![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 15 of 15. This is the beginning of the thread.
Posted by jrbecker on March 10, 2003, at 19:30:30
The following is a very general synopsis of treatments in the pipeline. Seemed interesting enought to post...
Treatment of mood disorders
Charles B. Nemeroff & Michael J. Owens
Laboratory of Neuropsychopharmacology, Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Drive, Suite 4000, Atlanta, Georgia 30322, USA
Correspondence should be addressed to C B Nemeroff. e-mail: cnemero@emory.edu
Depression is a leading cause of morbidity and mortality, and its treatment includes a high percentage of the medications prescribed by physicians. Available antidepressant drugs are safe and effective, but less than half of all patients attain complete remission after therapy with a single antidepressant. Others exhibit partial, refractory or intolerant responses to treatment, emphasizing the need to discover new antidepressants. The mechanisms of action of available medications are directing the field toward new research avenues. This review highlights those areas we believe will influence the field and soon lead to better treatment.Depression is one of the most prevalent and costly brain diseases. In the last major epidemiology study conducted in the United States1, major depression had an overall lifetime prevalence rate of 17.1% (21% in women and 13% in men), and comparable figures have been obtained worldwide. These findings represent an increase of approximately 6% in the 15 years since the previous study2. Although space constraints preclude further discussion of bipolar disorder (also known as manic–depressive illness), another 1.3–1.8% of the population is afflicted with this disorder.
Affective disorders account for considerable psychiatric morbidity (pain and suffering), but also significant disability and consequent loss of productivity. Depression has been estimated to be the second leading cause of disability worldwide, surpassed only by ischemic heart disease3. Moreover, depression is often associated with comorbid psychiatric disorders, most notably anxiety disorders (panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive–compulsive disorder and post-traumatic stress disorder). The mean age of onset of depression has markedly decreased from the 40- to 50-year-old range noted several years ago to the 25- to 35-year range, and this phenomenon has been observed worldwide4. Depression often goes undetected, especially in children, adolescents and the elderly. Mood disorders are associated with a significant risk for suicide, which remains one of the top ten causes of death in the United States and in many countries throughout the world. Depression is a major independent risk factor for the development of coronary artery disease and stroke, and possibly other major medical disorders5. The presence of depression after myocardial infarction is associated with a markedly diminished survival rate over the 18 months after the initial episode6, 7. The precise pathophysiology of mood disorders remains obscure, as does the neurobiology of normal mood regulation. However, recent advances in neuroscience, particularly in molecular neurobiology and functional brain imaging, are rapidly advancing our understanding of the biological substrates of normal and pathological mood states.Three treatments for depression have shown unequivocal effectiveness: antidepressants, certain forms of psychotherapy and electroconvulsive therapy (ECT). Pharmacotherapy is still based almost exclusively on the serendipitous discovery that drugs that enhanced monoamine transmitter function were effective agents. Only recently has evidence arisen that the pathology of depression involves dysfunction of monoamine neurotransmitter circuits in the central nervous system, particularly serotonin (5-HT) and norepinephrine (NE). It should be noted that virtually all approved classes of antidepressants act in one of three ways: (1) blockade of presynaptic monoamine transporter proteins, which remove released transmitter from the extracellular space, (2) inhibition of monoamine oxidase, which degrades monoamine neurotransmitters or (3) inhibition or excitation of pre- or postsynaptic receptors that regulate monoamine transmitter release and/or neuronal firing rates.
Although the protein targets of these drugs are known and their effects within the CNS occur almost immediately, the vast majority of patients do not respond until 3–5 weeks after the initiation of treatment. This observation has led to the almost universal view that although monoamine systems are integral to the mechanism of action of antidepressants, they are not the final common pathway of action. Identifying such pathways represents one future direction in the pharmacotherapy of mood disorders. The mechanism of action of ECT remains obscure, but it generally works more rapidly than currently available antidepressants, suggesting that discovery of more rapidly acting agents is plausible. Finding these novel targets might involve recently developed techniques in genomics and proteomics, which would allow for large-scale screening of transcripts and proteins associated with mood disorders. However, although single gene mutations can result in complex phenotypes, mood disorders appear to be multifaceted8, complicating such studies. One potential set of targets is proteins involved in synaptic plasticity; notably the transcription factor CREB and brain-derived neurotrophic factor (BDNF) are affected by many antidepressants9, 10.
Three major areas in antidepressant pharmacotherapy need improvement. The first is efficacy. After 6–8 weeks, only 35–45% of patients treated with standard doses of the most commonly used antidepressants return to premorbid levels of functioning without any significant depressive symptoms11, 12. The remainder are improved but not well, or do not respond at all. Second is the issue of tolerability. The newer generation of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are clearly superior to the older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors in terms of tolerability; overdose is not lethal, and no adverse cardiac effects occur. However, they are not without their own problematic side effects, including sexual dysfunction. Third, as noted above, the slow response to treatment makes a more rapid action a desirable attribute for novel antidepressants. Although the development of therapeutic agents that act on novel targets is probably more than 10 years away, potentially useful approaches exist in the near future, possibly by the end of this decade.
Monoamine neurotransmitters
As noted earlier, 5-HT and NE circuits are involved in mood disorders13, 14, and dysregulation of dopamine (DA) may be as well15. Drugs that selectively antagonize 5-HT, NE and possibly DA transporters are effective antidepressants. Agents selective for the serotonin transporter (fluoxetine, citalopram, fluvoxamine) are the most widely used, but the ability to antagonize additional transporters has been suggested to provide increased efficacy, a superior response in treatment-refractory patients, and a broader therapeutic spectrum across several anxiety disorders12, 16. This may account for reports that dual-acting TCAs, which inhibit both 5-HT and NE transporters in vivo, are more effective than SSRIs16. Venlafaxine and paroxetine at the upper end of their dose range clearly inhibit both 5-HT and NE reuptake17. Sertraline at the higher end of the dosage range may act as a dual 5-HT and DA reuptake inhibitor18. Duloxetine, a potent 5-HT and NE reuptake inhibitor, will almost certainly be approved soon by the U.S. FDA for the treatment of depression. Milnacipran, a dual 5-HT and NE reuptake inhibitor approved for the treatment of depression in France, Japan and other countries, is being developed in the U.S. market for the treatment of fibromyalgia as a collaboration between Pierre Fabre and Cypress Biosciences. Because of evidence that DA neurons are involved in the pathophysiology of depression, focus on DA reuptake inhibitors has intensified, and the search for compounds that antagonize all three monoamine transporters is underway.Long-term treatment of laboratory animals with a variety of different antidepressants leads to augmented serotonergic neurotransmission, which most likely is mediated, at least in part, through an action on postsynaptic 5-HT1A receptors. Thus, 5-HT1A agonists (flesinoxan, 6-hydroxybuspirone, ipsapirone, gepirone) represent a novel class of antidepressants. Although the theoretical basis for this approach is strong, results with these agents have been disappointing, for several possible reasons. First, long-term 5-HT1A agonist administration may cause downregulation of 5-HT1A receptors. Second, some of these agents are partial agonists and may not achieve the complete receptor response that may be necessary. Third, the necessary percentage of receptor occupancy may not be obtained. Fourth, other 5-HT receptors in addition to the 5-HT1A receptor may need to be activated to achieve an antidepressant effect. Long-term treatment with SSRIs enhances serotonergic neurotransmission. Vilazodone, a 5-HT reuptake inhibitor/5-HT1A partial agonist, is being developed as an antidepressant by GlaxoSmithKline.
An alternative approach, perhaps counterintuitive, has also been suggested, namely the combination of a 5-HT1A receptor antagonist with an SSRI, the former to block presynaptic autoreceptors that normally reduce serotonergic neuronal activity. Such drugs should increase the proserotonergic effects of SSRIs. Some reports indicated positive effects with pindolol, a 5-HT1A and -adrenergic receptor antagonist19, whereas other studies found that the drug did not improve the rapidity of efficacy, perhaps due to insufficient occupancy of the 5-HT1A autoreceptor at the dose used20.Changing the pharmacokinetic profiles of existing drugs has also proven beneficial. For example, controlled or sustained-release preparations of venlafaxine, bupropion and paroxetine are now available, and methods to deliver a monoamine oxidase inhibitor and lithium via patch technology have been developed. These methods improve tolerability of the drug, as well as patient compliance.
Novel antidepressant classes
A substantial percentage of depressed patients show hypercortisolemia—excess glucocorticoid secretion, primarily cortisol in humans, from the adrenal gland. Other measures of hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, such as non-suppression of cortisol after administration of the synthetic glucocorticoid dexamethasone, are also seen. This critical endocrine axis is controlled by hypothalamic secretion of corticotropin-releasing factor (CRF), a 41 amino-acid peptide21, 22. CRF is heterogeneously distributed in the CNS, where it serves to orchestrate the endocrine (HPA axis), autonomic, immune and behavioral responses to stress. CRF neural pathways extensively interact with serotonergic and noradrenergic circuits. The behavioral effects of administered CRF in laboratory animals are strikingly similar to the symptoms of major depression. CRF is hypersecreted in some depressed patients, which led us and others to suggest that CRF receptor antagonists might act as antidepressants. There are two major CRF receptor subtypes, and several pharmaceutical companies are actively testing CRF1 receptor antagonists as antidepressants. In a variety of preclinical models, CRF1 receptor antagonists possess antidepressant properties. Janssen Pharmaceuticals halted development of R121919, a potent CRF1 receptor antagonist, because of hepatotoxicity, apparently unrelated to blockade of the CRF receptor. Nevertheless, early open clinical trials provided evidence of antidepressant efficacy23. A number of promising CRF1 receptor antagonists are currently under study.
Although most investigators believe that hypercortisolemia is a consequence of CRF hypersecretion associated with depression, the marked hypercortisolemia observed in psychotic depression, a subtype of depressives characterized by delusions and/or hallucinations, has led to impressive studies indicating that the glucocorticoid receptor antagonist mifepristone (RU486) is very effective in the treatment of psychotic depression24. Large-scale, double-blind, randomized clinical trials are currently being conducted by Corcept in the United States.The neurokinin1 (NK1) receptor is a tachykinin receptor for the endogenous neuropeptide transmitter substance P. NK1 antagonists were originally scrutinized for analgesic properties without success. However, an NK1 antagonist MK-869 (Merck) exhibited efficacy in a placebo-controlled clinical trial for depression, comparable to the active comparator paroxetine25. The finding of efficacy in this study has led other pharmaceutical companies to develop NK1 antagonist programs26.
Neuroimaging
There has been significant progress in the design and testing of radioligands for in-vivo positron emission tomography (PET) imaging in humans to identify pathophysiological subtypes of mood disorders and thus predict appropriate treatment(s) for patients. Serial imaging of the density of cell surface receptors and transporters in individuals will undoubtedly provide invaluable information concerning the biology of mood disorders. More immediate will be the use of such techniques to optimize drug choice and dosing. With PET or SPECT ligands now available for the DA and 5-HT transporters, and development of ligands for the NE transporter in progress, it will be of great interest to follow transporter occupancy as a function of antidepressant dose to determine if this measure correlates with antidepressant efficacy. Until recently, there has been surprisingly sparse information on the magnitude of transporter occupancy during antidepressant treatment. Approximately 80% of 5-HT transporter is occupied by standard doses of two SSRIs, paroxetine and citalopram27. It is not known what level of transporter occupancy is necessary for producing functional changes in neurotransmitter concentrations or whether small increments of blockade of NE or DA transporters, in the presence of considerable 5-HT transporter blockade, may provide additional clinical benefit.Future directions
Finally, we suggest several exciting areas of research that plausibly might lead to new treatments. Neurogenesis occurs in the adult hippocampus, glucocorticoids decrease neurogenesis, and both serotonergic and noradrenergic antidepressants, as well as ECT, increase neurogenesis. The link among the hippocampus, glucocorticoids, monoamine systems and mood disorders seems clear, although their exact mechanisms of interaction remain obscure. In addition, some agents used in the treatment of bipolar disorder modify apoptotic pathways; for instance, valproic acid increases expression of the protective protein bcl-2. In addition, chaperone proteins are important in regulating steroid receptor translocation, and other proteins are involved in trafficking of cell surface receptors and transporters over short (seconds to minutes) time spans. Thus, medications altering the function of these proteins may also modify neurotransmission. Should problems with delivery to the brain be overcome, antisense technology could be used in the treatment of psychiatric disorders as it has been for cystic fibrosis and cancer. Collectively, these approaches could conceivably represent new targets for mood disorder treatments.Received 1 July 2002; Accepted 4 September 2002; Published online 28 October 2002.
Posted by jrbecker on March 11, 2003, at 12:49:46
In reply to synopsis of new treatments of the future, posted by jrbecker on March 10, 2003, at 19:30:30
I realize this is more for the those interested in the "academic" side of psychopharmacology since most of this info is purely investigational. But it also helps show where the research is going.
This abstract was just released by Pfizer's research dept in regards to their research of CRH antagonist compounds. If I can find the full- text study, I will post it as well....
The Pharmacology of CP-154,526, a Non-Peptide Antagonist of the CRH1 Receptor: A Review.
Seymour PA, Schmidt AW, Schulz DW.
CNS Discovery, Pfizer Global Research and Development, Eastern Point Road, MS-8220-4193, Groton, CT 06340. patricia_a_seymour@groton.pfizer.com.
Since CRH has been shown to mediate stress-induced physiological and behavioral changes, it has been hypothesized that CRH receptor antagonists may have therapeutic potential in disorders that involve excessive CRH activity. CP-154,526 and its close analog antalarmin are potent, brain-penetrable, selective nonpeptide CRH1 receptor antagonists that were discovered in an effort to develop compounds with efficacy in CNS disorders precipitated by stress. Since its discovery many investigators have used CP-154,526 as a tool to study the pharmacology of CRH and its receptors and to evaluate its therapeutic potential in a variety of CNS and peripheral disorders. Systemically-administered CP-154,526 has been demonstrated to antagonize CRH- and stress-induced neuroendocrine, neurochemical, electrophysiological, and behavioral effects. These findings support the hypothesis that CRH1 receptor antagonists may have therapeutic utility in a number of neuropsychiatric disorders. CP-154,526, as well as other CRH1 receptor antagonists that have since been discovered, have also shown activity in several preclinical models of anxiety, depression, and substance abuse, while having little effect on locomotor activity and motor function. Although these effects are on occasion inconsistent among different laboratories, clinical evaluation of CRH1 antagonists appears justified on the basis of these and clinical data implicating the involvement of CRH in several CNS disorders. The effects of CRH1 antagonists on cognition, neurodegeneration, inflammation, and the gastrointestinal system have not been as extensively characterized and additional studies will be necessary to evaluate their therapeutic potential in these areas.
Posted by Shawn. T. on March 11, 2003, at 16:34:28
In reply to synopsis of new treatments of the future, posted by jrbecker on March 10, 2003, at 19:30:30
That's a good article; I hadn't seen that one before. An important fact to note is that people with atypical depression won't benefit from CRF antagonists. Unfortunately, atypical depression doesn't receive anywhere near the funding that typical depression does; I'm not sure when people with atypical depression might expect to see more effective drugs. If you want more in depth information about CRF and depression, go to http://www.neurotransmitter.net/crf.html
Shawn
Posted by jrbecker on March 11, 2003, at 17:23:12
In reply to Re: CRF and depression, posted by Shawn. T. on March 11, 2003, at 16:34:28
Good point, regarding the limited utility of the CRH anatagonists. I've actually been in contact with George Chrousos of NIMH as well as Charles Nemeroff at Emory. Both agree that there is a need for CRH partial agonists for atypical depression. However, they also see a possible utility of using CRH antagonists in some forms of atypical depression as well. This is evident because many sufferers do not fit exclusively in either category of melancholic or atypical type, and thus, cannot be suffering from consistent hypo- or hyper-active states, respectively, all of the time. There is a study I used to have cited that shows that the breakdown of sufferers who actually meet the criteria for both subtypes, and who falls somewhere in the middle, but it eludes me now. Anyway, the point is that, for many, a complete desensitization of the stress system has not fully occurred, and that their features are not wholely atypical all of the time. Thus, in these individuals, there might also be some benefits to just modulating the stress system somehow, either through slight deregulation of the CRH pathway, or even through the means of a low-affinity antagonist itself.
On another note, there seems to be some preliminiary work being done to study regulation of the glucocorticoid receptor (GR). One compound in early development is Organon's Org-34517. It is hoped that this will increase the sensitivity of GR and reinstate normal control of the HPA axis. This would make theoretical sense for treating atypical sufferers.
Posted by Ilene on March 11, 2003, at 18:45:15
In reply to synopsis of new treatments of the future, posted by jrbecker on March 10, 2003, at 19:30:30
Should problems with delivery to the brain be overcome, antisense technology could be used in the treatment of psychiatric disorders
>Does anyone but me think this is funny?
--I.
Posted by hok on March 12, 2003, at 12:12:59
In reply to Re: CRF and depression, posted by Shawn. T. on March 11, 2003, at 16:34:28
> That's a good article; I hadn't seen that one before. An important fact to note is that people with atypical depression won't benefit from CRF antagonists. Unfortunately, atypical depression doesn't receive anywhere near the funding that typical depression does; I'm not sure when people with atypical depression might expect to see more effective drugs. If you want more in depth information about CRF and depression, go to http://www.neurotransmitter.net/crf.html
>
> Shawn
Great point Shawn. Considering that the majority of outpatients suffer from atypical depression, shouldn't the bulk of new treatment research reflect this? Especially since the majority of melancholic depressives benefit more from current therapies in comparison to unipolar atypicals and bipolar II-atypical individuals. Part of the issue of course is that atypical depression is a much more complicated condition. Nevertheless, there should be more pre-clinical work being done than there currently is.We should start a petition to NIMH or something!
Posted by Ilene on March 12, 2003, at 12:56:12
In reply to Re: CRF and depression, posted by Shawn. T. on March 11, 2003, at 16:34:28
> That's a good article; I hadn't seen that one before. An important fact to note is that people with atypical depression won't benefit from CRF antagonists. Unfortunately, atypical depression doesn't receive anywhere near the funding that typical depression does; I'm not sure when people with atypical depression might expect to see more effective drugs. If you want more in depth information about CRF and depression, go to http://www.neurotransmitter.net/crf.html
>
> ShawnNeurotransmitter.net looks interesting.
Have you poked around here?
American College of Neuropsychopharmacology
http://www.acnp.org/They have many (older) full-text articles on line in "The Fourth Generation of Progess" I read a few of the clinical ones. I feel like I need a seminar in brain physiology.
--I.
Posted by Shawn. T. on March 12, 2003, at 15:50:07
In reply to Re: need for atypical depression research » Shawn. T., posted by hok on March 12, 2003, at 12:12:59
Ilene-- thanks; yes I have poked around that site a bit.
Hok -- The data that I've gathered seems to show that from 22 to 38% of outpatients with depression suffer from atypical depression. Nonetheless, I personally find it shocking how little research on atypical depression is available. Perhaps one problem that currently exists is that not everyone agrees about what symptoms are associated with atypical depression. Benazzi's recent work seems to suggest that the defining characteristics of people with atypical depression are two reversed vegetative symptoms (oversleeping and overeating). The DSM-IV criteria are mood reactivity, hypersomnia, hyperphagia, leaden paralysis, and rejection sensitivity. However, Akiskal's recent work seems to show that mood reactivity and rejection sensitivity are characteristics of people with cyclothymia/bipolar II and atypical depression; some of Benazzi's work supports this concept. If you want to read the abstracts, go to http://www.neurotransmitter.net/atypicaldepression.html ... note that I've included most available information except for several articles on drug research (e.g. clinical research on MAOI's). I did find an interesting article today while updating that page: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12559660&dopt=Abstract
Apparently, chromium picolinate may help to relieve the symptoms of atypical depression in some people; however, the study was small, so it will need to be verified. 7/15 people responded to the treatment; that's not bad at all for a supplement.
Anyway, I might throw up a plea on my website for more atypical depression research. Most visitors are academic types; occasionally I get hits from government types, so perhaps the message might cross some influential eyes.
Shawn
Posted by Ilene on March 12, 2003, at 17:32:49
In reply to Re: need for atypical depression research, posted by Shawn. T. on March 12, 2003, at 15:50:07
>
> Anyway, I might throw up a plea on my website for more atypical depression research. Most visitors are academic types; occasionally I get hits from government types, so perhaps the message might cross some influential eyes.
>
> ShawnWhat's your website? I'm all ears. Uh, eyes.
PS: I might go to NLM soon. Mostly want to find a couple of journals that medline doesn't index. I need a kick in the pants, though. Maybe if someone needs an abstract for one of those "no abstract available" items I can get it for them. Even if I do manage to get down there, it's not exactly user-friendly. But last time I was there they had signs posted in Russian.
PPS: do you know about CRISP?
Posted by Ilene on March 12, 2003, at 18:02:12
In reply to Re: need for atypical depression research, posted by Shawn. T. on March 12, 2003, at 15:50:07
> Hok -- The data that I've gathered seems to show that from 22 to 38% of outpatients with depression suffer from atypical depression. Nonetheless, I personally find it shocking how little research on atypical depression is available. Perhaps one problem that currently exists is that not everyone agrees about what symptoms are associated with atypical depression. Benazzi's recent work seems to suggest that the defining characteristics of people with atypical depression are two reversed vegetative symptoms (oversleeping and overeating). The DSM-IV criteria are mood reactivity, hypersomnia, hyperphagia, leaden paralysis, and rejection sensitivity. However, Akiskal's recent work seems to show that mood reactivity and rejection sensitivity are characteristics of people with cyclothymia/bipolar II and atypical depression; some of Benazzi's work supports this concept.
Strange. I read that atypical depression was more common than melancholic.
I've read some on problems of diagnosis. The symptoms are so subjective! Hard to make a differential diagnosis.
One thing that interests me is that the existence of mental disorders in the family is significant, even if they are neither depression nor bipolar disorder. There is cluster of both "mental" and "physical" disorders (as if your head were somehow disconnected from the rest of you) that occur in the family tree.
>
> Apparently, chromium picolinate may help to relieve the symptoms of atypical depression in some people; however, the study was small, so it will need to be verified. 7/15 people responded to the treatment; that's not bad at all for a supplement.
>That is a *really* small study. When you read about meta-analyses (is that the right word? I have problems w/ word finding) you find out how unrigorous these things can be. The more depression research I read, the more skeptical I become. E.g, what is the criterion for response? How long did the response last? Were the patients treatment-naive? How severe was their depression? Blah blah blah blah
--I.
Posted by Shawn. T. on March 12, 2003, at 18:42:45
In reply to Re: need for atypical depression research » Shawn. T., posted by Ilene on March 12, 2003, at 18:02:12
Good point on the study; I looked up chromium and found out that it had already been argued about on this board last month, and the same points were made about the study. I'm simply pleased to see someone sticking their neck out on a study of new treatments for atypical depression; I linked to the study for that reason, and I definitely agree that no conclusions may yet be made. I checked out the CRISP website ( http://crisp.cit.nih.gov/ ); it seems like a good place to find out about new research projects. My website is http://www.neurotransmitter.net ... I suppose that I didn't make it clear that I was referring to my own site :)
Shawn
Posted by Shawn. T. on March 12, 2003, at 19:08:30
In reply to Re: need for atypical depression research » Shawn. T., posted by Ilene on March 12, 2003, at 18:02:12
I forgot to reply to a couple things. Forgive me if the following is obvious. With the hereditary relationships that you speak of, the effect is likely a result of susceptibility genes that contribute to several different disorders. Depending on neurodevelopmental factors and the existence of other susceptibility genes, one particular gene can be involved in several disorders. In addition, studies occasionally find "modification" type genes that alter or negate the effects of a certain susceptibility gene.
Regarding the articles without abstracts, my snobbish attitude is that a research article should have an abstract if is worth reading; most major journals require them anyway. When I search PubMed, I typically use the feature that leaves out articles without abstracts. A trip to the NLM would be a nice way around the unbelievable prices for journals. There's a big push among some people to have more free articles made available; hopefully this concept will take hold eventually.
Shawn
Posted by Ilene on March 12, 2003, at 20:32:59
In reply to Re: need for atypical depression research » Ilene, posted by Shawn. T. on March 12, 2003, at 19:08:30
> I forgot to reply to a couple things. Forgive me if the following is obvious. With the hereditary relationships that you speak of, the effect is likely a result of susceptibility genes that contribute to several different disorders. Depending on neurodevelopmental factors and the existence of other susceptibility genes, one particular gene can be involved in several disorders. In addition, studies occasionally find "modification" type genes that alter or negate the effects of a certain susceptibility gene.
>Yeah, I know. It's complicated.
For many years I thought my mother had a masked mood disorder. Stress triggered her migraines; and she was ... strange.
It wasn't until recently that I discovered there was a correlation between migraine & depression (or was it BP? not worth checking right now), not only in an individual, but in the family.
I don't remember what all the disorders are supposed to be, but I remember migraine was there, and irritable bowel syndrome. Migraine is supposed to be caused by serotonin; I wonder if there is a relationship between IBS & serotonin, given that there is so much of it in your gut. Just haven't been curious enough to research it.
So how does a "susceptibility" gene work? What does it make? How does it affect different disorders? And what's a "modification" gene?
> Regarding the articles without abstracts, my snobbish attitude is that a research article should have an abstract if is worth reading; most major journals require them anyway. When I search PubMed, I typically use the feature that leaves out articles without abstracts. A trip to the NLM would be a nice way around the unbelievable prices for journals. There's a big push among some people to have more free articles made available; hopefully this concept will take hold eventually.
>
> ShawnYes, I am familiar w/ the problems regarding journal subscriptions. Haven't paid attention for the last year and 1/2. People don't realize how expensive they are. Even less expensive would make them more accessible.
There are problems w/ using PubMed as your sole bibliographic database, plus there are internal problems w/ it. I love it anyway.
--I.
Posted by hok on March 13, 2003, at 14:16:31
In reply to Re: need for atypical depression research » Ilene, posted by Shawn. T. on March 12, 2003, at 19:08:30
Shawn,
Thanks for your offer to help the cause. whatever you could do to advocate atypical-type research would be VERY much appreciated. And if you have any suggestions for me (e.g., writing to the NIMH, etc), I'm all ears. Thanks.
HK
Posted by Shawn. T. on March 13, 2003, at 16:09:24
In reply to Re: need for atypical depression research » Shawn. T., posted by Ilene on March 12, 2003, at 20:32:59
Hok- you're welcome. I don't know that I have any suggestions; I'm generally unfamiliar with dealing with the NIH beurocracy.
Ilene- The correlation between migraine and affective disorders applies to both bipolar disorder (moreso with bipolar II) and unipolar depression. Activation of serotonin 5-HT1B/5-HT1D receptors seems to relieve migraine headaches. There is some evidence that decreased serotonin turnover exists in some migraine sufferers. 29-35% of people with unipolar depression exhibit decreased serotonin turnover, so there may be some connection there; that's a purely hypothetical notion, however. 5-HT4 agonists and 5-HT3 antagonists have been shown to be effective treatments for some people with irritable bowel syndrome. 5-HT4 agonists are effective in constipation- predominant IBS, and 5-HT3 antagonists are more effective in diarrhea- predominant IBS. I believe that the effects of serotonin on receptors in the brain may be as important as its effects in the gut; I'm not quite sure about precisely how large of a role serotonin in the gut plays. The S/S genotype of the serotonin transporter gene may be associated with constipation- dominant IBS, and the L/S genotype may be associated with diarrhea- predominant IBS. Migraine sufferers with S/S genotypes may experience more frequent migraine attacks. Note that L stands for "long" and that L alleles are associated with greater expression of serotonin transporters. Different serotonin transporter genotypes may affect unipolar and bipolar disorders as well; age of onset, frequency of episodes, and response to SSRI's may be affected by certain genotypes. Note that my brother has IBS; my mom experiences migraines; my sister may have atypical depression; and I have cyclothymia/bipolar II with atypical depression. Otherwise, I might be a bit less familiar with some of this information. Ask me for any references that you might like to see; I usually include references but am feeling lazy today.
A "modification gene" is a term that I made up; it's basically a gene that modifies the effects of another gene. I'm sure that other people may use similar terms to describe the same thing. Serotonin transporter genotypes do not cause increased susceptibility to any disorders by themselves; they do, however, modify the effects of susceptibility genes. A "susceptibility gene" is one that increases the likelihood that a person will experience a certain disorder. Researchers are careful about implying that susceptibility genes cause certain disorders; neurodevelopmental factors and the presence of other contributing genetic factors are often seen as necessary co-factors in causing various disorders. A susceptibility gene generally encodes a protein, enzyme, or other type of biological substance that may occur in a specific region of the body or in several regions.
I agree that relying solely on PubMed for reference links on my site may create some problems, but I use it for a very specific reason. There are other sites, like Infotrieve, that might even contribute some money to my efforts when people using my site transfer to their site and decide to purchase an article. PubMed recently created PubMed Central to encourage more prevalent free access to journal articles. One cannot access PubMed Central links from databases like Infotrieve's, and I cannot always link to full text articles because the abstract is too new. So I link solely to PubMed so that people might have a greater chance of obtaining a full text article in the future. I personally believe that research funded by tax payers should be available to those tax payers free of charge.
Shawn
This is the end of the thread.
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