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FORAM MOMENTOS MUITO BOM. AMEI TER IDO.

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DE CORAÇÃO NA MÃO!!!
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... MAS SOU EU AQUI...BEM, PARA POSTAGEM NÃO FICAR MUITO EXTENSA, LOGO POSTAREI MAIS UM POUQUINHO. ATÉ MAIS.

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Sinal de Liberdade-uma expressão de sentimento-

Worst. Antidepressant. Ever.

Reboxetine is an antidepressant. Except it's not, because it doesn't treat depression.

This is the conclusion of a much-publicized article just out in the BMJ: Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and SSRI controlled trials.

Reboxetine was introduced to some fanfare, because its mechanism of action is unique - it's a selective norepinephrine reuptake inhibitor (NRI), which has no effect on serotonin, unlike Prozac and other newer antidepressants. Several older tricyclic antidepressants were NRIs, but they weren't selective because they also blocked a shed-load of receptors.

So in theory reboxetine treats depression while avoiding the side effects of other drugs, but last year, Cipriani et al in a headline-grabbing meta-analysis concluded that in fact it's the exact opposite: reboxetine was the least effective new antidepressant, and was also one of the worst in terms of side effects. Oh dear.

And that was only based on the published data. It turns out that Pfizer, the manufacturers of reboxetine, had chosen to not publish the results of most of their clinical trials of the drug, because the data showed that it was crap.

The new BMJ paper includes these unpublished results - it took an inordinate amount of time and pressure to make Pfizer agree to share them, but they eventually did - and we learn that reboxetine is:

• no more effective than a placebo at treating depression.
• less effective than SSRIs, which incidentally are better than placebo in this dataset (a bit).
• worse tolerated than most SSRIs, and much worse tolerated than placebo.
  

The one faint glimmer of hope that it's not a complete dud was that it did seem to work better than placebo in depressed inpatients. However, this could well have been a fluke, because the numbers involved were tiny: there was one trial showing a humongous benefit in inpatients, but it only had a total of 52 people.)

Claims that reboxetine is dangerous on the basis of this study are a bit misleading - it may be, but there was no evidence for that in these data. It caused nasty and annoying side-effects, but that's not the same thing, because if you don't like side-effects, you could just stop taking it (which is what many people in these trials did).

Anyway, what are the lessons of this sorry tale, beyond reboxetine being rubbish? The main one is: we have to start forcing drug companies and other researchers to publish the results of clinical trials, whatever the results are. I've discussed this previously and suggested one possible way of doing that.

The situation regarding publication bias is far better than it was 10 years ago, thanks to initiatives such as clinicaltrials.gov; almost all of the reboxetine trials were completed before the year 2000; if they were run today, it would have been much harder to hide them, but still not impossible, especially in Europe. We need to make it impossible, everywhere, now.

The other implication is, ironically, good news for antidepressants - well, except reboxetine. The existence of reboxetine, a drug which has lots of side effects, but doesn't work, is evidence against the theory (put forward by Joanna Moncrieff, Irving Kirsch and others) that even the antidepressants that do seem to work, only work because of active placebo effects driven by their side effects.

So given that reboxetine had more side effects than SSRIs, it ought to have worked better, but actually it worked worse. This is by no means the nail in the coffin of the active placebo hypothesis but it is, to my mind, quite convincing.

Link: This study also blogged by Good, Bad and Bogus.

Eyding, D., Lelgemann, M., Grouven, U., Harter, M., Kromp, M., Kaiser, T., Kerekes, M., Gerken, M., & Wieseler, B. (2010). Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials BMJ, 341 (oct12 1) DOI: 10.1136/bmj.c4737

Worst. Antidepressant. Ever.

Reboxetine is an antidepressant. Except it's not, because it doesn't treat depression.

This is the conclusion of a much-publicized article just out in the BMJ: Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and SSRI controlled trials.

Reboxetine was introduced to some fanfare, because its mechanism of action is unique - it's a selective norepinephrine reuptake inhibitor (NRI), which has no effect on serotonin, unlike Prozac and other newer antidepressants. Several older tricyclic antidepressants were NRIs, but they weren't selective because they also blocked a shed-load of receptors.

So in theory reboxetine treats depression while avoiding the side effects of other drugs, but last year, Cipriani et al in a headline-grabbing meta-analysis concluded that in fact it's the exact opposite: reboxetine was the least effective new antidepressant, and was also one of the worst in terms of side effects. Oh dear.

And that was only based on the published data. It turns out that Pfizer, the manufacturers of reboxetine, had chosen to not publish the results of most of their clinical trials of the drug, because the data showed that it was crap.

The new BMJ paper includes these unpublished results - it took an inordinate amount of time and pressure to make Pfizer agree to share them, but they eventually did - and we learn that reboxetine is:

• no more effective than a placebo at treating depression.
• less effective than SSRIs, which incidentally are better than placebo in this dataset (a bit).
• worse tolerated than most SSRIs, and much worse tolerated than placebo.
  

The one faint glimmer of hope that it's not a complete dud was that it did seem to work better than placebo in depressed inpatients. However, this could well have been a fluke, because the numbers involved were tiny: there was one trial showing a humongous benefit in inpatients, but it only had a total of 52 people.)

Claims that reboxetine is dangerous on the basis of this study are a bit misleading - it may be, but there was no evidence for that in these data. It caused nasty and annoying side-effects, but that's not the same thing, because if you don't like side-effects, you could just stop taking it (which is what many people in these trials did).

Anyway, what are the lessons of this sorry tale, beyond reboxetine being rubbish? The main one is: we have to start forcing drug companies and other researchers to publish the results of clinical trials, whatever the results are. I've discussed this previously and suggested one possible way of doing that.

The situation regarding publication bias is far better than it was 10 years ago, thanks to initiatives such as clinicaltrials.gov; almost all of the reboxetine trials were completed before the year 2000; if they were run today, it would have been much harder to hide them, but still not impossible, especially in Europe. We need to make it impossible, everywhere, now.

The other implication is, ironically, good news for antidepressants - well, except reboxetine. The existence of reboxetine, a drug which has lots of side effects, but doesn't work, is evidence against the theory (put forward by Joanna Moncrieff, Irving Kirsch and others) that even the antidepressants that do seem to work, only work because of active placebo effects driven by their side effects.

So given that reboxetine had more side effects than SSRIs, it ought to have worked better, but actually it worked worse. This is by no means the nail in the coffin of the active placebo hypothesis but it is, to my mind, quite convincing.

Link: This study also blogged by Good, Bad and Bogus.

Eyding, D., Lelgemann, M., Grouven, U., Harter, M., Kromp, M., Kaiser, T., Kerekes, M., Gerken, M., & Wieseler, B. (2010). Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials BMJ, 341 (oct12 1) DOI: 10.1136/bmj.c4737

O REGRESSO

REGRESSANDO A MINHA CASA..

NUNCA IMAGINEI QUE FOSSE SOFRER TANTO. CHOREI DE MEDO E EMOÇÃO..
ESTAR ENTRE AS NUVENS, ACIMA E ABAIXO DELAS É FASCINANTE. MUITO MAIS, QUANDO ESTAMOS DENTRO DELAS.
MINHA PRIMEIRA VEZ FOI REALMENTE DOLORIDO. SOFRI MUITO. TIVE MUITO MEDO. ACHEI QUE FOSSE MORRER QUANDO O AVIÃO SUBIU. ME DEU UMA CRISE DE CHORO. SÓ QUEM ESTÁ LÁ, TEM A NOÇÃO DO QUE É ESTAR NAS ALTURAS.
UMA LOUCURA. JAMAIS ESQUECEREI.
NA VOLTA TIVE QUE TOMAR CALMANTE PARA ME ACALMAR.
É UMA TRAUMA QUE TENHO. E RESOLVI SUPERAR E TENTAR ESTE DESAFIO DO MEDO. QUEM NUNCA VIAJOU DE AVIÃO, NÃO TEM A NOÇÃO DO QUE É ESTAR LÁ EM CIMA.

(ANA, NÃO FOI FÁCIL..MAS CONSEGUI. LEMBREI MUITO DE VOCÊ....
A MARLETE E MAIS UMA SENHORA SEGURARAM A MINHA MÃO, ACHEI QUE MEU CORAÇÃO FOSSE SAIR PELA BOCA. UMA VIAGEM SIMPLESMENTE INCRÍVEL)....FOMOS NUM GRUPO DE 29 PESSOAS

VAMOS VER SE TEREI CORAGEM DE VIAJAR PARA A EUROPA E ESTADOS UNIDOS, NO FINAL DE ANO E NA PRÓXIMA PRIMAVERA.

FORTALEZA É FANTÁSTICA. SUAS PRAIAS SÃO LINDA E MARAVILHOSA. TEM SEUS PROBLEMAS COMO QUALQUER CIDADE.

MAS ISTO COMENTAREI EM OUTROS MOMENTOS. AINDA ESTOU EM EXTASE COM A VIAGEM DE AVIÃO.
AMIGOS,
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OBRIGADA PELAS MENSAAGENS DE CONFORTO E CORAGEM DEIXADOS NA POSTAGEM ABAIXO. MUITO OBRIGADA.

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MEUS MIMOS RECEBIDOS/OFERECIDOS.

Cannabinoids in Huntington's Disease

Two recent papers have provided strong evidence that the brain's endocannabinoid system is dysfunctional in Huntington's Disease, paving the way to possible new treatments.

Huntington's Disease is a genetic neurological disorder. Symptoms generally appear around age 40, and progress gradually from subtle movement abnormalities to dementia and complete loss of motor control. It's incurable, although medication can mask some of the symptoms. Singer Woodie Guthrie is perhaps the disease's best known victim: he ended his days in a mental institution.

The biology of Huntington's is only partially understood. It's caused by mutations in the huntingtin gene, which lead to the build-up of damaging proteins in brain cells, especially in the striatum. But exactly how this produces symptoms is unclear.

The two new papers show that cannabinoids play an important role. First off, Van Laere et al used PET imaging to measure levels of CB1 receptors in the brain of patients in various stages of Huntington's. CB1 is the main cannabinoid receptor in the brain; it responds to natural endocannabinoid neurotransmitters, and also to THC, the active ingredient in marijuana.

They found serious reductions in all areas of the brain compared to healthy people, and interestingly, the loss of CB1 receptors occurred early in the course of the disease:

That was an important finding, but it didn't prove that CB1 loss was causing any problems: it might have just been a side-effect of the disease. Now another study using animals has shown that it's not: Blazquez et al. They studied mice with the same mutation that causes Huntington's in humans. These unfortunate rodents develop Huntington's, unsurprisingly.

They found that Huntington's mice who also had a mutation eliminating the CB1 receptor suffered more severe symptoms, which appeared earlier, and progressed faster. This suggests that CB1 plays a neuroprotective role, which is consistent with lots of earlier studies in other disorders.

If so, drugs that activate CB1 - like THC - might be able to slow down the progression of the disease, and indeed it did: Huntington's mice given THC injections stayed healthier for longer, although they eventually succumbed to the disease. Further experiments showed that mutant huntingtin switches off expression of the CB1 receptor gene, explaining the loss of CB1.

This graph shows performance on the RotaRod test of co-ordination: mice with Huntington's (R6/2) got worse and worse starting at 6 weeks of age (white bars), but THC slowed down the decline (black bars). The story was similar for other symptoms, and for the neural damage seen in the disease.

They conclude that:

Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these receptors in patients with Huntington’s disease may attenuate disease progression.

Now, this doesn't mean people with Huntington's should be heading out to buy Bob Marley posters and bongs just yet. For one thing, Huntington's disease often causes psychiatric symptoms, including depression and psychosis. Cannabis use has been linked to psychosis fairly convincingly, so marijuana might make those symptoms worse.

Still, it's very promising. In particular, it will be interesting to try out next-generation endocannabinoid boosting drugs, such as FAAH inhibitors, which block the breakdown of anandamide, one of the most important endocannabinoids.

In animals FAAH inhibitors have pain relieving, anti-anxiety, and other beneficial effects, but they don't cause the same behavioural disruptions that THC does. This suggests that they wouldn't get people high, either, but there's no published data on what they do in humans yet...

Van Laere K, et al. (2010). Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 51 (9), 1413-7 PMID: 20720046

Blázquez C, et al. (2010). Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease. Brain : a journal of neurology PMID: 20929960

Cannabinoids in Huntington's Disease

Two recent papers have provided strong evidence that the brain's endocannabinoid system is dysfunctional in Huntington's Disease, paving the way to possible new treatments.

Huntington's Disease is a genetic neurological disorder. Symptoms generally appear around age 40, and progress gradually from subtle movement abnormalities to dementia and complete loss of motor control. It's incurable, although medication can mask some of the symptoms. Singer Woodie Guthrie is perhaps the disease's best known victim: he ended his days in a mental institution.

The biology of Huntington's is only partially understood. It's caused by mutations in the huntingtin gene, which lead to the build-up of damaging proteins in brain cells, especially in the striatum. But exactly how this produces symptoms is unclear.

The two new papers show that cannabinoids play an important role. First off, Van Laere et al used PET imaging to measure levels of CB1 receptors in the brain of patients in various stages of Huntington's. CB1 is the main cannabinoid receptor in the brain; it responds to natural endocannabinoid neurotransmitters, and also to THC, the active ingredient in marijuana.

They found serious reductions in all areas of the brain compared to healthy people, and interestingly, the loss of CB1 receptors occurred early in the course of the disease:

That was an important finding, but it didn't prove that CB1 loss was causing any problems: it might have just been a side-effect of the disease. Now another study using animals has shown that it's not: Blazquez et al. They studied mice with the same mutation that causes Huntington's in humans. These unfortunate rodents develop Huntington's, unsurprisingly.

They found that Huntington's mice who also had a mutation eliminating the CB1 receptor suffered more severe symptoms, which appeared earlier, and progressed faster. This suggests that CB1 plays a neuroprotective role, which is consistent with lots of earlier studies in other disorders.

If so, drugs that activate CB1 - like THC - might be able to slow down the progression of the disease, and indeed it did: Huntington's mice given THC injections stayed healthier for longer, although they eventually succumbed to the disease. Further experiments showed that mutant huntingtin switches off expression of the CB1 receptor gene, explaining the loss of CB1.

This graph shows performance on the RotaRod test of co-ordination: mice with Huntington's (R6/2) got worse and worse starting at 6 weeks of age (white bars), but THC slowed down the decline (black bars). The story was similar for other symptoms, and for the neural damage seen in the disease.

They conclude that:

Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these receptors in patients with Huntington’s disease may attenuate disease progression.

Now, this doesn't mean people with Huntington's should be heading out to buy Bob Marley posters and bongs just yet. For one thing, Huntington's disease often causes psychiatric symptoms, including depression and psychosis. Cannabis use has been linked to psychosis fairly convincingly, so marijuana might make those symptoms worse.

Still, it's very promising. In particular, it will be interesting to try out next-generation endocannabinoid boosting drugs, such as FAAH inhibitors, which block the breakdown of anandamide, one of the most important endocannabinoids.

In animals FAAH inhibitors have pain relieving, anti-anxiety, and other beneficial effects, but they don't cause the same behavioural disruptions that THC does. This suggests that they wouldn't get people high, either, but there's no published data on what they do in humans yet...

Van Laere K, et al. (2010). Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 51 (9), 1413-7 PMID: 20720046

Blázquez C, et al. (2010). Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease. Brain : a journal of neurology PMID: 20929960

In Dreams

Freud's The Interpretation of Dreams is a very long book but the essential theory is very simple: dreams are thoughts. While dreaming, we are thinking about stuff, in exactly the same way as we do when awake. The difference is that the original thoughts rarely appear as such, they are transformed into weird images.

Only emotions survived unaltered. A thought about how you're angry at your boss for not giving you a raise might become a dream where you're a cop angrily chasing a bank robber, but not into one where you're a bank robber happily counting his loot. By interpreting the meaning of dreams, the psychoanalyst could work out what the patient really felt or wanted.

The problem of course is that it's easy to make up "interpretations" that follows this rule, whatever the dream. If you did dream that you were happily counting your cash after failing to get a raise, Freud could simply say that your dream was wish-fulfilment - you were dreaming of what you wanted to happen, getting the raise.

But hang on, maybe you didn't want the raise, and you were happy not to get it, because it supported your desire to quit that crappy job and find a better one...

Despite all that, since reading Freud I've found myself paying more attention to my dreams (once you start it's hard to stop) and I've found that his rule does ring true: emotions in dreams are "real", and sometimes they can be important reminders of what you really feel about something.

Most of my dreams have no emotions: I see and hear stuff, but feel very little. But sometimes, maybe one time in ten, they are accompanied by emotions, often very strong ones. These always seem linked to the content of the dream, rather than just being random brain activity: I can't think of a dream in which I was scared of something that I wouldn't normally be scared of, for example.

Generally my dreams have little to do with my real life, but those that do are often the most emotional ones, and it's these that I think provide insights. For example, I've had several dreams in the past six months about running; in every case, they were very happy ones.

Until several months ago I was a keen runner but I've let this slip and got out of shape since. While awake, I've regretted this, a bit, but it wasn't until I reflected on my dreams that I realized how important running was to me and how much I regret giving it up.

While awake, we're always thinking about things on multiple levels: we don't just want X, we think "I want X" (not the same thing), and then we go on to wonder "But should I want X?", "Why do I want X?", "What about Y, would that be better?", etc. Thoughts get piled up on top of one another: it's all very cluttered.

In a dream, most of the layers go silent, and the underlying feeling comes closer to the surface. The principle is the same, in many ways, as this.

But how do I know that feelings in dreams are the "real" ones? In most respects, dreams are less real than waking stuff: we dream about all kinds of crazy stuff. And even if we accept that dreams offer a window into our "underlying" feelings, who's to say that deeper is better or more real?

Well, "buried" feelings matter whenever they're not really buried. If a desire was somehow "repressed" to the point of having no influence at all, it might as well not exist. But my feelings about running were not unconscious as such - I was aware of them before I had these dreams - but I was "repressing" them, not in any mysterious sense, but just in terms of telling myself that it wasn't a big deal, I'd start again soon, I didn't have time, etc.

The problem was that this "repression" was annoying, it was causing long-term frustration etc. In dreams, all of these mild emotions spanning several months were compressed into powerful feelings for the duration of the dream (a few minutes, although the dreams "felt like" they lasted hours).

Overall, I don't think it's possible or useful to interpret dreams as metaphorical representations in a Freudian sense (a train going into a tunnel = sex, or whatever). I suspect that dreams are more or less random activity in the visual and memory areas of the brain. But that doesn't mean they're meaningless: they're activity in your brain, so they can tell you about what you think and feel.