"Prozac doesn't work" new study concludes

[andyandy]

.....for all but the most severely depressed that is....

Quote:

Prozac, the bestselling antidepressant taken by 40 million people worldwide, does not work and nor do similar drugs in the same class, according to a major review released today.

The study examined all available data on the drugs, including results from clinical trials that the manufacturers chose not to publish at the time. The trials compared the effect on patients taking the drugs with those given a placebo or sugar pill.

When all the data was pulled together, it appeared that patients had improved - but those on placebo improved just as much as those on the drugs.

The only exception is in the most severely depressed patients, according to the authors - Prof Irving Kirsch from the department of psychology at Hull University and colleagues in the US and Canada. But that is probably because the placebo stopped working so well, they say, rather than the drugs having worked better.

"Given these results, there seems little reason to prescribe antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed," says Kirsch. "This study raises serious issues that need to be addressed surrounding drug licensing and how drug trial data is reported."

The paper, published today in the journal PLoS (Public Library of Science) Medicine, is likely to have a significant impact on the prescribing of the drugs. The National Institute for Health and Clinical Excellence (Nice) already recommends that counselling should be tried before doctors prescribe antidepressants. Kirsch, who was one of the consultants for the guidelines, says the new analysis "would suggest that the prescription of antidepressant medications might be restricted even more".

The review breaks new ground because Kirsch and his colleagues have obtained for the first time what they believe is a full set of trial data for four antidepressants.

They requested the full data under freedom of information rules from the Food and Drug Administration, which licenses medicines in the US and requires all data when it makes a decision.

The pattern they saw from the trial results of fluoxetine (Prozac), paroxetine (Seroxat), venlafaxine (Effexor) and nefazodone (Serzone) was consistent. "Using complete data sets (including unpublished data) and a substantially larger data set of this type than has been previously reported, we find the overall effect of new-generation antidepressant medication is below recommended criteria for clinical significance," they write.

Two more frequently prescribed antidepressants were omitted from the study because scientists were unable to obtain all the data.
[snip]

Eli Lilly was defiant last night. "Extensive scientific and medical experience has demonstrated that fluoxetine is an effective antidepressant," it said in a statement. "Since its discovery in 1972, fluoxetine has become one of the world's most-studied medicines. Lilly is proud of the difference fluoxetine has made to millions of people living with depression."

A spokesman for GlaxoSmithKline, which makes Seroxat, said the authors had failed to acknowledge the "very positive" benefits of the treatment and their conclusions were "at odds with what has been seen in actual clinical practice".

He added: "This analysis has only examined a small subset of the total data available while regulatory bodies around the world have conducted extensive reviews and evaluations of all the data available, and this one study should not be used to cause unnecessary alarm and concern for patients."

http://www.guardian.co.uk/society/20...edicalresearch

i think there might be a storm over this one

[JoeEllison]

I think there may be bunches of stupidity over this, thanks to media incompetence.

[tkingdoll]

Hmm, I'm surprised that this study was ethically approved, considering a previous study has shown that placebo groups (and exercise groups) do as well as prozac, but once the placebo group is informed that they were in fact the placebo group, they tend to spiral into depression worse than before the trial started.

Anyway, it's unsurprising. Exercise is also as effective, if not more effective, than drugs for mild to moderate depression.

[robinson]

Originally Posted by andyandy

i think there might be a storm over this one

Nah. Obviously the researcher is an antidrug nutcase.

[shep]

Interesting... time for some anecdotage!

I was on SSRIs for a while, and they appeared to help me a lot. One day I just never went to pick up my prescription. Still feeling fine.

However, that was Cipramil, in the same class as Prozac, but not exactly the same. I was first started on Prozac and after about 3 weeks my entire body was one huge, incredibly itchy rash. Agony. Apparently, the same thing had happened to my mum when she had tried it. I switched to Cipramil and didn't suffer the same effect, though it did appear to 'lift me out of' my depression.

So, placebo it may be, but there's definately some kind of active ingredient in Prozac that isn't in all other SSRIs, and I'm definately allergic to it!

To end the story on a humorous note, I went to pick up a prescription for some some malaria pills before heading off overseas to China (not really necessary but I was playin it safe), and once I got home and opened the box, there was my Cipramil from last August. Whoops. That'll learn me.

I will also note that placebo effect is nothing to be looked down on. If we shoot this stuff down too much in the media, we'll have to invent another miracle cure doctors can pretend they're giving us!

[Deetee]

But it does work - It's just as good as homeopathy!

[baron]

That's depressing news.

[Ivor the Engineer]

So does this indicate mild to moderate depression is a different condition physiologically to severe depression?

Or is the efficacy of treatment with SSRI's for severe depression also misleading?

[Big Les]

This is the article;

Kirsch, I., Deacon, B.J., Huedo-Medina, T.B., Scoboria, A., Moore, T.J., & Johnson, B.T. (2008) Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine 5(2): e45. doi:10.1371/journal.pmed.0050045

And one of the authors - http://psy.hull.ac.uk/Staff/i.kirsch/#L2

[Professor Yaffle]

This is very interesting, as I have had very mixed results with anti depressants. I started with tricyclics which seemed to work after a lot of tinkering with the dose, and me feeling better after about 5-6 months. However, that was before I knew that my depression was mostly seasonal, and I would have been getting better around about then. I later tried one or two SSRIs which didn't have much, if any, effect. Then I was put on venlafaxine (effexor) which seemed to help a bit then tail off, then help again when the dose was raised, etc until I got to the highest allowed dose and the doctor added mirtazepine and that seemed to have a really good effect. In hindsight, I think the way the mirtazepine worked was a little circuitous. When depressed I have really low motivation, and therefore do very little exercise etc. I also completely lose my appetite, so have no energy. Mirtazepine had definite side effects of increasing motivation and appetite. All of a sudden, I went from real apathy and lack of energy to rearranging all the furniture in my house and eating really well. Maybe it was the exercise and diet that resulted in me recovering from the depression, and the drug just facilitated me in getting that exercise.

[Acleron]

The results appear very solid. They might even have overestimated the drug/placebo results because some negative trials might have been excluded. I say 'might' because the discussion of what they included becomes a little vague.

Only quibble with it is the conclusion that the drugs only worked in the most severely affected patients because the placebo effect was lower. To only consider drugs to be working when showing an effect when a high placebo effect occurs is slightly ridiculous.

The GlaxoSmithKline response is slightly worrying.

Quote:

at odds with what has been seen in actual clinical practice

Sort of response that comes from the homeopaths.

[Rolfe]

Well, both Prozac and Cipramil seemed to do something for me. It just wasn't good.

The first time, I went into my doctor's surgery with some physical symptoms, and burst into tears. He started off on a list of tests, but he also said "I think you need something to lift your mood right at the moment". To be fair this was in about 1995. He gave me Prozac. Within about 36 hours I was feeling so much worse that I threw the stuff in the bin. (After the test results came back I was sorted out quite easily, no antidepressants required.)

The second time was in 2000. An unrelated occurrence and I was more stressed and probably more anxious than depressed. This time, the prescription for the SSRI was probably more sensible. This time it was Cipramil. Same result. Because I felt worse than the first time I persevered for nearly a week. It was awful. About half an hour after taking a tablet I went crashing into a panic/anxiety attack. I eventually gave these tablets back to the doctor and told her I would not be taking any more like them. (Ironically, what really did help was lorazepam, but I was given such a tiny amount that it wasn't much practical good - all because of worries about dependence. I've never had the slightest trouble with benzodiazepine dependence and they do seem to work well for me.)

I think the fact that not only do these things not work for everyone, they are actually counterproductive to a subset of patients, needs to be better understood. You can find it in the small print, but most doctors seem to assume that at the very least, if it disnae dae ye ony guid, it'll no dae ye ony herm.

Rolfe.

[JoeEllison]

Originally Posted by Rolfe

I think the fact that not only do these things not work for everyone, they are actually counterproductive to a subset of patients, needs to be better understood.

Well... that's "understood" to be normal, isn't it? My understanding is that the folks prescribing pretty much any drugs are supposed to look out for lack of effect/ negative side effects, and change drugs as needed. So, this "lack of effect" is completely expected, and doesn't necessarily point to a complete lack of effect.

Anecdote time: Prozac made me sick the one time I tried it... and Ambien, one of the most popular sleeping pills out there, doesn't work on me at all. In fact, the one time I took it I was up for 2 days. Does that mean that Ambien doesn't work, period, and it is all placebo?

[Dancing David]

The usual problem with these studies is the way that they rate the depression, the usually use the BDI( Beck Depression Inventory) which is a toool for assessing the precense of depression not the level of depression.

In this case the HRSD (Hamilton Rating Scale Depression) which I would categorise as a gross scale it has only very gross indicators of derpression and is not what i would term a fine scale for rating depression.

Take part 3 (suicide)

Quote:

3
SUICIDE
0= Absent
1= Feels life is not worth living
2= Wishes he were dead or any thoughts of possible death to self
3= Suicidal ideas or gesture
4= Attempts at suicide (any serious attempt rates 4)

You could not use this gross a scale to determine risk of suicidal action. There is a very fine scaling when it comes to the difference betweent scores 2,3,4 and this is only a gross indication of suicidal patterns. Certainly not useful for assesing suicidai ideation, past and recent attemps, severity of plan, etc.

And it actually gets worse as the scale progresses, especialy on the sleep disturbance and somatization.

Quote:

4
INSOMNIA EARLY
0= No difficulty falling asleep
1= Complains of occasional difficulty falling asleep—i.e., more than ½ hour
2= Complains of nightly difficulty falling asleep

5
INSOMNIA MIDDLE
0= No difficulty
1= patient complains of being restless and disturbed during the night
2= Waking during the night—any getting out of bed rates 2 (except for purposes of voiding)

6
INSOMNIA LATE
0= No difficulty
1= Waking in early hours of the morning but goes back to sleep
2= Unable to fall asleep again if he gets out of bed

This is not any more than a very groos assesment of sleep disturbance, i would have been fired if i had used something this vague in an assesment.

Quote:

10
ANXIETY (PSYCHOLOGICAL)
0= No difficulty
1= subjective tension and irritability
2= worrying about minor matters
3= Apprehensive attitude apparent in face or speech
4= Fears expressed without questioning

11
ANXIETY SOMATIC: Physiological concomitants of anxiety, (i.e., effects of autonomic overactivity, “butterflies,” indigestion, stomach cramps, belching, diarrhea, palpitations, hyperventilation, paresthesia, sweating, flushing, tremor, headache, urinary frequency).
Avoid asking about possible medication side effects (i.e., dry mouth, constipation)
0= Absent
1= Mild
2= Moderate
3= Severe
4= Incapacitating

12
SOMATIC SYMPTOMS (GASTROINTESTINAL)
0= None
1= Loss of appetite but eating without encouragement from others. Food intake about
normal
2= Difficulty eating without urging from others. Marked reduction of appetite and food
intake

13
SOMATIC SYMPTOMS GENERAL
0= None
1= Heaviness in limbs, back or head. Backaches, headache, muscle aches. Loss of energy and fatigability
2= Any clear-cut symptom rates 2

14
GENITAL SYMPTOMS (Symptoms such as: loss of libido; impaired sexual performance; menstrual disturbances)
0= Absent
1= Mild
2= Severe

If I had been this vague and gross in assesment, the supervisors would have had a long talk with me and then i would have been fired.

This would be a great tool for determining if someone is depressed but a very poor tool for assesing the efficacy of treatment. This scale is not what i would call a good one for determining the level of depression.

[Ivor the Engineer]

Originally Posted by Rolfe

<snip>

(Ironically, what really did help was lorazepam, but I was given such a tiny amount that it wasn't much practical good - all because of worries about dependence. I've never had the slightest trouble with benzodiazepine dependence and they do seem to work well for me.)

<snip>

Rolfe.

I thought the problem with use of benzodiazepines was tolerance, meaning higher doses are required to achieve the same therapeutic effect?

Don't low-dose benzodiazepines stop working after about two weeks of continuous use?

I've noticed the fast acting and short half-life benzodiazepines are becoming popular for conscious sedation during dental procedures in the UK. The other (desirable?) effect they have when used in this way is inducing anterograde amnesia.

[Dancing David]

Originally Posted by Rolfe

I think the fact that not only do these things not work for everyone, they are actually counterproductive to a subset of patients, needs to be better understood. You can find it in the small print, but most doctors seem to assume that at the very least, if it disnae dae ye ony guid, it'll no dae ye ony herm.

Rolfe.

This is the crucial factor, the assesment and treatment of mental illness is a very art side of medicine. Diagnosis flows more from treatment than it does the other way. the categories in the DSM are useful but they require a substantial history and a very honest patient with great insight to be useful in the first interview.

In the ER, it is very hard to tell a person with depressed bipolar, psychotic depression and scizophrenia apart. In fact a person in the early stages of schizophrenia will show more agitation and psychomotor activity than the depressed bipolar person.

History is crucial and people, even family members are very poor historians. Add to that the use of substances, hiding of family history and outright denial and it is a real crap shoot. Clinicians are unfortunately often just left with the 'gut feeling' sort of differentiation in the first interview.

Administration of medications often defines the diagnosis, unfortunately.

I am glad they finaly found something that works for you, benzodiazepine dependance is usually a factor of two things the addiction profile of the medication (xanaxor ativan: very bad) and the dosing schedule, most benzos should never be perscribed PRN.

[Dancing David]

Originally Posted by Ivor the Engineer

I thought the problem with use of benzodiazepines was tolerance, meaning higher doses are required to achieve the same therapeutic effect?

Don't low-dose benzodiazepines stop working after about two weeks of continuous use?

I've noticed the fast acting and short half-life benzodiazepines are becoming popular for conscious sedation during dental procedures in the UK. The other (desirable?) effect they have when used in this way is inducing anterograde amnesia.

Well thsi where the ruber meets the road and shows the difficulties inherent in mental health treatment.

To be effective a medication should also be accompanied by lifestyle changes and cognitive behavioral therapy.

So the sedation effects (which is very noticible in some medications) wears off and the consumer complains that their anxiety has returned. Does that mean it really has or that the sedation has been tolerated?

this gets into the other issues as well:
-is there another medical issue impacting the consumer
-lifestyle changes; is the consumer changing thier life around or just expecting the medication to perform miracles
-is the consumer using stimulants
-is the consumer engaging in drug seeking behavior (they are looking to be high not less anxious, often very indeliberate)
-how does the consumer define anxiety and what are the actual symptoms, frequence, settings and impacts

Now a GP or even a [sychiatrist is not going to have much time to go into this.

[aggle-rithm]

It all depends on what you mean by "works".

If you expect Prozac to be a "happy pill" (as the popular culture would lead you to believe), you might be disappointed.

It doesn't make normal people feel happier; it makes depressed people feel normal.

[Ivor the Engineer]

Originally Posted by aggle-rithm

It all depends on what you mean by "works".

If you expect Prozac to be a "happy pill" (as the popular culture would lead you to believe), you might be disappointed.

It doesn't make normal people feel happier; it makes depressed people feel normal.

And therein lies the fundamental problem with providing mental health care to the masses: Defining what is "normal".

[Deetee]

Originally Posted by Rolfe

Well, both Prozac and Cipramil seemed to do something for me. It just wasn't good.

....He gave me Prozac. Within about 36 hours I was feeling so much worse that I threw the stuff in the bin.

The second time was in 2000. This time it was Cipramil. Same result. Because I felt worse than the first time I persevered for nearly a week. It was awful. About half an hour after taking a tablet I went crashing into a panic/anxiety attack. Rolfe.

Rolfe - these were signs they were working - "Aggravations" as we medics like to call them.

[Ivor the Engineer]

Originally Posted by Deetee

Rolfe - these were signs they were working - "Aggravations" as we medics like to call them.

You may jest:

http://en.wikipedia.org/wiki/Citalopram

Quote:

Occasionally, panic attacks, thoughts of suicide or self-injury may occur or increase in the first few weeks, before the antidepressant effect starts.[10]

[Professor Yaffle]

I thought this graph from the paper was a nice illustration:

http://medicine.plosjournals.org/per...50045&id=96823

I also just learned that NICE doesn't currently recommend antidepressants for mild depression, only for moderate to severe.

[Deetee]

Re the PLoS study:
The first thing I noted was how the investigators grade efficacy:

Antidepressants are only viewed as being effective if they result in what is accepted as a "clinically significant" difference between drug and placebo. In the NICE scoring system, this is regarded as a 3 point difference on the HRSD scale (a 50% improvement in symptoms).

The investigators do show statistically significant differences between drug and placebo, however these fail to achieve the criterion for clinical significance except for severe depression.

Quote:

Confirming earlier analyses [2], but with a substantially larger number of clinical trials, weighted mean improvement was 9.60 points on the HRSD in the drug groups and 7.80 in the placebo groups, yielding a mean drug–placebo difference of 1.80 on HRSD improvement scores. Although the difference between these means easily attained statistical significance (Table 2, Model 3a), it does not meet the three-point drug–placebo criterion for clinical significance used by NICE. (my bold)

Now - for a side track rant:

Therein lies one of the primary differences regarding the between orthodox scientific enquiry and woo-woo quackery. The homeopaths inundate us with reference to the handful of poor quality studies that show marginal statistical significance for selected outcomes that emerge from data-dredging exercises (oscillococcinum for flu, COPD studies etc), and then assume these demonstrate unequivocal benefit from homeopathy. However, the clinical significance of these differences is always negligible or irrelevant (eg the astounding reduction in flu symptoms by a whopping 0.28 days), yet the woos keep screaming their results from the rooftops as though they actually mean something.

ETA: Good heavens - I never knew the "rant" code produced something that looked like that.....

[Professor Yaffle]

And a nice redrawing of it in MS Paint here

http://endofphil.blogspot.com/2008/0...epression.html

[Deetee]

Originally Posted by Professor Yaffle

And a nice redrawing of it in MS Paint here

http://endofphil.blogspot.com/2008/0...epression.html

Nice...
Also it provides a link to here, where my point about clinical vs statistical significance is also expanded upon.

I find the authors' conclusions rather difficult to interpret:

Quote:

Thus, the increased benefit for extremely depressed patients seems attributable to a decrease in responsiveness to placebo, rather than an increase in responsiveness to medication.

This seems a strange way to phrase things.

My own interpretation of the studies is that drug results in a clinically-significant improvement in depression scores for all types of depression. However, there is no clinically-significant benefit of drug as compared to placebo for grades of depression other than the most severe. This seems to be explained by the existence of a greater effect of placebo at lower grades of depression as compared to severe grades of depression, for which the placebo effect appears less relevant.

[Badly Shaved Monkey]

Originally Posted by Deetee

Re the PLoS study:
The first thing I noted was how the investigators grade efficacy:

Antidepressants are only viewed as being effective if they result in what is accepted as a "clinically significant" difference between drug and placebo. In the NICE scoring system, this is regarded as a 3 point difference on the HRSD scale (a 50% improvement in symptoms).

The investigators do show statistically significant differences between drug and placebo, however these fail to achieve the criterion for clinical significance except for severe depression.

I did notice that in the Today programme coverage and was hoping to be able to see whether I had gained the correct impression. Clearly I had. The Big Pharma Stooge (=ABPI spokesman) missed the opportunity to point this out, because the headline version- "NO better than placebo" is rather different from "Not clinically significantly better than placebo for lower grades of depression using a specific definition of clinically significant". The latter hardly trips off the tongue but is more accurate.

Prof Kirsch seemed to give carefully nuanced answers but I don't think this point would have been clear to anyone who did not have some understanding of these technicalities.

[Deetee]

Once again, the importance of using placebo controls in drug efficacy trials is demonstrated.

[Terry]

well... another anecdote. I went to the doctor extremely reluctantly to get some help when I got to the point that exercising stopped making me feel better. Prozac worked very well for me.

ETA: this is somewhat in response to tkingdoll's "its not surprising, exercise works just as well as drugs", rather than to the study itself.

[Dancing David]

Originally Posted by Ivor the Engineer

And therein lies the fundamental problem with providing mental health care to the masses: Defining what is "normal".

Well, if you have had multiple and longterm depression, it is sort of hard to remember.

But it is not 'normal' to wake at three am, have such a low mood that you can't function or obsess about death by fire.

[Dancing David]

Originally Posted by Terry

well... another anecdote. I went to the doctor extremely reluctantly to get some help when I got to the point that exercising stopped making me feel better. Prozac worked very well for me.

ETA: this is somewhat in response to tkingdoll's "its not surprising, exercise works just as well as drugs", rather than to the study itself.

Well, some of us used to practice with the jo stick for two hours and stretch for an hour when waking at three am, and then was still depressed, I was in great shape however.

[Sefarst]

So Tom Cruise was right?

Psychiatry

[ponderingturtle]

Originally Posted by Sefarst

So Tom Cruise was right?

Psychiatry

No. It is effective for seriously depressed people, it is even effective for less depressed people, but it might not be more effective than placebo for those people.

So Tom Cruise is still very very wrong.

[tkingdoll]

Originally Posted by Terry

well... another anecdote. I went to the doctor extremely reluctantly to get some help when I got to the point that exercising stopped making me feel better. Prozac worked very well for me.

ETA: this is somewhat in response to tkingdoll's "its not surprising, exercise works just as well as drugs", rather than to the study itself.

Well, the studies I've seen show that exercise is as effective as drugs for mild/moderate depression, so could it be that you were wandering into the 'severe' category? Or maybe there's a cutoff point after which exercise ceases to work? After what sort of period of time did you find exercise no longer effective?

I must say, if I let my exercise levels drop, I get into a depressive state very quickly (part of that is simply because I put weight on, though). I wonder if exercise just 'tops you up' to normal, in which case it wouldn't help for severe depression.

[Arkan_Wolfshade]

Originally Posted by aggle-rithm

It all depends on what you mean by "works".

If you expect Prozac to be a "happy pill" (as the popular culture would lead you to believe), you might be disappointed.

It doesn't make normal people feel happier; it makes depressed people feel normal.

Or, in the case of myself and Effexor, it allows me to interact w/ people w/o wanting to stab them in the face w/ a bazooka.

[Terry]

Originally Posted by Dancing David

Well, some of us used to practice with the jo stick for two hours and stretch for an hour when waking at three am, and then was still depressed, I was in great shape however.

I used to ride my bike. Climbing a good stiff hill is remarkably effective at getting the heart pounding and the endorphins flowing. But there came a time when I hit the top of the hill and I still felt like everything was pointless and I might as well die. That's when I went to the doctor.

[ponderingturtle]

Originally Posted by tkingdoll

Well, the studies I've seen show that exercise is as effective as drugs for mild/moderate depression, so could it be that you were wandering into the 'severe' category? Or maybe there's a cutoff point after which exercise ceases to work? After what sort of period of time did you find exercise no longer effective?

Also just because they are effective in the same percentage of people, why would you assume that they are equally effective for an individual?

[Rolfe]

Originally Posted by Ivor the Engineer

You may jest:

http://en.wikipedia.org/wiki/Citalopram

Indeed, exactly that was pointed out to me. That's why I gave the Cipramil a bit longer than the Prozac. However, before too long I decided that the game most certainly wasn't worth the candle.

There wasn't really a huge amount wrong with me, and if this is the point where I remark that hypnotherapy appeared to work wonders I suppose I'll get flamed. (But it did.) A bit more lorazepam short-term would have helped quite a bit I think, but the stuff does have a bad name.

Oh well, that was eight years ago anyway. I'm fine.

Rolfe.

[The Kilted Yaksman]

Originally Posted by Arkan_Wolfshade

Or, in the case of myself and Effexor, it allows me to interact w/ people w/o wanting to stab them in the face w/ a bazooka.

Same here. I tried Prozac early in my treatment and it didn't make me feel any better, or any worse, but it did almost completely kill my appetite.

[JoeEllison]

Originally Posted by Rolfe

Indeed, exactly that was pointed out to me. That's why I gave the Cipramil a bit longer than the Prozac. However, before too long I decided that the game most certainly wasn't worth the candle.

There wasn't really a huge amount wrong with me, and if this is the point where I remark that hypnotherapy appeared to work wonders I suppose I'll get flamed. (But it did.) A bit more lorazepam short-term would have helped quite a bit I think, but the stuff does have a bad name.

Oh well, that was eight years ago anyway. I'm fine.

Rolfe.

"Hypnotherapy"? Hey, it could have "worked", just not by the mechanism claimed by the more woo elements?

[annexw]

Quote:

and Ambien, one of the most popular sleeping pills out there, doesn't work on me at all. In fact, the one time I took it I was up for 2 days. Does that mean that Ambien doesn't work, period, and it is all placebo?

Purely anecdotal, but codeine and other sleep aids make me completely wired. Have done since I was a child. Is it possible that our brains could just be reacting differently to whatever is in the pills?

that or we really really don't want to sleep.