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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 22 of 22. This is the beginning of the thread.
Posted by linkadge on December 27, 2008, at 22:08:34
in geriatric patients:
http://stroke.ahajournals.org/cgi/content/abstract/39/3/857
Linkadge
Posted by iforgotmypassword on December 27, 2008, at 22:48:31
In reply to Use of SSRI leads to white matter losses, posted by linkadge on December 27, 2008, at 22:08:34
> in geriatric patients:
>
> http://stroke.ahajournals.org/cgi/content/abstract/39/3/857
>
> Linkadgeand causes many non-geriatric patients to feel like geriatric patients.
note in case this statement is moderation worthy: i don't intended this as an exaggeration so i say many not all. the amount of people who suffer deadening but not immediately describable* side effects is substantial.
*(by virtue of the nature of the s/e symptomology itself)
Posted by Jay_Bravest_Face on December 28, 2008, at 16:01:34
In reply to Re: Use of SSRI leads to white matter losses, posted by iforgotmypassword on December 27, 2008, at 22:48:31
Well, I will testify to the wonderful endurance of fluoxetine. It completely made my life so much easier, more enjoyable, and livelier. Now, I have Bipolar 2, so I had to add some mood stabilizers, but I've been on between 80-100mg for almost 8 years, and like most have had to do some switching, and yes I still have bad days, but fluoxetine has always been my 'anchor'. I am completing another University degree while on fluoxetine, and hold an honour's average mark in my 4th year.
I also know I am not the 'exception', because many people I attend university with, including professors, are on SSRI's or SNRI's. These people contribute extremely positively to their academic community. Again, yes some do still have their 'downtime', but the endurance and quality they bring to the table are of no quality less then any non-psychiatric treated student or faculty.
Personally, I accept the fact that I have an illness, and will always (for the rest of my life) need medication for it. Nobody has the right to deny me (or anyone else) that. If there is *better* medication in the future, I will certainly not hesitate to investigate. For now, I am doing a great job at living, and don't wish to waste any more of my breath.
Jay
Posted by linkadge on December 28, 2008, at 17:55:03
In reply to Re: SSRI bashing, posted by Jay_Bravest_Face on December 28, 2008, at 16:01:34
I didn't say you couldn't take your medication, I was just saying that this study suggested that SSRI's could accelerate the loss of white matter. Seing as depression is aready associated with abormalities in white matter, I was concerned as I too am on fluoxetine.
Linkadge
Posted by seldomseen on December 29, 2008, at 8:39:54
In reply to Use of SSRI leads to white matter losses, posted by linkadge on December 27, 2008, at 22:08:34
The white matter lesions detected were only significantly worse with the use of TCAs and not SSRIs. There was no significant difference with the use of SSRIs.
Even then, the study did not, and could not, prove causality.
In fact, if one looked at the confidence interval for the odds ratio, then in a larger study (the cohort size in the abstract was misleading, not all of the cohort was on ADs), one might actually find a neutral or even protective effect of the SSRIs.
Odds ratios less than 1 indicate protective effects.
Seldom.
Posted by Phillipa on December 29, 2008, at 13:02:23
In reply to Actually, that's not what the study found., posted by seldomseen on December 29, 2008, at 8:39:54
Seldomseen how would an SSRI protect the brain seriously don't know get so confused here. Love Phillipa
Posted by seldomseen on December 29, 2008, at 15:13:22
In reply to Re: Actually, that's not what the study found. » seldomseen, posted by Phillipa on December 29, 2008, at 13:02:23
well, it was the authors' original hypothesis that SSRIs WOULD be protective against white matter loss, as, evidentally there have been reported that SSRIs inhibit platelet function.
Reduced platelet function might make people less likely to have strokes, therefore, there may be a protective effect.
The author's did not find the protective effect in this study.
Seldom.
Posted by linkadge on December 30, 2008, at 8:26:31
In reply to Re: Actually, that's not what the study found. » Phillipa, posted by seldomseen on December 29, 2008, at 15:13:22
Yes but it said they found a trend towards worsening white matter in the SSRI group.
Posted by SLS on December 30, 2008, at 9:14:41
In reply to Re: Actually, that's not what the study found., posted by linkadge on December 30, 2008, at 8:26:31
> Yes but it said they found a trend towards worsening white matter in the SSRI group.
It is a tough study to refute without having another research team investigate the same issue. What would be interesting is to examine chronically depressed patients who have never taken an antidepressant prior to entry into the study.
I wonder how the decreased volume of white matter seen in these patients actually affects psychometric testing results; before and after.
- Scott
Posted by SLS on December 30, 2008, at 9:24:24
In reply to Re: Actually, that's not what the study found. » Phillipa, posted by seldomseen on December 29, 2008, at 15:13:22
In addition, one needs to take into consideration the loss of brain tissue in various regions that is a consequence of depression itself. There is white matter loss seen, which becomes more pronounced with advancing age. Of course, we are familiar with the loss of volume of the hippocampus that occurs, regardless of age and treatment status. These types of changes are more pronounced in bipolar disorder
- Scott
Posted by Larry Hoover on December 30, 2008, at 10:15:46
In reply to Re: Actually, that's not what the study found., posted by linkadge on December 30, 2008, at 8:26:31
> Yes but it said they found a trend towards worsening white matter in the SSRI group.
In the discussion, the authors discuss the lack of context of use of the medication, as they did not collect information with respect to diagnoses which led to the use of medication. The loss of white matter might be a direct consequence of the presence of major depression, which would then be more likely to attract treatment with antidepressants. If that is the case, both white matter loss and antidepressant use become dependent variables of major depression, and significant correlation (or trends towards signficance) would be reasonable, if not expected.
The study raises questions, but provides no answers.
Regards,
Lar
Posted by linkadge on December 30, 2008, at 15:47:17
In reply to Re: Actually, that's not what the study found. » linkadge, posted by Larry Hoover on December 30, 2008, at 10:15:46
But, the fact that TCA use is associated with significant white matter loss suggests there is some link between antidepressants and white matter loss. I.e. what is the mechanism by which TCA's accelerate white matter loss?
Granted, it could be less with SSRI's (or non-existent).
Linkadge
Posted by Larry Hoover on December 30, 2008, at 17:58:36
In reply to Re: Actually, that's not what the study found., posted by linkadge on December 30, 2008, at 15:47:17
> But, the fact that TCA use is associated with significant white matter loss suggests there is some link between antidepressants and white matter loss. I.e. what is the mechanism by which TCA's accelerate white matter loss?
No, not necessarily. If factor A leads to outcomes B and C, B and C will be correlated, although they are otherwise independent. The study authors themselves raised the idea that TCAs may be prescribed more often for severe depression, "Finally, participants may be prescribed TCAs if their depression is more severe, and such individuals may have more severe cerebrovascular disease."
In discussing limitations of the study, the authors also say, "These (limitations) include the relatively small sample size of individuals on antidepressants, as well as the lack of data on why participants were taking them and for what duration....We are also unable to capture interval development and course of depression during this time period."
So, until they can systematically assess (and adjust for) the influence of depression per se, and its time course, the correlation between antidepressants and white matter loss is unexplained.
As I said, IMHO, the report raises questions, but answers none.
Lar
Posted by linkadge on December 30, 2008, at 20:58:26
In reply to Re: Actually, that's not what the study found. » linkadge, posted by Larry Hoover on December 30, 2008, at 17:58:36
Yes, but in spite of the initial state of the partipants, the TCA group still deteriorated faster in terms of white matter. Yes, I suppose that this could be a result of worsening depression. It could also simply be that the TCA was infact producing white matter atrophy.
For a while, enhanced cardiac mortality on TCA's was also blamed on depression. It is now strongly believed that TCA's perpetuate cardiac disease.
I understand that the study may not be conclusive proof of anything, but it is still worth considering the possability. I mean there are a few potential mechanisms by which such such an effect could occur.
I know certain anticonvulsants (ie tegretol) is linked to white/grey matter atrophy as well as cytotoxicity. Many of the SSRI's are cytotoxic as well many increase oxidative stress. The TCA's can definately enhance cortical excitability and glutamatergic output. Some antidepressants, like elavil and fluoxetine directly decrease glutamate reuptake. There was a study which demonstrated how fluvoxamine enhanced glutamate neurotoxicity associated with MSG. Anyhow.
Linkadge
Posted by Larry Hoover on December 30, 2008, at 22:10:53
In reply to Re: Actually, that's not what the study found., posted by linkadge on December 30, 2008, at 20:58:26
> Yes, but in spite of the initial state of the partipants, the TCA group still deteriorated faster in terms of white matter. Yes, I suppose that this could be a result of worsening depression. It could also simply be that the TCA was infact producing white matter atrophy.
Those two explanations are equally valid, IMHO, which is all I was suggesting. There may be other explanations, not yet considered.
> For a while, enhanced cardiac mortality on TCA's was also blamed on depression. It is now strongly believed that TCA's perpetuate cardiac disease.
It can be very difficult to discriminate with respect to causation when both disease and treatment are potential explanations for a single phenomenon. It takes a lot of work to sort it out, once the question has been raised.
> I understand that the study may not be conclusive proof of anything, but it is still worth considering the possability. I mean there are a few potential mechanisms by which such such an effect could occur.I think it deserves consideration, absolutely.
> I know certain anticonvulsants (ie tegretol) is linked to white/grey matter atrophy as well as cytotoxicity. Many of the SSRI's are cytotoxic as well many increase oxidative stress. The TCA's can definately enhance cortical excitability and glutamatergic output. Some antidepressants, like elavil and fluoxetine directly decrease glutamate reuptake. There was a study which demonstrated how fluvoxamine enhanced glutamate neurotoxicity associated with MSG. Anyhow.
>
>
> LinkadgeIt all gets so complicated.
When I first saw the following paper (full-text link at bottom), I had a moment of personal epiphany. Treatments for depression are all incomplete. None addresses all of the adverse biochemical effects of the underlying disease, depression itself. Even when treatment is considered to be successful, functional brain pathologies persist. During treatment, the brain continues to endure unremediated effects of the underlying illness. I wonder if it is even possible to isolate the possible adverse effects of treatment from those of the natural progression of the disease, so I don't even try to do so. I address whatever challenges I face with CBT techniques, mindfulness, exercise, nutritional approaches, and so on, because I'd rather face the future than try to label the past.
Didn't mean to sound preachy. I hope I didn't.
Lar
Here's the abstract:
Eur Neuropsychopharmacol. 2002 Dec;12(6):527-44.
Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism.
Drevets WC, Bogers W, Raichle ME.
Neuroimaging in Mood and Anxiety Disorders Section, National Institutes of Health, NIMH/MIB, Bethesda, MD 20892, USA. drevetsw@intra.nih.govNeurophysiological studies of major depression performed using PET imaging have shown abnormalities of regional cerebral blood flow (CBF) and glucose metabolism in multiple prefrontal cortical and limbic structures that have been more generally implicated in emotional processing. The current study investigated the effects of antidepressant drug treatment in these regions using PET measures of glucose metabolism. Subjects with primary MDD (n=27) were imaged while unmedicated and depressed, and, of these, 20 were rescanned following chronic antidepressant drug treatment. Regional metabolism was compared between unmedicated depressives and controls and between the pre- and post-treatment conditions in regions-of-interest (ROI) where metabolism or flow had previously been shown to be abnormal in unmedicated depressives. At baseline, the mean metabolism was increased in the left and right lateral orbital cortex/ventrolateral prefrontal cortex (PFC), left amygdala, and posterior cingulate cortex, and decreased in the subgenual ACC and dorsal medial/dorsal anterolateral PFC in the unmedicated depressives relative to controls, consistent with the results of previous studies. Following treatment, metabolism significantly decreased in the left amygdala and left subgenual ACC, and corresponding changes in the orbital and posterior cingulate cortices approached significance. The metabolic reduction in the amygdala and right subgenual ACC appeared largely limited to those subjects who both responded to treatment and remained well at 6 months follow-up, in whom the reduction in amygdala metabolism tightly correlated with the reduction in HDRS scores. The magnitude of the treatment-associated, metabolic change in the amygdala also correlated positively with the change in the stressed plasma cortisol levels measured during scanning. These data converge with those from other PET studies to indicate that primary MDD is associated with abnormal metabolism in limbic and paralimbic structures of the mesiotemporal and prefrontal cortices. Chronic antidepressant drug treatment reduces metabolism in the amygdala and ventral ACC in subjects showing a persistent, positive treatment response. In contrast, the persistence of the abnormal metabolic deficits in the dorsomedial/dorsal anterolateral PFC in MDD during treatment may conceivably relate to the histopathological changes reported in these regions in post mortem studies of MDD.
Posted by linkadge on December 31, 2008, at 10:30:26
In reply to Re: Actually, that's not what the study found. » linkadge, posted by Larry Hoover on December 30, 2008, at 22:10:53
Yes, I have seen that study. Most treatments are really only providing symptomatic effects.
In some ways I think we are making the disease more chronic with treatment, however. This is a theory that is likely never going to be systematically explored or voiced till a few hundred years from now.
Linkadge
Posted by shasling on January 3, 2009, at 0:48:20
In reply to Re: Actually, that's not what the study found. » seldomseen, posted by SLS on December 30, 2008, at 9:24:24
> In addition, one needs to take into consideration the loss of brain tissue in various regions that is a consequence of depression itself. There is white matter loss seen, which becomes more pronounced with advancing age. Of course, we are familiar with the loss of volume of the hippocampus that occurs, regardless of age and treatment status. These types of changes are more pronounced in bipolar disorder
>
>
> - ScottCheers to that this comment,which ill add also goes for a lot of BENZO W/D worry,lets not forget why one began a medication to start with,stopping say a benzo without some solid assurance your a anxiety is under control with not only bring the obvious w/d with it,but it never cured you just treated so a return of original symptoms shouldent be surprising.
Posted by linkadge on January 3, 2009, at 9:04:59
In reply to Re: Actually, that's not what the study found., posted by shasling on January 3, 2009, at 0:48:20
>Of course, we are familiar with the loss of >volume of the hippocampus that occurs, >regardless of age and treatment status. These >types of changes are more pronounced in bipolar >disorder
I realize that, but I also think that there is strange inability to consider the possability that certain treatments may not slowing disease progression and/or are promoting disease progression.
I don't think that is inconcieveable I just think that people don't want to consider it.
Linkadge
Posted by SLS on January 3, 2009, at 9:24:39
In reply to Re: Actually, that's not what the study found., posted by linkadge on January 3, 2009, at 9:04:59
> > Of course, we are familiar with the loss of volume of the hippocampus that occurs, regardless of age and treatment status. These types of changes are more pronounced in bipolar disorder
> I realize that, but I also think that there is strange inability to consider the possability that certain treatments may not slowing disease progression and/or are promoting disease progression.
In my opinion, the study you cited at the beginning of this thread is worthy of consideration. I think it was designed pretty well. I'll leave it to Larry to change my mind.
:-)
> I don't think that is inconcieveable
It is very much conceivable.
> I just think that people don't want to consider it.
There are always going to SOME people who are uncomfortable with things that are new. The implications of this study are pretty heave-duty.
It is worth noting that there are studies that report a recovery of white matter tissue along with hippocampal tissue after a robust antidepressant response is maintained.
- Scott
Posted by Larry Hoover on January 3, 2009, at 16:20:45
In reply to Re: Actually, that's not what the study found., posted by SLS on January 3, 2009, at 9:24:39
> In my opinion, the study you cited at the beginning of this thread is worthy of consideration. I think it was designed pretty well. I'll leave it to Larry to change my mind.
>
> :-)Its design is a post-hoc analysis of data that were collected between 1989 and 1999, primarily for the purpose of assessing cardiovascular risk factors and their influence on cognitive decline. In all, 70 variables were assessed. White matter decline was observed with smoking, use of diuretics and statins, as examples. (Reference 11 in the full-text.)
That same dataset was subsequently used for the purposes of the present study, a post-hoc analysis of data collected for another purpose altogether. I happen to hold to a particular skeptical view of data subjected to post-hoc analysis, what some call "data-mining". Essentially, you just don't know how complete the data really are, or if bias or uncontrolled variables influence the data that were collected.
I've previously questioned the meaning attributable to the correlation between antidepressant use and white matter decline, particularly because data with respect to diagnosis and course of major depression were not collected. It's impossible to know if depression caused both antidepressant use and white matter decline, or if antidepressant use alone was the dominant factor.
If you plotted height vs use of make-up for people under 20, you'd find a positive correlation. But, each factor is really an outcome of maturation. Despite the correlation, height doesn't cause make-up use, nor the other way around. Moreover, there would be other factors influencing the correlation, e.g. gender, ethnicity, and religion. A discussion of the correlation wouldn't be complete without taking those into account.
Getting back to the present study, depression is already in a well-established correlation with cardiovascular disease, for which causation need not even be considered in the present context. Diuretics and statins are often used in CV treatment, yet these variables, previously shown by these same authors to significantly promote white matter decline, were neither mentioned nor adjusted for in the present study. Nor was smoking. Why not?
The link between depression per se and white matter loss may even be inferred from the very small sample (15 subjects) who used both serotinergic agents and TCAs during the study period. Fully 60% of that small group experienced white matter declines, but with their exclusion from the stats, no significant effect of antidepressant use remains. I'm tempted to consider that unremitted depression, in some cases calling for multiple treatments, is the underlying issue, rather than medication use. The data allow such an interpretation, whether I may be right or wrong.
So long as there are multiple reasonable interpretations of the data, I can only conclude that questions/concerns have been raised that have not been answered. The authors' own hypothesis was that serotonergic meds would be protective, and upon a quite reasonable basis. Their data-mining excursion did not support their hypothesis, but nor did they manage to exclude explanations that did not support a possible causative relationship between antidepressant use and white matter decline.
I'm not trying to change anybody's mind. I am saying that I haven't made up my mind, due to insufficient and incomplete data for consideration.
Lar
Posted by Larry Hoover on January 3, 2009, at 16:40:07
In reply to Re: Actually, that's not what the study found. » SLS, posted by Larry Hoover on January 3, 2009, at 16:20:45
I was going to include these, but I forgot.
Here's a full-text link to a study showing white matter declines in major depressives in mid-life:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18982175
And here's one (abstract) of white matter problems in *treatment-naive* young people:
Brain Res. 2007 Sep 7;1168:124-8. Epub 2007 Jul 31.
Prefrontal white matter abnormalities in young adult with major depressive disorder: a diffusion tensor imaging study.
Li L, Ma N, Li Z, Tan L, Liu J, Gong G, Shu N, He Z, Jiang T, Xu L.
Mental Health Institute, The Second Xiangya Hospital of Central South University, Changsha, Hunan, PR China. llj2920@163.comPrefrontal impairments have been hypothesized to be most strongly associated with the cognitive and emotional dysfunction in depression. Recently, white matter microstructural abnormalities in prefrontal lobe have been reported in elderly patients with major depressive disorder (MDD) using diffusion tensor imaging (DTI). However, it is still unclear whether the same changes exist in younger patients. In the present study, we first utilized DTI to detect prefrontal white matter in young adults with MDD. Nineteen first-episode, untreated young adults with MDD and twenty age- and gender-matched healthy controls were recruited. DTI and localizing anatomic data were acquired. Then, the regions of interest (ROIs) were located in prefrontal white matter at 4 mm inferior, and 0, 4, 8, 12, 16 and 20 mm superior to the anterior commissure-posterior commissure (AC-PC) plane, respectively. Compared with healthy controls, patients with MDD showed significantly lower fractional anisotropy (FA) values in prefrontal white matter at bilateral 20 mm, right 16 mm and right 12 mm above the AC-PC. Furthermore, there was no significant correlation between the FA value of any ROI and illness course as well as severity of depression. Together with previous findings, the present results suggest that microstructural abnormalities in prefrontal white matter may occur early in the course of MDD and may be related to the neuropathology of depression throughout adulthood from young to elderly.
Posted by SLS on January 3, 2009, at 16:44:05
In reply to Re: Actually, that's not what the study found. » SLS, posted by Larry Hoover on January 3, 2009, at 16:20:45
I didn't realize it was a post-hoc study. You make some very important observations.
If one were to accept the conclusions of the study, the associations between white matter volume and antidepressant use in the elderly would be opposite to that which is consistently observed in young patients.
Thanks for chiming in, Larry.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2533397
- Scott
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