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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 21 to 45 of 45. Go back in thread:
Posted by SLS on July 31, 2005, at 7:44:25
In reply to Re: We need placebo » SLS, posted by ed_uk on July 31, 2005, at 6:56:17
Another aspect of the study of individual compounds as antidepressants is that any one antidepressant may work for only a fraction of an ultimately responsive population. We know this to be true. Yet, we place demands upon new drugs that they be able to produce response rates tantamount to being silver bullets. We don't ask this much of other drugs in most other illnesses. If each of 5 antidepressant drugs work in only 35% (compared to the generally observed 70%) of cases in different sets of people, depending on the heterogeneity of the population and the degree of overlap, you could conceivably cull a 95% rate of remission. An example of this shortsightedness is the rejection by the FDA of gepirone, a drug that did not show as robust a statistical advantage over placebo as was desired by that agency. Yet, this drug does seem to be effective enough to get some people well. From what I understand, new data on gepirone is to be included in a resubmission to the FDA by the manufacturer.
By the way, my silly little idea did not call for the abolition of placebos, just a different way of designing placebo-controlled studies. It doesn't look like it would be a viable solution, but I think it helps bring into focus the difficulty in evaluating antidepressants against placebo when a rate of placebo response of 1/3 has yet to be explained and adjustments made to the design of studies, their statistical evaluation, or perhaps only our unreasonable expectations of a single drug.
- Scott
Posted by ed_uk on July 31, 2005, at 13:39:42
In reply to Re: We need placebo » ed_uk, posted by SLS on July 31, 2005, at 7:44:25
Hi Scott,
>Another aspect of the study of individual compounds as antidepressants is that any one antidepressant may work for only a fraction of an ultimately responsive population. We know this to be true.
Absolutely. Now we need a better method of determining which drug is likely to work for a particular individual!
>Yet, we place demands upon new drugs that they be able to produce response rates tantamount to being silver bullets.
Very true..... and we'll never have a silver bullet which effectively treats all forms of depression.
>If each of 5 antidepressant drugs work in only 35% (compared to the generally observed 70%) of cases in different sets of people, depending on the heterogeneity of the population and the degree of overlap, you could conceivably cull a 95% rate of remission.
Excellent point. We need a variety of drugs with different mechanisms of action so that this can be the case. We don't need another ten SSRIs! Hopefully we'll soon have Valdoxan...... and I do hope that none of the TCAs or MAOIs are discontinued. It would be a truly depressing situation if the SSRIs and SNRIs were all we had to work with. I remember when my doctor said that he'd 'never needed to use an MAOI'. What rubbish. What about his patients who were chronically incapacitated - living in psychiatric residential homes?
In the UK at least, we urgently need to move away from the idea that people who's depression doesn't respond to SSRIs and SNRIs are untreatable. Psychiatrists must be willing to utilise a wide variety of treatment options in order to help as many patients as possible.
>From what I understand, new data on gepirone is to be included in a resubmission to the FDA by the manufacturer.
http://news.biocompare.com/newsstory.asp?id=85989
>placebo response of 1/3
If the studied population consists mainly of people suffering from relatively mild acute depression, spontaneous recovery might account for the high rate of 'placebo' response.
Posted by Kon on July 31, 2005, at 13:55:43
In reply to Re: We need placebo, posted by SLS on July 30, 2005, at 10:19:03
> I am not convinced that placebo controls are necessary for medical research. Like I said, there is much debate surrounding this issue.
I'm sure pharmaceutical companies would love such a scheme. Wouldn't exclusion of placebo controls result in a high likelihood that ineffective antidepressants/anxiolytics and other drugs be unnecessarily foisted on the public?
Also not to downplay Dr. Quitkin's findings but even his recent study excluded patients over 65 and those with very severe depression. Dr. Quitkin has also had some associations with Pfizer and been a speaker and on advisory board for Eli Lilly.
As a pharmacy student, I'm really having trouble to know what the "truth" is wrt efficacy of a given medication and what is best for the patient since trials funded by pharmaceutical companies rarely produce unfavourable results. I'm becoming more skeptical of not just the efficacy of many psychotropics but also anti-cholesterol and anti-hypertensive drugs. Can research funded by pharmaceutical companies truly be unbiased or are medical journals becoming an extension of the marketiung arm of pharmaceutical companies as some researchers/academics have argued? Dunno...And I'm saying this even though I do believe that certain drugs are extremely useful and life-changfing for patients. For example, I've had great relief with benzos for my anxiety whereas SSRIS and CBT were totally useless.
Posted by ed_uk on July 31, 2005, at 14:36:27
In reply to Re: We need placebo » SLS, posted by Kon on July 31, 2005, at 13:55:43
Hi Kon,
I'm a pharmacy student too.
~Ed
Posted by Kon on July 31, 2005, at 17:53:46
In reply to Re: We need placebo » Kon, posted by ed_uk on July 31, 2005, at 14:36:27
Hi Ed,
I have 2 more years left. Boring so far...It seems the most interesting stuff in pharmacy can befound on the internet. Good luck in your studies.
Posted by SLS on August 1, 2005, at 8:16:32
In reply to Re: We need placebo » SLS, posted by Kon on July 31, 2005, at 13:55:43
> > I am not convinced that placebo controls are necessary for medical research. Like I said, there is much debate surrounding this issue.
> I'm sure pharmaceutical companies would love such a scheme.I imagine they would love anything that would bring a drug to market that would make them money without being subject to law suits.
> Wouldn't exclusion of placebo controls result in a high likelihood that ineffective antidepressants/anxiolytics and other drugs be unnecessarily foisted on the public?
This seems to be the prevailing opinion.
I have nothing against using placebo controls, I just think that a new paradigm for evaluating the efficacy of antidepressants is necessary, even if it is merely a change in the selection criteria for people with depressive disorder. Perhaps all that is needed is a rating scale such that a 25% advantage of active compound versus placebo is considered efficacioius. A good way to judge such a rating scale - or any other new investigational paradigm is to evaluate its accuracy retrospectively using the raw data from previous studies. Another use of placebos is to evaluate the validity of a study. Judging placebo response rates versus a known active compound versus the test compound is a good way to isolate failed studies. This is why we don't see reboxetine in the US. The placebo response rate was high and showed equivalancy to Prozac. Prozac is a putative antidepressant often used as a standard rating compound. It has been established as being better than placebo.
> Also not to downplay Dr. Quitkin's findings but even his recent study excluded patients over 65 and those with very severe depression. Dr. Quitkin has also had some associations with Pfizer and been a speaker and on advisory board for Eli Lilly.
Conflict of interest? It would be difficult to tell whether there is a bias on his part. The bulk of his work has utilized tricyclics and MAOIs.
It would be difficult to find people who are not in some way affiliated with drug companies. The NIH has been reviewing its own ethical standards and the affiliations and fundings with private enterprises. They are in the midst of making changes.
> As a pharmacy student, I'm really having trouble to know what the "truth" is wrt efficacy of a given medication and what is best for the patient since trials funded by pharmaceutical companies rarely produce unfavourable results.Moclobemide was found to be ineffective by the FDA according to manufacturer-funded US studies. At least Roche seems to be truthful.
Rarely, if ever, has an antidepressant been approved by the FDA using these results that hasn't ultimately been found to be effective in subsequent clinical usage. Even maprotiline has utility. So far, the system works pretty well, despite complaints by some that studies using placebos don't separate the test antidepressant compound robustly enough to demonstrate efficacy. For the most part, the scientists know that a ratio of 65-70%/30% in favor of the test compound over placebo is a robust value when it comes to antidepressants.
> I'm becoming more skeptical of not just the efficacy of many psychotropics but also anti-cholesterol and anti-hypertensive drugs.
Which ones in particular?
> Can research funded by pharmaceutical companies truly be unbiased or are medical journals becoming an extension of the marketiung arm of pharmaceutical companies as some researchers/academics have argued?
> Dunno...
Me either. You will have plenty of time in your career to more fully explore these issues. I'm sure your future experience with these drugs will help you answer your questions and identify the "duds" when it comes to drugs.
> And I'm saying this even though I do believe that certain drugs are extremely useful and life-changfing for patients. For example, I've had great relief with benzos for my anxiety whereas SSRIS and CBT were totally useless.
Just remember that individual drugs don't have to be effective in a majority of cases to be an important component of an arsenal against a particular disease or set of diseases.
- Scott
Posted by ed_uk on August 1, 2005, at 13:25:25
In reply to Re: We need placebo, posted by Kon on July 31, 2005, at 17:53:46
Hi Kon,
>I have 2 more years left.
Me too. I hate my degree. We hardly study anything clinical at all - which is what I'm interested in.
>It seems the most interesting stuff in pharmacy can befound on the internet.
I agree!
Kind regards
~Ed
Posted by WeeWilly on August 1, 2005, at 18:01:07
In reply to Re: We need placebo » ed_uk, posted by SLS on July 31, 2005, at 7:44:25
It's way past time for advancement in mental health treatment. Each us of us has our own unique biochemistries and problems with them. None of our problems are due to not enough prozac, neurontin, depakote, etc., in our systems. What I am saying is that we do have to much or not enough of certain elements or they are not being produced in the proper cycle. The bottom line is that pharmaceutical companies see that understanding the biochemical causes of mental disorders is not a lucrative endeavor. They like the status quo, of coming up with an element foreign to our bodies that they can patend. Eventually without pharmaceutical companies help, research will progress the understand of our disorders and proper treatment will become available. Best wishes
Posted by Kon on August 1, 2005, at 21:44:39
In reply to Re: We need placebo » Kon, posted by ed_uk on August 1, 2005, at 13:25:25
>I hate my degree. We hardly study anything clinical at all - which is what I'm interested in.Ed,
I'm in a catch-22. We have some clinicals (some real and some make-believe with patient actors) which in theory I should find more interesting but my SAD prevents me from enjoying them. In fact, they're a nightmare. If not for benzos I probably would have quit...again. I did 2 years of med-school previously but quit due to severe anxiety when the clinical component began. When I have to perform/think in front of people (whether peers or patients) my anxiety goes through the roof and my IQ approaches that of a chipmunk.
Posted by Kon on August 1, 2005, at 21:52:55
In reply to Re: We need placebo » Kon, posted by SLS on August 1, 2005, at 8:16:32
> Which ones in particular?Hi Scott,
Statins, in particular. Again you may find the views expressed by this group of researchers and some non-researchers a bit biased but it did raise some skepticism for myself, especially when I looked at some of the studies and arguments they use. Again....I dunno.
http://www.thincs.org/unpublic.ArchIntMed.htm
http://www.thincs.org/discuss.htm
Posted by Kon on August 2, 2005, at 0:25:39
In reply to Re: We need placebo, posted by SLS on July 30, 2005, at 10:19:03
>When one includes only a population of depressives rated as severe, the placebo response approaches zero while the response rate remains at 65-70%.
Just to add to the dunno category...this argument has been questioned in the recent July 16, 2005 BMJ:
http://www.freerepublic.com/focus/f-chat/1445096/posts
The authors write:
"A key claim in the NICE guideline is that the superiority of antidepressants over placebo correlates positively with the severity of depression being treated. This belief is an old one. In 1958 Kuhn suggested that endogenous depression was more responsive to antidepressants than neurotic or reactive depression, which was generally regarded as less severe.7 Regression to the mean may account for this impression since it entails that people with more severe depression at baseline will show greatest overall levels of improvement. But it does not explain drug-placebo differences, because greater improvement among patients with more severe depression occurs regardless of whether they are treated with a drug or placebo.
An early review of controlled trials found that evidence about whether endogenous symptoms predicted response was inconsistent.8 Recent evidence comes from post-hoc analysis in trials with otherwise negative resultsw6 w7 and from meta-analyses. The meta-analysis by Angst et al is often cited in support of the severity hypothesis, but severity effects were weak and mostly non-significant.9 Effects in another meta-analysis were more impressive, but data were provided only for investigational antidepressants and not established ones, where the evidence seemed to be weaker.10 In contrast, another recent meta-analysis found no relation between severity and antidepressant effect,11 and a meta-analysis of older studies showed that differences between antidepressants and placebo were smaller and non-significant in inpatient trials compared with outpatient trials.12 The NICE meta-analysis failed to find a consistent gradient of effect from "moderate" (Hamilton score 14-18) through "severe" (19-22) to "very severe" depression ( 23).1 In fact, the middle group, which would generally be referred to as moderately depressed, tended to show larger effects than either of the other two, but numbers of studies were small.
Thus there seems to be little support for the suggestion that recent failure to find marked differences between antidepressants and placebo is due to recruitment of patients with mild depression that is less responsive to antidepressants.1 Indeed, in the meta-analysis by Kirsch et al, all but one of the trials were conducted in patients with severe to very severe depression according to NICE criteria.6 The possibility that patients in the mid-range of severity show a greater antidepressant response, as suggested by the NICE data and by Joyce and Paykel,8 would not be expected from a simple biological effect. It may indicate that this group is more susceptible to some methodological artefact such as infringement of the double blind (see below)."
Posted by SLS on August 2, 2005, at 9:53:55
In reply to Re: We need placebo » SLS, posted by Kon on August 2, 2005, at 0:25:39
Hi Kon.
> Thus there seems to be little support for the suggestion that recent failure to find marked differences between antidepressants and placebo is due to recruitment of patients with mild depression that is less responsive to antidepressants
My conjecture is not that people with mild depression are less responsive to antidepressants. It is that they are far more apt to respond to placebo.
Kirsch et al. has stimulated debate. His reviews post-hoc are not the only ones that exist, though. It has been several years since he reached a conclusion for which he seems to now search out affirmation. This is, of course, part of the process, but it seems to me that his search is resulting in his reaching a bit to far for coroboration.
Regarding Kuhn, old ideas are not invalid simply because of their age.
In his conclusion, Kirsch writes:
"The NICE review data suggest that selective serotonin reuptake inhibitors do not have a clinically meaningful advantage over placebo"
It is his interpretation of the data that suggests to him affirmation of his thesis, not the data itself.
These drugs work. Many of us who have experienced the profound therapeutic effects that these drugs exert would consider there to be something profoundly wrong with the conclusions of Kirsch and others who are still reluctant to acknowledge that a relatively smaller statistical separation of drug versus placebo in our current investigations is significant and sufficient when it comes to evaluating antidepressants as efficacious.
One comment about Kirsch's work can be found here:
http://www.journals.apa.org/prevention/volume5/pre0050024c.html
- Scott
Posted by ed_uk on August 2, 2005, at 13:40:45
In reply to Re: We need placebo » ed_uk, posted by Kon on August 1, 2005, at 21:44:39
Hi Kon,
>When I have to perform/think in front of people (whether peers or patients) my anxiety goes through the roof and my IQ approaches that of a chipmunk.
I'm the same. I wanted to study medicine but I couldn't - too much anxiety.
Kind regards
~Ed
Posted by SLS on August 6, 2005, at 6:12:33
In reply to Re: We need placebo » Kon, posted by ed_uk on August 2, 2005, at 13:40:45
I stumbled across this while researching something for Ace (Nardil King).
- Scott
Posted by Kon on August 6, 2005, at 10:58:10
In reply to Re: We need placebo » Kon, posted by SLS on August 2, 2005, at 9:53:55
> My conjecture is not that people with mild depression are less responsive to antidepressants. It is that they are far more apt to respond to placebo.
If you read over the Kirsch review they claim that this is not true. In fact, they argue that the opposite may be the case. Interestingly in the Khan study you provided in your most recent post, the placebo response was as great in patients with severe depression as those with milder depression (with the lowest placebo response actually found in the milder depressives-though not statistically significant). The authors of the study you mention write:
"However, our results also suggest that the magnitude of placebo response was similar in the four subgroups (low moderate, high moderate, moderately severe and severe). This is in contrast to earlier findings that suggest that placebo response is higher in depressed patients with lower pre-treatment depressive symptoms."
So what does this mean? Greater response in severely depressed is due to actual drug effect and not differences in placebo response or are other confounding factors involved some of which the Khan mention:
"Finally, specific items on the HAM-D may induce greater antidepressant/placebo differences. For example, the 17-item HAM-D contains three questions pertaining to sleep. If a patient has difficulty with sleep or has few sleep-related problems, results of the HAM-D could be skewed depending on the amount of sleep problems the patient experiences.”
For instance if severely depressed have greater difficulty sleeping than less severely depressed and SSRIs improve this aspect then their better drug response may amount to this. I don't know if this is true but it's possible.
Posted by ed_uk on August 6, 2005, at 11:15:44
In reply to Re: We need placebo, posted by SLS on August 6, 2005, at 6:12:33
To what extent do people believe that the 'placebo effect' which is observed in trials of psychoactive drugs represents a 'true' placebo effect versus spontaneous improvement?
Placebo effect = when people respond to a 'sugar pill' because they expect that it will help them.
Spontaneous improvement = improvement which would have been achieved without the use of the 'sugar pill'.
~Ed
Posted by SLS on August 6, 2005, at 11:20:41
In reply to Placebo effect vs spontaneous improvement, posted by ed_uk on August 6, 2005, at 11:15:44
> To what extent do people believe that the 'placebo effect' which is observed in trials of psychoactive drugs represents a 'true' placebo effect versus spontaneous improvement?
>
> Placebo effect = when people respond to a 'sugar pill' because they expect that it will help them.
>
> Spontaneous improvement = improvement which would have been achieved without the use of the 'sugar pill'.
>
> ~Ed
Check this out:http://sl.schofield3.home.att.net/medicine/placebo_response_in_clinical_trials.pdf
(I hope I copied the link properly).
- Scott
Posted by SLS on August 6, 2005, at 11:59:58
In reply to Re: We need placebo, posted by Kon on August 6, 2005, at 10:58:10
Hi Kon.
You bring up good points that I would have been disappointed had you missed them. :-)
> > My conjecture is not that people with mild depression are less responsive to antidepressants. It is that they are far more apt to respond to placebo.
> If you read over the Kirsch review they claim that this is not true. In fact, they argue that the opposite may be the case. Interestingly in the Khan study you provided in your most recent post, the placebo response was as great in patients with severe depression as those with milder depression (with the lowest placebo response actually found in the milder depressives-though not statistically significant). The authors of the study you mention write:
> "However, our results also suggest that the magnitude of placebo response was similar in the four subgroups (low moderate, high moderate, moderately severe and severe). This is in contrast to earlier findings that suggest that placebo response is higher in depressed patients with lower pre-treatment depressive symptoms."Yeah. I don't know how they got the wrong results... :-)
I was surprised to read this as it contradicts previous studies. Actually, I think there might be an "over reporting" of improvements made by placebo "responders" simply because they feel that they are getting help. They probably aren't really feeling that much better. There might even be a doctor-pleasing tendency with these people. Regardless of what the cause is of the high percentage of placebo responders (reporters), I feel that there should be some way to compensate for this in the design or interpretation of studies. Perhaps we should throw out our current primitive rating scales and move in the direction of more complete psychometric testing.
> So what does this mean? Greater response in severely depressed is due to actual drug effect and not differences in placebo response or are other confounding factors involved some of which the Khan mention:
> "Finally, specific items on the HAM-D may induce greater antidepressant/placebo differences. For example, the 17-item HAM-D contains three questions pertaining to sleep. If a patient has difficulty with sleep or has few sleep-related problems, results of the HAM-D could be skewed depending on the amount of sleep problems the patient experiences.”
> For instance if severely depressed have greater difficulty sleeping than less severely depressed and SSRIs improve this aspect then their better drug response may amount to this. I don't know if this is true but it's possible.I think you are right. In my opinion, the current self-reporting rating system is ridiculous. I don't know why there has not been as much effort applied to designing more effective rating systems for depression as has been devoted to detailing its physiology. It is quite possible that psychometric testing will discriminate between placebo "reporters" who haven't truly improved and placebo "responders" who, for whatever reason, experience a true global improvement of the illness. Perhaps the rate of the latter will more closely approximate that of rate of spontaneous remissions seen in the general population. Perhaps the placebo response rate is more of a sum of spontaneous remitters plus those who would be otherwise responsive to psychotherapy, and thus responsive to the support given by the investigating personel in the clinical study and the suggestion of a cure that the placebo brings.
I don't know. I'm just thinking out loud.
Be well.
- Scott
Posted by ed_uk on August 6, 2005, at 12:22:56
In reply to Re: Placebo effect vs spontaneous improvement, posted by SLS on August 6, 2005, at 11:20:41
That's very interesting Scott, thanks for posting :-)
>The efficacy analysis should include only those subjects who showed no predefined improvement within the first 2 weeks of the trial, regardless of treatment received.
I found this an interesting suggestion. What if a new AD 'kicks in' more quickly than establishded ADs - in less than 2 weeks?
~Ed
Posted by ed_uk on August 6, 2005, at 12:44:39
In reply to Re: We need placebo » Kon, posted by SLS on August 6, 2005, at 11:59:58
>In my opinion, the current self-reporting rating system is ridiculous.
Depression rating scales are really very poor. Since the symptoms of depression are so variable, both between individuals and within individuals, creating a truly sensitive rating scale which can be used to rate the severity of depression in all subjects is probably an impossible task.
1. Certain subjects may suffer numerous depressive symptoms which are not listed on the standard scales.
2. Certain symptoms may be much more problematic than others. This will vary between individuals.
3. Many listed symptoms may be irrelevant to certain subjects eg. some depressed patients never experience increased/decreased appetite.
4. A given individual's symptoms may be very variable and difficult to rate.
5. Patient's and clinicians may differ in their view of which symptoms are most important.
6. Emphasis on somatic symptoms may obscure changes in a patient's mood/core symptoms.
7. Perhaps severity of depression could be measured based on the 5 symptoms (picked from a list) which are most important to an individual patient eg. depressed mood, anhedonia, insomnia, suicidal thoughts and agitation ..........or apathy, increased appetite, excessive sleep, cognitive impairment and anhedonia.
~Ed
Posted by SLS on August 6, 2005, at 14:30:55
In reply to Re: Placebo effect vs spontaneous improvement » SLS, posted by ed_uk on August 6, 2005, at 12:22:56
> That's very interesting Scott, thanks for posting :-)
>
> >The efficacy analysis should include only those subjects who showed no predefined improvement within the first 2 weeks of the trial, regardless of treatment received.
>
> I found this an interesting suggestion. What if a new AD 'kicks in' more quickly than establishded ADs - in less than 2 weeks?:-)
Then I guess we have a problem.
I think a good psychometric exam once a week and once a day self-ratings along with a revision of selection criteria should be able to resolve the placebo problem.
- Scott
Posted by ed_uk on August 6, 2005, at 15:42:40
In reply to Re: Placebo effect vs spontaneous improvement, posted by SLS on August 6, 2005, at 14:30:55
Hi Scott,
In the clinical trials you've participated in, how frequently were you assessed and how often did you have to fill in self-assessment forms?
~Ed
Posted by SLS on August 7, 2005, at 8:35:03
In reply to Re: Placebo effect vs spontaneous improvement » SLS, posted by ed_uk on August 6, 2005, at 15:42:40
> Hi Scott,
>
> In the clinical trials you've participated in, how frequently were you assessed and how often did you have to fill in self-assessment forms?
>
> ~EdWhen I was at the NIMH, we were asked to fill in a self-rating scale every day. I found the questions to be somewhat more targeted than the Burns inventory, but not much. It was a double-blind procedure for which observations were made by staff and physicians. I was asked to take a few psychometric tests, but they were not set up as a before-after treatment comparison. My guess is that the most weight was given to the self-rating forms and a global assessment made by the physician who saw me every two or three days.
It is interesting that among a cohort of patients, it was the fellow patients who would first notice signs of improvement in a proband, even before the proband fully recognized it for themselves. We knew immediately when someone was getting well enough to be discharged. The responses to treatment were that robust.
- Scott
Posted by ed_uk on August 7, 2005, at 14:27:33
In reply to Re: Placebo effect vs spontaneous improvement » ed_uk, posted by SLS on August 7, 2005, at 8:35:03
Hi Scott,
>I was asked to take a few psychometric tests.......
What did these involve?
~Ed
Posted by SLS on August 8, 2005, at 6:40:20
In reply to Re: Placebo effect vs spontaneous improvement » SLS, posted by ed_uk on August 7, 2005, at 14:27:33
> Hi Scott,
>
> >I was asked to take a few psychometric tests.......
>
> What did these involve?
>
> ~Ed
I see now that they are used for employment, but that was not their original intent. They do measure aptitude in specific skills. By doing so, they can also infer where in the brain there might be some pathology. People with depression seem to do particularly poorly in tests that involve the left frontal lobe (if my memory serves). Psychometric testing has morphed over the years, it seems, to become more geared towards being a tool of employers to screen potential employees. Interestingly, and to the surprise of my doctors, I scored very high on the "prisoner of war" scale on the MMPI. That makes sense to me, though. Depression is very much like a torturous cage.
- Scott
This is the end of the thread.
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