throwaway98031's comments

I'm not sure where you're getting your information from, but a lot of it is very incorrect and has a strong anti-pharma bias. For example:

> Paradoxically if they were stepping away from the monoamine hypothesis, they would produce polymonoamine regulatory drugs which would more subtly manipulate multiple monoamines in order to get the desired modulation of maloperating neural circuits, the target du jour.

The suggestion that pharmaceutical companies aren't exploring other pathways has never been more wrong, as we have quite a few very novel compounds in the pipeline that operate through very different pathways. Search for my other comment in this thread where I listed several of the other pathways and medications being explored.

Furthermore, I'm confused by your simultaneous dismissal of the monoamine hypothesis and insistence that "polymonoamine" drugs are the way to go, which isn't compatible with your assertion that the monoamine hypothesis is false. For what it's worth, there are several drugs in the pipeline that work through different combinations of monoaminergic pathways, but the most promising developments are actually in drugs that don't work through monoaminergic pathways at all (e.g. NSI-189, GABA-A5 antagonists, and so on.)

Thanks for sharing your experience.

I'm still surprised that more doctors aren't taking a proactive approach to telling their patients what to expect. I suspect part of it stems from lack of education, but I think some doctors are afraid to tell depressed patients that they might get worse before they get better because that suggestion alone might make them not take the medication in the first place.

> Then there's the academic problem: the monoamine hypothesis (the underlying theory behind the actions and use of SSRIs etc) is at best a crude approximation with precious little in vivo data to support ideas that are known to be inaccurate and incomplete.

The monoamine hypothesis of depression (the idea that all depressions are directly attributable to negative alterations in monoamine dynamics) has been known to be inadequate for a decade or two now in the scientific community. The idea that researchers are still operating on this basis is totally false at this point, but anti-pharma crusaders still hold it up as a convenient straw-man because it's so easy to discredit now using (ironically enough) all of the latest research that the scientific community actually uses for our current understanding of depression.

We're all very well aware that depression isn't caused by "low serotonin levels" or other such completely wrong marketing-speak of the 90s. In fact, there are quite a few very promising anti-depressants in the pipeline and stage III clinical trials that don't directly manipulate monoaminergic systems at all.

Finally, your suggestion that the monoamine hypothesis is the theory behind the actions of SSRIs is completely false. We've known for a very long time that the therapeutic effects of SSRIs lag the near-immediate alterations of monoaminergic. You can't equate discrediting the monoaminergic hypothesis of depression with discrediting SSRIs.

> pharmas are able to start clinical trials and then shut them down without reporting result is a problem.

As you've worked in the industry, I'm curious: What do you think could remedy this situation?

Forcing all registered clinical trials to release all of their data seems like the obvious solution. We still need the ability to shut down clinical trials if unexpected side effects such as increased suicide rates appear, but allowing companies to keep the results private is obviously problematic.

The study is interesting and worth following up on, but the biggest takeaway from your post is your statement that:

> We don't know which way causality runs.

The study found a correlation, not a causation, and even the authors suggest that reverse causation is actually a very possible explanation.

Note that the study was performed in Sweden, where they do a much better job of rehabilitating offenders than we do in the USA. So good, in fact, that the reoffending rates in Sweden are half of other European countries. Sweden is actually closing prisons lately because their prison population is dropping so much.

I can't find any direct evidence to back this up, but it's not a stretch to think that young violent offenders in Sweden are much more likely than the general population to end up receiving psychiatric treatment, and thus are more likely to be prescribed SSRIs than the general population.

As such, I wouldn't read too much in that study.

Sure! Here is a somewhat recent study on the topic: http://www.sciencedirect.com/science/article/pii/S1053811911...

Some of these studies are difficult to interpret without the appropriate background, though, because it's easy to see phrases like "antidepressants decrease resting-state functional connectivity" and assume that decreasing functional connectivity in your brain is necessarily a bad thing. In reality, some types of depression might stem from detrimental alterations in functional connectivity in certain areas that are reversed by anti-depressants.

The most exciting aspect of these types of studies is that researchers are just starting to scratch the surface of being able to tailor antidepressant treatment to different types of depression.

This study: http://www.ncbi.nlm.nih.gov/pubmed/21205435 for example, found that resting state connectivity in certain areas was correlated with treatment outcome, suggesting that it might be possible to actually measure some of these things and prescribe medications that have a higher chance of working in a given patient.

Very exciting stuff!

This is an egregious violation on many levels. It highlights a massive gap in the clinical trials process (companies can stop trials without reporting negative results) that really should be addressed. I think everyone (outside of drug companies) can agree on that much.

I would like to say a few words on SSRIs (the class of drugs that Paxil is in) and their risks in general, because articles like these tend to cultivate strongly negative feelings toward SSRIs due to the deplorable drug company actions mentioned in this article. I don't blame people for mistrusting the drug companies after reading something like this. I also feel that SSRIs are prescribed too quickly and with too little extra guidance from doctors, although that trend is changing a bit as doctors become more educated.

But my biggest concern is that we're starting to see many people with severe depression who refuse to take SSRIs because they don't trust the drug companies and they've come to believe that their severe depression is still better than the side effects or risks of an SSRI, which couldn't be farther from the truth.

The bottom line is that SSRIs, while far from perfect, are still one of the most effective first-line treatments for severe depression that we have, and they do it with a side effect profile that is head-and-shoulders above previous generation anti-depressants.

Perhaps the biggest problem with SSRI treatment is the delayed onset of action. Unlike short-term rewarding drugs such as stimulants or opioids that may boost one's mood in the short term but quickly develop tolerance, SSRIs work through long-term adaptive changes. These changes are numerous, from increased BDNF and hippocampal growth to HPA axis normalization and restoration of brain connectivity back to a state that more closely matches that of non-depressed patients. However, the problem is that all of this happens as downstream effects of an alteration in how serotonin moves through the brain, which is very disruptive in the short-term while the brain adapts to the changes.

SSRI stands for selective serotonin reuptake inhibitor, which means that it inhibits the ability of serotonin-releasing neurons to take serotonin back up from the synapse after they release it. This doesn't "raise serotonin levels" as many describe it (unfortunately perhaps due to some awful SSRI marketing in the 90s and 00s) but rather alters the dynamics of how serotonin-based circuits operate. Serotonin will now spend more time in the synaptic cleft, activating post-synatpic serotonin receptors and synaptic transmission becomes a bit more smoothed out as the transmission takes longer to terminate via MAO deactivation of the serotonin or via uptake from the ~20% of uninhibited serotonin transporters.

Over time (4-8 weeks on average) the post-synaptic receptors adjust to the "new normal" levels of serotonin that they see in the synaptic space. This adjustment might even be key to some of the therapeutic effects of SSRIs, as some serotonin circuits may be too active in depressed or anxious patients, but the chronic SSRI administration quiets those receptors down, somewhat counter-intuitively. The big problem here is that until those receptors compensate, the patient may actually feel worse in the short-term. (Note that some patients actually feel substantially better during this phase, so please don't take this as a given). In the worst-case, depression or anxiety are actually worsened temporarily, combined with an increased energy due to the SSRI's activating effects. At the extreme worst-case scenario, this can lead to suicidal ideation, and for whatever reason this is more common in teenagers.

I wrote all of this out because the HN crowd tends to want to know how things work behind the scenes or under the hood when making decisions for themselves. My goal is not to suggest that everyone who experiences depression should be on SSRIs, because I actually feel that medication is probably best reserved as a first-line treatment for moderate to severe depression. Instead, my goal is to keep everyone informed such that they can work with their doctor to find the best treatment for themselves without unnecessarily fearing SSRIs due to these deplorable actions of drug companies a few years ago.

If you're feeling depressed, work with your doctor to find a solution. If you question your doctor's decision, see someone else. But it's important to explore all options if depression is taking a toll on your life, and if you choose to go the SSRI route then be aware that therapeutic effects are 4-8 weeks out, at least, and talk to your doctor right away if you're concerned.

> Now let's find out if this anti-depressant really helps anyone, or is it just another terrible drug with horrid side effects? If it doesn't help better than placebo; take it off the market?

The claim that SSRIs are no better than placebo is increasingly popular on the internet and among some researchers eager to make headlines, but the claim is not backed by the data. At best, it represents a misunderstanding of how the studies work, what they're showing, and how surprisingly effective placebo is in cases of mild depression.

Scott Alexander has already done a great job debunking these claims: http://slatestarcodex.com/2014/07/07/ssris-much-more-than-yo...

> I do know drug companies have pretty much stopped all research in new anti-depressants. Why--they were caught with their pants down, lying, hiding bad studies, and fooling doctors and patients alike with their Slick claims.

This incident is deplorable and highlights a huge problem in our clinical trials process that needs to be addressed, but your extrapolations here not only don't make sense but they are flat-out incorrect.

There is quite a huge amount of research on new antidepressants. In the past few years alone we've added Vilazodone and Vortioxetine to our arsenal, both of which are primarily SSRIs but have some additional properties that might reduce the side effects due to requiring lower doses. We also have Levomilnacipran which is the first SNRI that favors norepinephrine over serotonin, which can be very helpful in some patients.

There are many interesting compounds in the pipeline as well, from rapid-acting compounds for addressing suicidal patients (ketamine infusion, esketamine nasal spray, GABA-A5 antagonists) to completely novel antidepressant compounds: opiod-modulating drugs like ALKS-5461 which have been very impressive in clinical trials, NMDA and sigma-1 antagonists, mGluR5 antagonists, NR2B antagonists, some very impressive BDNF modulators, anti-glucocorticoid strategies, and so on.

Contrary to your claims that "ruthless drug companies" have stopped all research, this is the most exciting time for anti-depressant research we've ever seen.

> I'd like to see how I react to both together, but hesitant given my poor reaction to Adderall. When I was younger I remember preferring Ritalin over Adderall.

I always advise against poly-pharmacy if possible. Particularly when dealing with powerful stimulants for which the mechanism of action isn't fully understood (Modafinil).

Interestingly, Modafinil might somewhat antagonize the Adderall due to an interaction between their mechanisms of action. Modafinil's MOA is partially due to dopamine reuptake inhibition (similar to Ritalin), but Adderall relies largely on being taken in to the presynaptic terminals and forcing dopamine out. By inhibiting dopamine uptake, Modafinil can (theoretically) decrease the amount of Adderall taken in to the terminal as well as the amount of dopamine available in the terminal for release. We've seen this in a few studies where Modafinil can actually reduce the neurotoxic effects of Adderall, likely due to this antagonizing of Adderall's core MOA.

The magnitude of this effect at therapeutic dosages is unknown, but it's possible and even likely that the combination would be distinctly different than what you might expect a combination of the two drugs to feel like.

> EDIT: Adding to the throwaway comment below, the long halflife of Modafinil is true, especially when trying to sleep. For me, after months of 3-4 days on a week, there seemed to be no long term issues with this, where days I had taken Modafinil I only slept 3-4 hours.

It's expected that your body would adapt somewhat to sleeping on the medication, but that doesn't mean that you were getting quality sleep. Humans are notoriously bad at judging sleep quality, for one, but more importantly here: You were taking a wakefulness-promoting agent, which would have covered any subjective feelings of poor sleep. My concerns with Modafinil stem more from potential long-term implications of interrupting sleep, particularly when the traditional signs of poor sleep (daily fatigue and sleepiness) are then obscured by the drug itself, leading to a false sense of restedness.

However, we can begin to infer poor sleep quality by other, indirect markets, such as:

> I definitely had issues with alcohol and Modafinil, where at my weight (220lbs) I could normally drink 3-4 pints to reach 'buzzed' status, this seemed to happen at 1-2 pints. This trend stayed consistent - and proper 'drunk' came much quicker. This had the effect of limiting my drinking, to the point where I would switch to light beers and stop drinking after 1-2.

Getting subjectively incapacitated from a lower number of beers could, theoretically, be indicative of a subtle sleep-deprived state, for example.

Again, much of this is just semi-educated conjecture, but given the importance of sleep to long-term health I'm wary of these stimulants with long half-lives.

Everyone is different, of course, but after 10 years it would be reasonable to assume that your brain was well-adapted to many of the effects of the Adderall and that you were taking a reasonable therapeutic dosage with a proper, healthy dosing schedule.

On the other hand, those who abuse Adderall for the initial euphoric and energetic properties with sporadic dosing schemes are likely to experience unpleasant withdrawal as those effects disappear.

> Isn't "Do they respond to ADHD medication?" our only test?

No, absolutely not. It's a common internet myth that response to ADHD medication is indicative of ADHD. In reality, nearly anyone who takes ADHD medication acutely will experience increased focus and productivity (again, acutely) due to the acute (pre-tolerance build-up) effects of the drugs. Additionally, new users experience a short-lived euphoria that convinces many people that they need a stimulant to feel "normal," when in fact they're just experiencing the initial euphoric effects of the drug. Be warned that the euphoria fades and, more importantly, does not return without abusing dosing schedules.

ADHD marketing materials combined with pop-psychiatry have stretched the definition of ADHD to encompass nearly anyone. It's trivial to find low-grade internet forums in which users believe that anything and everything is a symptom of ADHD. You can even find a large number of people who believe that something called "hyperfocus" (being able to focus very intently on one thing for a long period of time) is a symptom of ADHD, believe it or not. Of course, the term "hyperfocus" does not appear in ADHD medical literature or any ADHD studies.

ADHD is a complex disorder, and the modern world can (and does) drive people in to ADHD-like states with all of the distractions available to us. The single best approach to dealing with this is to pursue constant discipline and self-monitoring, in order to train yourself back to a healthier mental process. ADHD medications can help people implement those disciplines and healthy processes, but they don't actually substitute for proper habits. It's not uncommon for people to pop Adderall expecting their ADHD to disappear, only to be drawn in to extended video game or web-browsing sessions that are in no way productive.

So my advice would be to make efforts to structure your life in ways to minimize distractions and hold yourself accountable for your results. Realize that everyone is distracted in modern life, but that's not necessarily indicative of a disease. Stimulant medications are not to be taken lightly, and you're best avoiding them long-term if possible.

> Adderall is not the answer as these journalists like to claim though. It's useless for basically anything other than very rare usage and has difficult to manage loss of productivity during withdraw. It has an incredibly fast tolerance buildup. If your work requires steady output instead of rare bursts, it's questionable whether it even surpasses coffee because of these downsides.

The problem here is that Adderall isn't meant to be used in this manner, nor is it meant to provide the user with bursts of productivity or euphoria when dosed properly.

Proper usage, as in ADHD or sleep disorders, involves titrating the daily dose to a point at which the attention and/or wakefulness-promoting effects reach the appropriate therapeutic level over the long term. This process takes in to account the inevitable tolerance that comes with downregulation of the systems that are directly (norepinephrine, dopamine) and indirectly elevated by Adderall usage.

Casual users and abusers, on the other hand, are always chasing the initial rush of drug-induced euphoria and the associated productivity and mood boost that comes in the early phases of treatment. These effects are highly prone to tolerance and downregulation (as intended) and thus can't be maintained without constant dose escalation or taking frequent breaks to pay back the built-up tolerance. Neither situation is sustainable or healthy, which is precisely why Adderall should not be considered to be a substitute for the milder stimulants that people consume casually every day.

Beyond that, Adderall has some potential neurotoxicity issues due to the way it upsets dopamine sequestration in neurons (dopamine has neurotoxic metabolites and the systems that clean up these metabolites can be overwhelmed in certain Adderall dosing schemes). Coffee, on the other hand, is associated with a reduction of certain neurodegenerative diseases.

Unfortunately, most casual and first-time users associate Adderall with the honeymoon phase you spoke of, not the actual long-term therapeutic effects that come from proper therapeutic use and dosing schedules.

Generally speaking, conversations around using Adderall for productivity center more around the hyperactivity and unnatural engagement brought on by too-high dosing or acute use. Adderall is meant for long-term therapeutic use at reasonable doses, where the hyperactivity and super-focus aspects give way to tolerance and leave the user with just enough of a correction to offset their ADHD.

Abusers and non-ADHD users, on the other hand, tend to chase the initial euphoria and the hyperactivity that comes with sporadic, acute dosing and higher-than-normal dosages. Tolerance inevitably catches up to this manner of usage, and the downregulation of prolonged elevated dopamine and norepinephrine levels combined with compounded sleep debt inevitably catches up with them.

> I believe that one of the most "abused" drugs for "productivity" is currently Modafinil, far more powerful than Adderall and without all those side effects.

Modafinil is easier to acquire than Adderall, but it certainly isn't "far more powerful" than Adderall. Just the opposite, in fact, which is also why Adderall is a more tightly controlled substance than Modafinil.

Modafinil is a poorly-understood medication, but we do know that it has a moderate affinity for the dopamine reuptake transporter, which is a mode of action that overlaps slightly with other stimulants such as Methylphenidate. The remaining, additional modes of Modafinil's action are still a matter of active research.

Adderall, meanwhile, not only inhibits dopamine reuptake like Methylphenidate and Modafinil, but also enters the presynaptic terminals to exert effects within the cell. Through a series of actions, it forces more dopamine into synapses than would normally be released. This essentially makes it more powerful, and thus more prone to abuse, than Modafinil.

Those same intra-neuron actions also make Adderall potentially more neurotoxic than Modafinil. By upsetting the natural dopamine balance within a cell, Adderall can theoretically overwhelm certain systems that keep the cells working properly. Dopamine metabolism can unfortunately produce toxic metabolites, which are difficult for cells to cope with when produced in excess. Adderall can indirectly produce enough of these toxic metabolites to cause cell death. There is much debate over the exact dosage level at which this damage happens, but there is already one controversial study showing damage in non-human primates at typical therapeutic doses.

Modafinil is not the safest medication either, given the number of potential sensitivity reactions that some people have. Taking Modafinil without a doctors supervision, as many here seem to do, is thus not a good idea. Fortunately Modafinil seems to be more self-limiting due to the unpleasant side effects many experience at higher doses, such as decreased verbal fluency.

Long-term, the largest problem with Modafinil might just be its long half-life. Although the marketing material would lead you to believe it doesn't affect sleep, it's virtually impossible for a wake-promoting agent with an incredible 15-hour half-life would not negatively impact sleep. The 15-hour half-life means that by the time you're ready for bed, your body has only eliminated roughly half of your Modafinil does from the morning. Long-term sleep impairment is not conducive to long-term health.

Beyond all of this, there is a conversation about how the "productivity" aspect of these stimulants is largely limited to acute dosing, and is heavily prone to tolerance and withdrawal effects, but I've gone on long enough already.