by Peter Kramer in his 1993 best-seller, Listening to Prozac. It has come to refer to the use of psychoactive substances to effect changes in function for conditions that are either normal or subclinical variants. In this paper, I ask: What distinguishes an existential ailment from clinical depression, or either of those from normal depressed mood, melancholic temperament, dysthymia or other depressive disorders? Can we reliably distinguish one from the other? Are the boundaries of illness and disorder really so distinct? If not, how can we know that treatment of 'depression' with Prozac in any given instance constitutes a cosmetic as opposed to, say, a medical or clinical use of psychopharmacology - a distinction that seems to turn on our ability to clearly differentiate the clinical from the cosmetic. If we cannot reliably distinguish between such conditions, can we even have a cosmetic psychopharmacology that is not a form of malpractice, broadly speaking? What if we unplugged Prozac from all the amplitude and hype that resulted in Listening to Prozac becoming an instant best-seller and simply asked whether or not we can clearly distinguish an appropriate cosmetic use of Prozac for 'depression' from an inappropriate cosmetic use of Prozac, and both of those from Prozac's appropriate clinical, that is, non-cosmetic uses? If we cannot make these distinctions, perhaps it is too early to say there can be such a thing as a cosmetic psychopharmacology.


Prozac boom: industrially/culturally constructed?

The Prozac boom and its placebogenic counterpart -- a culturally fashioned phenomenon.

BACKGROUND: The placebo effect describes the mind-body process of altering the body's physiological state as well as the brain's neurological state. Catalyzed by the mind's believing in a certain drug, ritual, and/or treatment, it generally refers to the phenomenon of an ill individual recovering to health. Subsequent to the Prozac boom (fluoxetine), which occurred during the 1980s and 90s in the United States, a new form of placebogenic phenomena was defined: 'cosmetic psychopharmacology', whereby the healthy individual is transformed to fit better in his/her cultural medium (defined by one's values and beliefs). In order to discover how cultural metaphors (e.g. media-generated symbolism, social ideals) influence psychopharmacological treatment, this report investigates the following questions: Is the Prozac Boom culturally fashioned? Is cosmetic psychopharmacology culturally fashioned? Are cosmetic psychopharmacology and its ability to better the individual (relative to American ideals) a placebogenic phenomenon? MATERIAL/METHODS: The data and speculation for the present report was obtained via a cultural and critical review. RESULTS: It would appear that (1) the Prozac Boom and subsequently its by product, cosmetic psychopharmacology, are culturally fashioned; (2) cosmetic psychopharmacology is considered to result from one's belief in a drug and thus is placebo-influenced. CONCLUSIONS: Media-generated symbolism, which represents and reciprocally fashions the ideals and values of that society, influence the social perceptions of a drug's effectiveness and the quality of a particular treatment. In the clinical setting, the influential role of these preconceived notions about a certain treatment and/or drug need to be further considered and studied.


Cosmetic Neurology Paper

Cosmetic neurology: the controversy over enhancing movement, mentation, and mood.

Advances in cognitive neuroscience and neuropharmacology are yielding exciting treatments for neurologic diseases. Many of these treatments are also likely to have uses for people without disease. Here, I review the ways in which medicine might make bodies and brains function better by modulating motor, cognitive, and affective systems. These potential "quality of life" interventions raise ethical concerns, some related to the individual and others related to society. Despite these concerns, I argue that major restraints on the development of cosmetic neurology are not likely. Neurologists and other clinicians are likely to encounter patient-consumers who view physicians as gatekeepers in their own pursuit of happiness.


Glucose in Facial Recognition Tasks

Glucose enhancement of a facial recognition task in young adults.

Numerous studies have reported that glucose administration enhances memory processes in both elderly and young adult subjects. Although these studies have utilized a variety of procedures and paradigms, investigations of both young and elderly subjects have typically used verbal tasks (word list recall, paragraph recall, etc.). In the present study, the effect of glucose consumption on a nonverbal, facial recognition task in young adults was examined. Lemonade sweetened with either glucose (50 g) or saccharin (23.7 mg) was consumed by college students (mean age of 21.1 years) 15 min prior to a facial recognition task. The task consisted of a familiarization phase in which subjects were presented with "target" faces, followed immediately by a recognition phase in which subjects had to identify the targets among a random array of familiar target and novel "distractor" faces. Statistical analysis indicated that there were no differences on hit rate (target identification) for subjects who consumed either saccharin or glucose prior to the test. However, further analyses revealed that subjects who consumed glucose committed significantly fewer false alarms and had (marginally) higher d-prime scores (a signal detection measure) compared to subjects who consumed saccharin prior to the test. These results parallel a previous report demonstrating glucose enhancement of a facial recognition task in probable Alzheimer's patients; however, this is believed to be the first demonstration of glucose enhancement for a facial recognition task in healthy, young adults.

Glucose administration and memory performance

The effect of retrograde and anterograde glucose administration on memory performance in healthy young adults.

Memory for a list of 20 words can be enhanced by preceding learning by consumption of 25 g of glucose, compared with consumption of an equally sweet aspartame solution (Psychopharmacology 137 (1998) 259; Psychopharmacology 157 (2001) 46). However, using this anterograde administration procedure, it is impossible to separate whether glucose affects encoding, consolidation, or retrieval. The present placebo-controlled, double-blind study investigated the effect of anterograde and retrograde administration on memory performance in healthy young participants. In order to evaluate whether post-acquisition administration of glucose can improve memory performance and to compare possible differences in the size of the effect, participants were administered 25 g of glucose immediately before or immediately after presentation of a word list. Moreover, in order to investigate whether the effect of glucose administration on memory performance is time-dependent, a third group received 25 g of glucose 15 min before learning the word list. Word- list recall was tested 30 min and 24 h after word list presentation. Measures of spatial memory performance and working memory were also evaluated. The results of this study showed that both pre- and post-acquisition oral glucose administration (25 g) can improve memory performance. However, as the time interval between anterograde glucose administration and memory encoding increased, the glucose memory facilitation effect decreased. This study provides evidence that glucose enhances memory performance in healthy young people even when it is given after learning has taken place, and that this effect is observed at least up to 24 h after glucose administration. Moreover, it provides evidence that the effect of glucose on memory performance may be time-dependent, as the enhancement of retention was decreased when the administration-learning interval was increased. Copyright 2002 Elsevier Science B.V.


Improvement of cognitive performance with Salvia lavandulaefolia

Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers.

Members of the Sage family, such as Salvia officinalis and Salvia lavandulaefolia, have a long history of use as memory-enhancing agents coupled with cholinergic properties that may potentially be relevant to the amelioration of the cognitive deficits associated with Alzheimer's disease. The current study utilised a placebo-controlled, double-blind, balanced, crossover design in order to comprehensively assess any mood and cognition modulation by S. lavandulaefolia. Twenty-four participants received single doses of placebo, 25 microl and 50 microl of a standardised essential oil of S. lavandulaefolia in an order dictated by a Latin square. Doses were separated by a 7-day washout period. Cognitive performance was assessed prior to the day's treatment and at 1, 2.5, 4 and 6 h thereafter using the Cognitive Drug Research (CDR) computerised test battery. Subjective mood ratings were measured using Bond-Lader visual analogue scales. The primary outcome measures were scores on the five cognitive factors that can be derived by factor analysis of the task outcomes from the CDR battery. The results showed that administration of S. lavandulaefolia resulted in a consistent improvement for both the 25- and 50-microl dose on the 'Speed of Memory' factor. There was also an improvement on the 'Secondary Memory' factor for the 25-microl dose. Mood was consistently enhanced, with increases in self-rated 'alertness', 'calmness' and 'contentedness' following the 50-microl dose and elevated 'calmness' following 25 microl. These results represent further evidence that Salvia is capable of acute modulation of mood and cognition in healthy young adults. The data also suggest that previous reports of memory enhancement by Salvia may be due to more efficient retrieval of target material.


Amphetamine improves cognitive function in healthy volunteers

Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers.

BACKGROUND: Recent research on schizophrenia indicates that cognitive deficits in this illness are important predictors of functional outcome, highlighting the need for treatments that have a positive impact on cognitive function. Here we explore the hypothesis that acute administration of d-amphetamine can improve cognitive function in individuals with schizophrenia who are well-treated with typical antipsychotics, as well as in healthy controls performing under dual task conditions designed to elicit performance deficits analogous to those found in schizophrenia. METHODS: Ten individuals with schizophrenia taking haldol or prolixin and 22 healthy controls performed spatial working memory, language production, and Stroop tasks under both placebo and 0.25 mg/kg of D-amphetamine. RESULTS: D-Amphetamine improved reactions times on the spatial working memory and Stroop tasks for both individuals with schizophrenia and controls, and improved working memory accuracy in schizophrenia. In addition, D-amphetamine improved language production for both individuals with schizophrenia and controls. CONCLUSIONS: These results provide support for the hypothesis that the adjunctive administration of dopamine agonist can improve cognitive in individuals with schizophrenia taking typical antipsychotics. The results are discussed in terms of their implications for understanding the nature of working memory deficits in schizophrenia, and potential future avenues for cognitive enhancement in this illness.


Stimulants and Performance with Sleep Deprivation

Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation.

Stimulants may provide short-term performance and alertness enhancement during sleep loss. Caffeine 600 mg, d-amphetamine 20 mg, and modafinil 400 mg were compared during 85 h of total sleep deprivation to determine the extent to which the three agents restored performance on simple psychomotor tasks, objective alertness and tasks of executive functions. Forty-eight healthy young adults remained awake for 85 h. Performance and alertness tests were administered bi-hourly from 8:00 hours day 2 to 19:00 hours day 5. At 23:50 hours on day 4 (after 64 h awake), subjects ingested placebo, caffeine 600 mg, dextroamphetamine 20 mg, or modafinil 400 mg (n=12 per group). Performance and alertness testing continued, and probe tasks of executive function were administered intermittently until the recovery sleep period (20:00 hours day 5 to 8:00 hours day 5). Bi-hourly postrecovery sleep testing occurred from 10:00 hours to 16:00 hours day 6. All three agents improved psychomotor vigilance speed and objectively measured alertness relative to placebo. Drugs did not affect recovery sleep, and postrecovery sleep performance for all drug groups was at presleep deprivation levels. Effects on executive function tasks were mixed, with imrovement on some tasks with caffeine and modafinil, and apparent decrements with dextroamphetamine on others. At the doses tested, caffeine, dextroamphetamine, and modafinil are equally effective for approximately 2-4 h in restoring simple psychomotor performance and objective alertness. The duration of these benefits vary in accordance with the different elimination rates of the drugs. Whether caffeine, dextroamphetamine, and modafinil differentially restore executive functions during sleep deprivation remains unclear.

citation here

Green Tea

Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1.

BACKGROUND: Although considerable experimental and animal evidence shows that green tea may possess potent activities of neuroprotection, neurorescue, and amyloid precursor protein processing that may lead to cognitive enhancement, no human data are available. OBJECTIVE: The objective was to examine the association between green tea consumption and cognitive function in humans. DESIGN: We analyzed cross-sectional data from a community-based Comprehensive Geriatric Assessment (CGA) conducted in 2002. The subjects were 1003 Japanese subjects aged > or =70 y. They completed a self-administered questionnaire that included questions about the frequency of green tea consumption. We evaluated cognitive function by using the Mini-Mental State Examination with cutoffs of <28, <26, and <24 and calculated multivariate-adjusted odds ratios (ORs) of cognitive impairment. RESULTS: Higher consumption of green tea was associated with a lower prevalence of cognitive impairment. At the <26 cutoff, after adjustment for potential confounders, the ORs for the cognitive impairment associated with different frequencies of green tea consumption were 1.00 (reference) for < or =3 cups/wk, 0.62 (95% CI: 0.33, 1.19) for 4-6 cups/wk or 1 cup/d, and 0.46 (95% CI: 0.30, 0.72) for > or =2 cups/d (P for trend = 0.0006). Corresponding ORs were 1.00 (reference), 0.60 (95% CI: 0.35, 1.02), and 0.87 (95% CI: 0.55, 1.38) (P for trend = 0.33) for black or oolong tea and 1.00 (reference), 1.16 (95% CI: 0.78, 1.73), and 1.03 (95% CI: 0.59, 1.80) (P for trend = 0.70) for coffee. The results were essentially the same at cutoffs of <28 and <24. CONCLUSION: A higher consumption of green tea is associated with a lower prevalence of cognitive impairment in humans.

citation and full information here

Wednesday, February 22, 2006

The Human Condition and Selective Serotonin Reuptake Accelerators

Thanks to Chris' and Andy's previous posts, I have the luxury of entering into this dialog with the majority of our premises already defined. We believe that modern society has now reached the point where neuroscience is on the cusp of understanding the brain in previously unimaginable detail. Future discoveries in drug design and neurobiology will allow us a fine grained control over the mind itself. The time for pubic policy debate is now, while we are at this frontier of possibilities.

Unfortunately, contemporary society has a rather large problem with mind altering substances – by this I refer not only to the cornucopia of scheduled drugs of which possession alone is often a federal offense, but also to the state and corporate sanctioned GDP-boosting kind. Depression, for instance, has now been targeted by big pharma, and thanks in part to many advertisements it is now rightly looked upon as a disease rather than an indication of “weak will or character”. Pfizer's Zoloft alone generated over $3 billion in US sales in 2004. Yet there is a large divergence between these advertisements and current scientific literature.

It has never been shown that depression is a result a serotonin deficiency, as is now commonly believed. This is in part due to the fact that there is no easy way to even measure serotonin levels in living humans.

“I spent the first several years of my career doing full-time research on brain serotonin metabolism, but I never saw any convincing evidence that any psychiatric disorder, including depression, results from a deficiency of brain serotonin. In fact, we cannot measure brain serotonin levels in living human beings so there is no way to test this theory.”

-David Burns, MD, Stanford University

“A serotonin deficiency for depression has not been found.”

-Joseph Glenmullen, MD, Harvard University

To blame mental illnesses such as depression on chemical imbalances is to sidestep important problems – both philosophical and biological. Ignoring these questions leave us personally and societally at a disadvantage. Being depressed at times and even committing suicide is part of being human. This is what it means to live in a world which was created by selfish replication molecules, copying themselves for the sake of copying themselves. Individual happiness does not come into play; it has never been, nor will it ever be, a goal of natural selection. Our feelings and cognitive abilities are evolutionary byproducts, built upon selfish genes.

As such, we can postulate possible causes for depression actually being an adaptive evolutionary condition – “...rank theory proposes that depression is an adaptive response to losing rank and conceiving of oneself as a loser. The adaptive function of the to facilitate losing and to promote accommodation to the fact that one has lost. In other words, the depressive state evolved to promote the acceptance of the subordinate role and the loss of resources which can only be secured by holding higher rank in the dominance hierarchy. The function of this depressive adaptation is to prevent the loser in a status conflict from suffering further injury....” (Evolutionary Psychology, Stevens and Price) Mother nature does not care how you feel, as long as you manage to reproduce.

This line of thought brings us closer to the root of the problem. We must recognize that these diseases are not based on the individual level, but stem from the very nature of our existence. Through this, we can then understand the rational need for cosmetic pharmacology. Humanity was not created perfect, and society has spent many thousands of years bringing us to our current point. There was a time in history when humans had not even developed written language. It is now time to open our eyes and realize what human engineered chemicals can do for us, both emotionally and cognitively. The science and technologies are coming, we need only make the decision of how to use them.

It is possibly for this reason that depression is currently disguised as a chemical imbalance. People have an easier time imagining “chemical imbalances” than the idea that prehistoric history influences the way in which their minds work. SSRIs are not so much curing their depression as relieving them from worry. ( This would also explain the great successes SSRIs have in treating other mental disorders, ranging from Post-Traumatic Stress Disorder to Obsessive-Compulsive Disorder. One secret of anti-depressive drugs is the fact the selective serotonin reptake *accelerators* are just as effective at treating depression as selective serotonin reuptake *inhibitors*, despite the two having completely opposite effects. This is not widely discussed, as there is only one SSRA on the market, Tianeptine, and it is not currently marketed in the United States.

Tianeptine (brand names: Stablon, Coaxil, Tatinol) is as efficacious in treating depression as Prozac, with fewer side effects. For instance, sexual dysfunction or anorgasmia, is a frequently reported side-effect of SSRIs, yet it has been shown to occur with much less frequency during Tianeptine usage. (Switching to tianeptine in patients with antidepressant-induced sexual dysfunction. Human Psychopharmacology, 2003 Jun;18(4):277-80) Tianeptine also has a mood-brightening effect, in contrast to the emotion flattening caused by SSRIs. Later posts will detail tianeptine in more depth, but pubmed currently contains a wealth of information.

The general human condition itself can be much improved upon, without even entering into the realm of diseases currently standardized in the DSM-IV. Mental diseases when defined in this manner seem to often be an essentialist attempt by society to categorize and classify different behaviors which are rooted in the human condition itself and are quite often unrelated to any one chemical disorder or imbalance. (ie. Rosenhan - “If sanity and insanity exist, how shall we know them?”) Society does this not only for financial gain, but also because it does not know any better. The ontological framework which is evolutionary biology is only currently being deployed, often to vigorous debate and violence by the current Luddite or bioconservative class. It is our goal to help usher in a era where all individuals are free to safely modify their neurochemical makeup to allow them happier and more productive lives.

Tuesday, January 31, 2006

Thought Experiments in Cosmetic Pharmacology

In order to draw attention to some ethical concepts regarding cosmetic pharmacology, here are a couple thought experiments regarding hypothetical drugs and philosophical issues they bring up. Consider the following drugs while asking yourself the following questions: Should any of the above drugs be able to be acquired by anyone over the counter? With a prescription? Should any of them never be used by anyone?

1) A drug that makes people extremely productive, happy, not "emotionally-flattened" without any side effects, except for once every two years at an unexpected time, send user into a fit of violent rage. It cures a subset of dementias completely.

2) Consider a drug that completely suppresses sexual desire without any side effects, with long-term safety established.

3) Consider a drug that completely flattens all emotions with no side effects and established long-term safety.

The first case I think brings up the issue of giving someone a drug that could, due specifically to the drugs action, endanger the health and well-being of others in society. SSRIs have been accused of this in the past due to such things as association with school shootings and violent criminal acts. Even if a drug has a massive benefit, with such great risks should it be completely suppressed? Should the drug be allowed to circulate but only under intense supervision such that the negative effects could be negated? Could such purported violence be curbed? Where do you draw the line with regard to negative side effects? If it simply makes people verbally aggressive, would it be an infringment upon their rights to refuse them its other benefits? What if it cures the dementia but makes them not want to integrate into society or work at all? Would you let the individual decide how much a drug alters their personality by simply drawing the line at risk of violence toward others? Should the individual, medical establishment, or government have the last say in the usage of such a drug or similar drugs that lie across the spectrum of possessing side effects? I'd argue that unless a drug has a proven risk of making an individual significantly more of a direct risk to society or themselves (direct and significant here indicating interpersonal violence or suicidal tendencies), then the individual should ultimately have the decision of whether to use the drug. A possible counter-example to this argument would be: what about heroin addicts? Can a caveat be defined where disallow blatantly self-destructive tendencies without infringing upon individual rights? This seems to tap into existing drug debates involving the DEA/FDA with regard to the use of such recreational drugs as marijuana. More on these ideas later.... (in subsequent posts)

The latter two examples bring up the idea that was is natural is good and what is unnatural is necessarily bad. Much debate against emerging technologies has revolved around the technologies being "unnatural" and that their use is therefore unethical. Possibly some of the most "unnatural" side effects of drugs could be an abolishment of sexual drive or flattening of emotions, two purported side effects of SSRIs. Personally, I see these concerns as asinine knee-jerk reactions, but they seem deep seated in the contemporary status quo. Traditional counter-responses to the "unnatural is bad" mentality include the fact that pacemakers, much of contemporary medicine, antibiotics, contraception, are all unnatural. Any form of technology is likewise as unnatural from telephones to calculators, from preachers via tv to orbital satellites. What cosmetic pharmacology brings to the table as new in this regard revolves around the fact that it could much more blatantly alter who we are. I believe that the modulation of the substrate of cognition and the direct alteration of personality coming into the purvey of scientific analysis constitutes a significant paradigm shift.

How should all these concerns guide drug development and evaluation of purpoted cosmetic pharmaceutics?

Apologies for the stream of consciousness writing style, trying to get as many ideas on the table as possible for greater cohesion on this site later on.... More soon.

Monday, January 30, 2006

"Better than Well" Variability and Dr. Healy's Let Them Eat Prozac

To follow up on Chris' well written post on Listening to Prozac, I thought I'd introduce another author who's written on the subject of antidepressants. A simplistic view of Dr. David Healy is that his opinions are somewhere in between Dr. Breggin and Dr. Kramer. Like Dr. Breggin, he's extremely outspoken against the practices of the pharmaceutical industry with regards to antidepressants, even losing a job to his opinions on Prozac's suidicial risk (see ). Unlike Dr. Breggin and more towards Dr. Kramer's outlook, he recognizes the usefulness of antidepressants in psychiatry and even presents an interesting arguement for their Over the Counter status (see The Antidepressant Era and Let Them Eat Prozac).

In terms of Healy's relationship to the idea of cosmetic pharmacology and the better than well effect, in his book Let Them Eat Prozac, he shares the result of a very interesting (albeit small) experiment he conducted at his hospital in the UK (Primary Care Psychiatry, 2000). Utilizing 19 healthy hospital employees, including psychiatrists, nurses, and administrators, Healy performed a 2 week cross over study with the SSRI Zoloft and the SNRI (Selective Noradrenaline Re-uptake inhibitor) Reboxetine. The findings? There was indeed a "better than well" effect, meaning these "normal" individuals felt good on drugs that are usually reserved for depressed individuals. The kicker comes in when we see that this effect was split down the middle: half the group like Zoloft and half the group liked Reboxetine. While the unliked drug usually only resulted in expected side effects, there were a couple individuals who had a negative response to either drug. It made their mood worse.

The results of Healy's small experiment speak to 2 very important ideas. The first is a rather old idea that is utilized by psychiatrists today: individual temperment can often predict response to an antidepressant with a particular mechanism (for more information on this, do a pubmed search for Joyce PR). While the exact details of this phenomenon have yet to be worked out (what types of people will respond to which drugs?), even non-depressed individuals might have specific responses to seroternergic or noradrenergic drugs. The second idea is that for any given drug, it appears there are always going to be three main groups of people: 1 group who responds well to the drug, 1 group who doesn't respond, and 1 group who responds adversely.

Sunday, January 29, 2006

Listening to Prozac by Dr. Kramer

First published in 1993, "Listening to Prozac" by Dr. Kramer contains the origin of the term "cosmetic pharmacology." It is derived from Kramer ascertaining the future sub-clinical use of SSRI antidepressants like Prozac in the general population. That is, based on his experience with Prozac with his clinically-diagnosed patients, he argues that individuals without any serious psychiatric problems could benefit from the use of the drug.

Kramer refers to case reports of patients of his that were either not responsive or minimally responsive with traditional psychotherapy, but upon treatment with Prozac underwent transcendental metamorphoses that alleviated their clinical symptoms. In addition, a number of these patients purportedly felt "better than well" and aspects of their lives completely independent of those being psychiatrically treated were bettered. Kramer attributes some of the effects of Prozac to it altering the neural substrate of personality, which traditionally has been (strangely) considered outside of the domain and capability of psychopharmacology.

I personally am very skeptical of the widespread use of SSRI's under the umbrella term of cosmetic pharmacology. As we shall address in the future, their popularization and ubiquity is a result of being firmly pushed by large pharmaceutical companies with mass marketing campaigns for both individual patients (TV ads) and medical professionals (free food, insurance benefits, etc. by catering via pharmaceutical representatives). At first glance I immediately dismissed concerns over this as conspiracy theories. However, Dr. Breggin, possibly the most direct counterpoint to Kramer, draws attention in his works (I read The Antidepressant Fact Book, but his related popular work is Talking back to Prozac) to how the majority of all the basic clinical research done on SSRI's and Prozac in particular are in serious question. Suicides are written off under "depression not cured" and not reported. Participant pools have weeded out individuals unlikely to give favorable data for the drugs. The double-blind portion of a number of the studies is easily broken via the identification of well-known side effects of SSRIs. In short, there have been a number of violations of both scientific ethics as well as the basic principles of the scientific method. In addition to concerns over the basic research, there is very little long-term data on the safety and efficacy of SSRIs. Contrary to popular belief, just because something has "been around for a long time" (here, only a few decades) or just because "a billion people have taken something" doesn't mean a drug is safe or efficacious. In a nutshell, a plethora of work is necessitated before SSRIs can be considered safe for clinical pathologies, let alone as cosmetic pharmaceutical agents. However, I don't think this means they aren't good candidates for cosmetic pharmacology; the data just isn't there yet to ascertain one way or the other.

Despite my skepticism over SSRIs as cosmetic pharmaceutics, Kramer paves a lot of philosophical groundwork for this emerging concept. He ties in his SSRI treatments with Dr. Mark Sullivan's suggestion that patient autonomy is the ethical yardstick to replace the contemporary standard of risk-to-benefit ratio. Kramer writes "In judging whether the use of a medicine is for good or ill, Sullivan proposes we ask whether it promotes or retards a person's capacity to run his or her own life. An addicting drug may make a well person happier, but, by virtue of the compulsion inherent in addiction, it compromises autonomy. Illness also compromises autonomy, so an addicting drug might be used in the treatment of illness and on balance meet the ethical guideline. The standard of autonomy makes us rethink what our objections might be to a mood brightener, a drug that is by definition not addicting." (p. 256)

I believe the above excerpt applies as well to cosmetic pharmacology as it does to contemporary medicine, in no small part due to the lack of a good alternative yardstick of efficacy. The majority of workings of the brain are still an enigma to modern science, the mechanistic fashion with which antidepressants specifically "work" foremost in relation to the current discussion. Because of this, brain imaging technologies and neurochemical analyses cannot yet prove sufficiently guiding in ascertaining whether or not a pharmaceutical is "working" for a patient. We therefore have to substitute the absurdly crude and arbitrary criteria of the DSM-IV and similar clinical evaluation tests to guide medical treatments. This notion of autonomy as an ethical yardstick partially resolves these "shooting in the dark" attempts to ascertain the efficacy of pharmaceuticals. While still crude and abstract, it seems to me a more concretely positive criterion than the aforementioned ones. Combined with sufficient clinical data for the efficacy and safety of pharmaceuticals, I hope that this concept of autonomy receives greater focus when applied to candidate cosmetic pharmaceutics.

"Listening to Prozac" is a great place to start with regard to exploring the topic of cosmetic pharmacology. It identifies well the potential scope of pharmaceutics' ability to alter a wide array of individual attributes both within and outside clinical pathology and addresses the knee-jerk reaction that "cosmetic pharmacology" evokes in within the medical ethics status quo. It also provides guidelines for evaluating cosmetic pharmaceutics and less explicitly (perhaps indirectly) illuminates how we should be more critical of candidate cosmetic pharmaceutics with regard to efficacy, safety, and how research data regarding them is acquired to ensure high quality and lack of bias.