![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 7 of 7. This is the beginning of the thread.
Posted by jrbecker on July 12, 2004, at 10:32:27
McMan's Depression and Bipolar Weekly
July 11, 2004 Vol 6 No 17Welcome
Lead Story: Researchers are taking a new approach to hunting for genetic and biological markers for mood, with enormous implications for diagnosis and treatment.Also in this issue: Summer of the endophenotype (the thalamus, GABA, suicidal brains, REM sleep), Important reader notice, Neonatal complications and ADs, Abilify in Europe, TMAP, When meds turn on you, Attitudes changing, Kids warehoused, More cuts, More on AD suicide controversy, Are depression and BP part of the same spectrum?, Drug industry paranoia, Free meds, The law no one heard of, Depressed in action, A patient’s eloquent testimony, McMan's Web, Donations.
Endo de Phenotype
Hussein Manji MD is no stranger to this Newsletter. In an article in this month’s "Neuropsychopharmacology," Dr Manji and his co-authors at the NIMH elaborate on what they’ve been up to lately - something to do with "endophenotypes" in depression.
What does this mean? In psychiatry, we identify "phenotype" according the group of symptoms one finds listed in the DSM-IV. But trying to match genes to mood can be as thankless as finding the perfect husband for JLo, say the authors in so many words. Accordingly, researchers are beginning to look to the underlying biology of endophenotype, such as sensitivity to stress and disrupted sleep. From there, investigators can work upstream one way to the culprit genes and downstream the other way to the resulting mood episode. Then it’s a matter of prospecting for new treatments.
There is likely no one-to-one association or simple cause and effect, say the authors. Instead, we have a sort of chaos theory turned loose inside the brain. Mutations in the serotonin transporter gene and the NMDA receptor gene, for example, may result in a decrease in amygdala volume and/or an increase in amygdala activity, associated with fear. This, combined with stress, may either lead to impaired learning and memory, which in turn triggers major depression, or may travel a different path to the same end via an inclination toward negative moods. In the meantime, stress is the proverbial bull in the china shop, this time beginning with genetic misprints in proteins responsible for cell maintenance - including BDNF, MR, CREB, and bcl-2 - that results in a trail of brain cell damage in the hippocampus, involved in emotional response. A shorted out hippocampus, in turn, combines with stress to feed into the chemical storm sweeping in from the amygdala. On and on it goes.
Some endophenotypes already appear as part of the DSM phenotype, such as disruptions in appetite and sleep. The authors identify 10 specifically biological ones, involving regional brain anomalies, neurotransmitter depletion, hormone dysregulation, and REM sleep abnormalities. A look at our old friend serotonin illustrates endophenotype in action:
To find out what goes on in the brains of individuals with low serotonin, study subjects are given an amino acid mixture that depletes tryptophan in the brain, which in turn leads to the reduction of serotonin. This usually results in major depression, but that’s not all. Recent studies have found that in vulnerable individuals, low serotonin induces mood-related memory bias, alters reward-related behaviors, impairs memory consolidation, slows responses to positive stimuli, and disrupts inhibitory affective processing. Biologically, severe serotonin depletion leads to enhanced norepinephrine transporter messenger RNA levels and reduced serotonin transporter messenger RNA levels, increased number of MR binding sites, and altered BDNF gene expression in the dentate gyrus. Genetically, a long variation of the serotonin transporter gene has predicted depressive response to tryptophan depletion.
You get the picture.
New gene array and neuro-imaging technologies are making endophenotype research possible, in concert with experiments on genetically-engineered mice and post-mortem brain studies. In the meantime, large population studies on the scale of the Framingham heart study are badly needed, say the authors.
Over at the NIMH, endophenotype is a major consideration in mapping out new research for both depression and bipolar. One of the article’s authors includes Dennis Charney MD, Chief of the Mood and Anxiety Disorders Research Program there. He and his co-authors wrap up their article by concluding: "We propose to dissect the behavioral phenotype into key components, and integrate specific environmental risk factors and neurobiological endophenotypes into the new classification system."
Depression and bipolar will never be the same.
MoreFor how endophenotype fits into the NIMH research agenda, check out the NIMH 2003 Strategic Plan for Mood Disorders Research.
The Summer of the Endophenotype
July is unofficial endophenotype month, if the latest psychiatric journals are anything to go by. Some studies:
A University of Texas Southwestern Medical Center at Dallas study of post mortem brains revealed higher neuron numbers in the thalamus of subjects with major depression compared to those with schizophrenia, bipolar, and healthy brains.
According to a McLean Hospital study: "The density of GABA interneurons that express the NMDA NR2A subunit appears to be decreased in schizophrenia and bipolar disorder." (Took the words right out of my mouth.)
Speaking of GABA, a Yale study of the brain scans of 33 patients with major depression found decreased GABA concentrations and increased glutamate in the occipital cortex compared to the control subjects, particularly with patients exhibiting melancholic (insomnia, loss of appetite, loss of pleasure) and psychotic features. The study replicates an earlier smaller study.
A University of Illinois/Maryland Psychiatric Research Center postmortem study of 17 brains of teens who had committed suicide found significant decreases in PKC activity in regions of the prefrontal cortex and hippocampus compared to the controls.
A University of Pittsburgh study of PET scans and EEGs of 24 unmediated patients with major depression has found that "increased anterior paralimbic activation from waking to REM sleep may be related to affective dysregulation in depressed patients" compared to the controls.
Important Subscriber NoticeI am urging readers to confirm their subscriptions by clicking on the "Confirm" link at the bottom of this Newsletter. Simply hit confirm and you will be taken to a confirm page. To protect your privacy, please leave all the fields blank save the one with your email address. Some ISPs such as Earthlink now bounce unconfirmed emails sent in bulk. I will not cut you off if you don’t confirm, but I have no control over your ISP. So if you have not already confirmed, I strongly urge you go to the bottom of this Newsletter and hit the confirm link. Sorry for the inconvenience. The Gods of the internet are funny that way.
Neonatal Complications and Antidepressants
This very curious notice on the FDA website, related to labeling changes on Effexor:
"Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester of pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery."
No data was supplied shedding light on the whether these complications were severe or whether a large population was affected. Nor did the FDA indicate why only Effexor’s manufacturer Wyeth made the labeling changes when the notice mentioned SSRIs, as well.
Wyeth's revised labeling now reads:
"Neonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. ... The physician may consider tapering Effexor XR in the third trimester."
A 1996 University of California, San Diego study on 482 mothers found, "women who take [Prozac] during pregnancy do not have an increased risk of spontaneous pregnancy loss or major fetal anomalies, but women who take [Prozac] in the third trimester are at increased risk for perinatal complications." A 2004 UCLA study on 62 mothers, on the other hand, found, "in contrast to other studies, our study did not demonstrate an adverse effect of [Prozac] exposure per se on obstetrical outcome."
Abilify Now Available in Europe
Abilify (aripiprazole) has just become available in Europe to treat schizophrenia. The drug, touted as "the first next-generation atypical antipsychotic," was approved in the US to treat schizophrenia in late 2002, and is being used off-label to treat mania. Bristol-Myers-Squibb has applied to the FDA for a mania indication.
TMAP > TAU
Last week’s Newsletter reported on the Texas Medication Algorithm Project (TMAP) and the claims by a whistle blower that the drug companies are using its depression, bipolar, and schizophrenia treatment algorithms as Trojan Horses to promote their own expensive brand name drugs (with individual states picking up the tab) over the cheaper generics. This week - by pure coincidence - TMAP published a study of 350 patients with major depression that found those who were treated according to the algorithm fared significantly better over 12 months than the treatment as usual patients.
When Meds Turn On You
A Liverpool University survey of 18,820 hospital admissions involving patients aged 16 and over during six months has found 6.5 percent were related to adverse drug reactions (ADR). Aspirin was the largest cause, responsible for 18 percent of these admissions. Seventy-four percent of these patients were taking low dose aspirin (75 mg), with GI bleeding the most common adverse effect. Antidepressants and lithium accounted for 7.1 percent of ADR-related admissions.
A Ray of Hope
Are attitudes beginning to change? The Houston Chronicle reports on a Rice University survey of 650 Houston area residents that found 63 percent believed mental illness is primarily due to brain disorders, with only five percent attributing mental illness to weak character. This compares to a 1996 National Mental Health Association survey that found 71 percent of Americans thought mental illness stemmed from emotional weakness and more than a third from sinful or amoral behavior.
But Not Yet Out of the Middle Ages
The AP reports that thousands of mentally ill youths are unnecessarily warehoused in juvenile detention centers while awaiting treatment, according to a US congressional subcommittee report. In 33 states, mentally ill youths were being held with no charges against them, averaging 23.4 days in detention compared to 17.2 days for all detainees. Seventeen facilities were holding kids aged 10 years and younger.
Curb Service
The LA Business Journal reports that at least seven Los Angeles area hospitals have either closed or downgraded their psychiatric units, resulting in 176 beds lost or downgraded.
Bipolar Kids
Should a psychiatrist give more weight to what children have to say about their own symptoms or to what the parents report? A Washington University (St Louis) study of 93 bipolar kids and 93 parents found concordance between parent and kid reports was poor to fair for all mania symptoms, and that the symptoms endorsed by the kids best differentiated mania from ADHD (ie elation, grandiosity, flight of ideas, racing thoughts, decreased need for sleep).
The Story That Won’t Go Away
More on the antidepressant suicide controversy, this time from an epidemiologist and a medical statistician (David Gunnell and Deborah Ashley of the University of Bristol and University of London, respectively), appearing in the British Medical Journal:
The authors contend that direct evidence that antidepressants prevent suicide is hard to come by. Eli Lilly data for Prozac failed to demonstrate a clear effect and a Khan et al meta-analysis found no benefit. The reason clinical trials fail to provide an answer, say the authors, is that suicide is a rare event, even in people with depression, so that much larger numbers are needed in studies to tease out meaningful data. Another reason is that the type of studies most likely to show a benefit would be long-term, which are virtually nonexistent. Finally, suicidal risk was not seriously investigated in these trials.
Various sources have cited population data (involving large numbers) to support the argument that a dramatic decline in youth suicides has corresponded to the widespread introduction of SSRIs. The authors, however, point out this correspondence is not exactly air-tight, and suggest some confounding variables. These include SSRIs being reasonably safe to take in overdose vs the potentially lethal older generation tricyclics, which would have prevented suicides independent of any clinical benefit, and a reduction of carbon monoxide in exhaust gases.
The authors stress that there is no clear evidence one way or the other regarding safety, and call for more detailed drug trials of long duration.
Depression and Bipolar - One Illness?
In a lead story, Newsletter 6#12 reported on the investigations of Ellen Frank PhD of the University of Pittsburgh into co-occurring bipolar and anxiety, and how she urged clinicians to think beyond the DSM-IV symptom list. This time, in an article in the American Journal of Psychiatry, Dr Frank and her co-authors make a strong case that bipolar and depression may be part of the same spectrum rather than discrete illnesses.
The argument is hardly a new one, the authors acknowledge. Hagop Akiskal MD of the University of California, San Diego, for example, has pointed out that many patients with so-called unipolar depression exhibit certain hypomanic symptoms. Though these symptoms may not add up to an actual episode, Dr Akiskal maintains they constitute sufficient evidence of bipolarity, and accordingly has urged that this population be diagnosed accordingly. The article’s authors go one step further by proposing there is a strong relationship between hypomanic or manic symptoms and the number and severity of depressive episodes.
To test this proposition, 117 adult patients with recurrent unipolar depression with no history of hypomanic episodes, and 106 patients with bipolar I were drawn from a larger Italian study group and administered a 140-item interview. Predictably the bipolar I patients had a lot more lifetime manic/hypomanic symptoms than the unipolar group. Nevertheless, there were 12 items associated with hypomania (from high mood to irritability) that were each present in at least 40 percent of the depressed patients. Patients with a higher number of lifetime manic/hypomanic symptoms had a higher number of lifetime depressed symptoms (and vice-versa), a finding that held for both the bipolar and unipolar patients.
Then the investigators zeroed in on indicators of paranoid and suicidal ideation. What they found was that in the group with unipolar depression, each manic/hypomanic item increased the likelihood of suicidal ideation by 4.2 percent. For 10 items, this would equate to a 42 percent increased risk. Also, earlier first onset depression correlated with a higher number of manic/hypomanic symptoms. In bipolar I patients the number of manic/hypomanic items was also related to paranoid and suicidal ideation, but not to number of lifetime episodes.
The authors contend that their findings "support a continuous view of the mood spectrum as a unitary phenomenon" and that clinical attention needs to be paid to manic/hypomanic manifestations that occur in recurrent unipolar depression.
A Bit of a Stretch
Time Magazine reports that at a conference of pharmaceutical industry executives, a PowerPoint presentation showed the drug industry as a kitten cowering before a phalanx of federal regulators, portrayed as German shepherds ready to pounce.
Free or Low Cost Meds
I have it on my Website, but a reader suggested I mention it here. One of the best-kept secrets in the pharmaceutical industry is their patient assistance programs. You do not necessarily have to be indigent to qualify (but Medicaid recipients may be ineligible). Patients and their doctors fill out paperwork supplied by the drug companies. The meds are then sent to the doctor for the patient to pick up. For more information, visit the PhRMA website at http://www.helpingpatients.org/index.cfm or the search the websites of the individual manufacturers.
The Law No One Heard Of
The tree falling in the forest conundrum. The Washington Post reports that there is a 1997 law that requires pharmaceutical companies to disclose the existence of clinical trials to a government database, but not even journal editors and professional medical associations are aware of it. The FDA acknowledges it has not enforced the law. Its database, ClinicalTrials.gov lists 5,754 ongoing studies, only 13 percent industry-sponsored, but according to JAMA editor Catherine DeAngelis MD, the true picture is more than 80 percent of trials are funded by for-profit companies.
Walking Wounded
A US Army survey has found that 15.6 to 17.1 percent of combat Army soldiers and Marines returning from duty in Iraq met the criteria for major depression, generalized anxiety, or PTSD vs 11.2 percent returning from Afghanistan.
A Study in Eloquence
Newsletter 6#15 reported on an FDA panel green-lighting a surgical implant, VNS, for treating treatment resistant depression. Despite a rather underwhelming 30 percent response rate, the FDA panel was influenced to make a positive decision by both the quality of the manufacturer’s submission and the testimony of some of the VNS study subjects. One of them was one of my readers, who identified herself as Patient 012 from Site 050, who testified before the FDA on her own volition and at her own expense. Her remarks are well worth quoting at length:
"My case (and testimony) may be of particular interest to this panel because: I went into the study on no medications; remained off medications throughout the study; and, am still on no medications. There is no other explanation for my response other than the device, itself. It is good science. Turn the device up, I respond. Turn the device down, I decline. ...
"I realize that most on this panel and most in attendance are experts in their field ... but there is one thing I can offer you about which you know nothing: and that is first-hand knowledge of what it is like to have severe, recalcitrant depression.
"And to do so, I ask you to imagine the unimaginable. To think the unthinkable. To experience second-degree emotional burns with third-degree prognosis. All you experience is pain, but with no cure. In fact, there is no viable treatment. You can attempt to salve it. Only death solves it.
"But the medical community does not accept death as a cure. It asks us to continue to hang on and to continue to live, yet offers us no viable treatments. Trust me, it’s not that we don’t want to live. It’s that we don’t want to live ‘like this.’ Our illness is embedded in our physical bodies, our cells, we are prisoners there and our sentence is life.
"Menacing insomnia; isolation; fear; anxiety; sadness; hopelessness; general malaise; malingering fatigue; physical exhaustion; apathy; lack of motivation, concentration, and focus; absence of pleasure; amplification of pain; agitation; sensitivity to criticism; thoughts that life isn’t worth living. You are familiar with this short-sheeted laundry list of symptoms. Now imagine having them all at once. Imagine passing from one room to another in the House of Pain where some symptoms are more prevalent than others, sometimes exacerbated by the very medications that were meant to alleviate them.
"I will not bore you with the details of the pharmacopoeia that I have tried and that have failed, not to mention the acupuncture; homeopathy; herbal remedies; extreme dietary changes and supplements; light therapy; counseling; yoga, and of course religion. What God would let a child suffer like this?
"And then comes the inevitable: electroconvulsive therapy. ECT. A therapy so beyond the vernacular, that it doesn’t even pass an automated spell check. I’d stop at the word, too. But as a person with treatment-resistant depression, I could not stop. I relented to this FDA-approved treatment as a last resort. Average session: 3-5 treatments: I had 33 nearly consecutive treatments. I lost, retrograde, 20 years of my life through memory loss: a dismal blessing. At least I could not remember the horrific pain that preceded it for years. ...
"I am not going to idealize nor sentimentalize the device. I know I am one of the third who have responded to it. I know there are others who continue to suffer the burden of treatment-resistant depression. I see it in their faces as I sit in the lobby and wait my turn at my site. I know that pain. I suffered it prior to the VNS. Still, I have windows of it now and again.
"I am passionate - yet realistic - about the device. I do not romanticize its results for me nor dismiss its lack-of-results for others. I am well aware of its side effects, shortcomings, and current experimental status. But, I do know one thing: we need viable treatment options for those with recalcitrant depression, and the VNS has worked for me."
McMan's Web
Check out more than 250 articles on all aspects of depression and bipolar, plus a bookstore, readers' forum, message boards, and other features at:
http://www.mcmanweb.comConsolidated: Several articles on food, dieting, and nutrition. See You Are What You Eat and follow the links on the left side of the page to the next articles.
Oldie but goodie: Virginia Woolf and Her Madness
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"Knowledge is necessity."Copyright 2004 John McManamy
Posted by SLS on July 12, 2004, at 13:12:53
In reply to McMan's Depression/Bipolar Weekly: Genetics, posted by jrbecker on July 12, 2004, at 10:32:27
I was not happy to read this. It leaves me with the feeling that my brain is damaged beyond repair. It probably is. I don't know what to do. I am trapped.
- Scott
> There is likely no one-to-one association or simple cause and effect, say the authors. Instead, we have a sort of chaos theory turned loose inside the brain. Mutations in the serotonin transporter gene and the NMDA receptor gene, for example, may result in a decrease in amygdala volume and/or an increase in amygdala activity, associated with fear. This, combined with stress, may either lead to impaired learning and memory, which in turn triggers major depression, or may travel a different path to the same end via an inclination toward negative moods. In the meantime, stress is the proverbial bull in the china shop, this time beginning with genetic misprints in proteins responsible for cell maintenance - including BDNF, MR, CREB, and bcl-2 - that results in a trail of brain cell damage in the hippocampus, involved in emotional response. A shorted out hippocampus, in turn, combines with stress to feed into the chemical storm sweeping in from the amygdala. On and on it goes
Posted by jrbecker on July 12, 2004, at 14:12:59
In reply to Re: McMan's Depression/Bipolar Weekly: Genetics, posted by SLS on July 12, 2004, at 13:12:53
Oh come on Scott. We know you better than that than to not stay optimistic.
Think of this knowledge as positive rather than pessimistic. They're learning so much right now. We're on the threshold of something big here. Psychiatry will be making leaps and bounds in these formative years. And they will translate to truly innovative treatments. I know that's not the solution you want for the here and now, but consider it hope.
By the way, some of this new research is being put into practice in early drug treatments (e.g., PDE4 inhibitors, CRF1 inhibitors, triple reuptake inhibitors, mitochondrial enhancers, glucocorticoid modulators, and much more in pre-clinical research). http://www.neurotransmitter.net/newdrugs.html
For more on what McMan was talking about, see...http://www.nature.com/cgi-taf/DynaPage.taf?file=/npp/journal/vaop/ncurrent/full/1300506a.html
keep hope.JB
> I was not happy to read this. It leaves me with the feeling that my brain is damaged beyond repair. It probably is. I don't know what to do. I am trapped.
>
>
> - Scott
>
>
> > There is likely no one-to-one association or simple cause and effect, say the authors. Instead, we have a sort of chaos theory turned loose inside the brain. Mutations in the serotonin transporter gene and the NMDA receptor gene, for example, may result in a decrease in amygdala volume and/or an increase in amygdala activity, associated with fear. This, combined with stress, may either lead to impaired learning and memory, which in turn triggers major depression, or may travel a different path to the same end via an inclination toward negative moods. In the meantime, stress is the proverbial bull in the china shop, this time beginning with genetic misprints in proteins responsible for cell maintenance - including BDNF, MR, CREB, and bcl-2 - that results in a trail of brain cell damage in the hippocampus, involved in emotional response. A shorted out hippocampus, in turn, combines with stress to feed into the chemical storm sweeping in from the amygdala. On and on it goes
Posted by jrbecker on July 12, 2004, at 20:12:35
In reply to Re: McMan's Depression/Bipolar Weekly: Genetics, posted by jrbecker on July 12, 2004, at 14:12:59
whoops, I guess the link doesn't allow you all access to the Neuropsychopharmacology article, so I pasted it below...
Neuropsychopharmacology advance online publication 23 June 2004;
doi:10.1038/sj.npp.1300506Discovering Endophenotypes for Major Depression
Gregor Hasler, Wayne C Drevets, Husseini K Manji and Dennis S Charney
Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, USACorrespondence: Dr G Hasler, Mood and Anxiety Disorders Program, National Institutes of Health, National Institute of Mental Health, 15K North Drive, Room 300C, MSC 2670, Bethesda, MD 20892-2670, USA. Tel: +1 301 594 0234; Fax: +1 301 402 6353; E-mail: g.hasler@bluewin.ch
Received: 16 January 2004
Revised: 13 April 2004
Accepted: 10 May 2004
ABSTRACT
The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.Keywords: depression; phenotype; genetics; classification; biological psychiatry; epidemiology
INTRODUCTION
Scientific advances suggest that the time is at hand to begin to elucidate the genetic basis of mood disorders: (1) detection of genes for brain diseases such as Huntington's disease and Alzheimer's disease; (2) dramatic developments in molecular genetics including the human genome project and increasing availability of genetic markers throughout the genome; and (3) consistent evidence from twin and family studies that genes are substantially involved in the susceptibility to mood disorders. However, despite costly candidate gene association studies and genome-wide linkage scans, no genes for major depression have been consistently identified. Fortunately, in certain families, there is preliminary evidence that recurrent, early-onset major depression is linked to a region containing the CREB1 gene. This gene constitutes an attractive candidate as a susceptibility allele for major depression because CREB1 plays major roles in neuronal plasticity, cognition, and memory (Zubenko et al, 2002).The limited success of genetic studies of complex disorders has resulted in a considerable debate regarding the reasons for the failure in the past, and the best methodological approach to take in the future. Questions have been raised concerning both the definition of genetically relevant phenotypes and the number and nature of the underlying genes.
The use of the current classification schemas including DSM-IV undoubtedly contributes to the difficulties in finding genes for psychiatric disorders. They are based on clusters of symptoms and characteristics of clinical course that do not necessarily describe homogenous disorders, and rather reflect common final pathways of different pathophysiological processes (Charney et al, 2002). Moreover, it has been argued that a continuum of depressive symptoms exists from normal to pathological, and that clinical symptomatology does not point to a simple categorical classification (Angst and Dobler-Mikola, 1984; Angst and Merikangas, 2001). Finally, mood and anxiety disorders as defined by the DSM show high comorbidity and substantial symptomatic fluidity with frequent changes of diagnostic subtypes over time (Angst and Dobler-Mikola, 1985; Angst et al, 1990; 2000; Merikangas et al, 2003).
Moreover, genes and behaviors may not be associated on a simplistic, one-to-one basis; the true relationship between a gene and a behavior is probably more akin to chaos theory's 'sensitive dependence on initial conditions'. For example, there is presumably no gene for 'language'; there are a number of genes that pattern the embryonic brain in such a way as to facilitate, and allow the physiological processes necessary for, language acquisition. In a similar manner, no gene has been found to singularly code for a human psychiatric condition. Indeed, it is unlikely that any single gene does code for a psychiatric condition per se, but rather that susceptibility genes interacting with developmental factors, both day-to-day and profound environmental events, epigenetic DNA modifications, and possible entirely stochastic mechanisms eventually lead to the development of normal and abnormal human behaviors (Petronis, 2001; Glazier et al, 2002).
In this paper, we will present strategies to overcome the methodological difficulties mentioned above with respect to the elucidation of the genetic basis of major depressive disorder (MDD) by proposing putative endophenotypes. The term 'endophenotype' was described as an internal phenotype (ie not obvious to the unaided eye) that fills the gap between available descriptors and between the gene and the elusive disease process (Gottesman and Shields, 1973), and therefore may help to resolve questions about etiological models. The endophenotype concept was based on the assumption that the number of genes involved in the variations of endophenotypes representing relatively straightforward and putatively more elementary phenomena (as opposed to behavioral macros) are fewer than those involved in producing a psychiatric diagnostic entity (Gottesman and Gould, 2003). Endophenotypes provide a means for identifying the 'downstream' traits of clinical phenotypes, as well as the 'upstream' consequence of genes. The methods available to identify endophenotypes include neuropsychological, cognitive, neurophysiological, neuroanatomical, and biochemical measures (Figures 1 and 2). The evaluation of endophenotypes is based on the following criteria (Tsuang et al, 1993):
Figure 1
Example of how neuroanatomical abnormalities may relate to candidate genes and to key components of major depression. Some of the key components have a greater potential to serve as endophenotypes than others (see Table 1). Not all functional directions are indicated for the purpose of clarity of the figure.
Figure 2
Example of how neurochemical abnormalities may relate to candidate genes and to key components of major depression. Some of the key components have a greater potential to serve as endophenotypes than others (see Table 1). Not all functional directions are indicated for the purpose of clarity of the figure.
Specificity: The endophenotype is more strongly associated with the disease of interest than with other psychiatric conditions.State-independence: The endophenotype is stable over time and not an epiphenomenon of the illness or its treatment.
Heritability: Variance in the endophenotype is associated with genetic variance.
Familial association: The endophenotype is more prevalent among the relatives of ill probands compared with an appropriate control group.
Cosegregation: The endophenotype is more prevalent among the ill relatives of ill probands compared with the well relatives of the ill probands.
Biological and clinical plausibility: The endophenotype bears some conceptual relationship to the disease.
We will present and discuss endophenotypes at two levels: First, we will dissect the DSM-IV phenotype into narrow psychopathological characteristics that are biologically and clinically meaningful and can be assessed quantitatively. We will refer to these core psychopathological features of major depression as key components; we will refer to those key components that meet some of the endophenotype criteria as psychopathological endophenotypes. Second, we present biological markers that are useful for genetic studies. We will refer to biological markers that meet some of the endophenotype criteria as biological endophenotypes. All endophenotypes presented in this paper have to be seen as putative endophenotypes because whether or not they consistently meet all required endophenotype criteria has not been determined yet. We will review the literature and indicate the strength and limitations of psychopathological and biological endophenotypes in MDD with a special emphasis on studies associating endophenotypes with genes. Finally, we present future directions for the elucidation of the genetic basis of MDD.
KEY COMPONENTS OF MAJOR DEPRESSION
The validity of symptoms and components of MDD has been difficult to achieve because the MDD criteria likely encompass a group of disorders that are heterogeneous with respect to etiology and pathophysiology. Based on factor and cluster analytic studies, Nelson and Charney (1981) found that mood bias toward negative emotions, anhedonia, and psychomotor symptoms best characterize MDD. However, the diagnostic criteria for a disorder based on clinical characteristics without knowledge of the underlying etiological processes cannot be validated adequately. The use of more indirect indicators of disease validity or validity of depressive subtypes such as family history, treatment response, longitudinal course and stability, patterns of comorbidity, and social consequences led to circularity in validating the criteria (Kendell, 1989). Not surprisingly, studies on the biological basis of depression have found stronger associations between specific biological dysfunctions and certain components of major depression than with the presence or absence of DSM-IV MDD: symptoms such as cognitive deficits, rumination, psychomotor retardation, anhedonia, and lowered mood have been associated with specific focal abnormalities of regional cerebral blood flow (CBF; Mayberg et al, 1999; Drevets, 2000). Moreover, components of major depression such as altered response to stress (Caspi et al, 2003), impaired cognitive abilities, and dysfunctional reward-related behaviors are easier to model in animals than the depressive syndrome itself (Redei et al, 2001). Finally, intermediate levels of recurrence of depressive episodes have been associated with high genetic liability of MDD (Kendler et al, 1999), while a high temporal stability of the phenotype is favorable for genetic studies. The ensuing discussion dissects MDD into its key components based on biological validity, availability of accurate and quantitative assessment methods, and clinical relevance.Depressed Mood (Mood Bias Toward Negative Emotions)
Depressed mood is a core symptom of MDD (Nelson and Charney, 1981). Attentional and mnemonic biases toward processing of mood-congruent information including sad, unpleasant and negative words, emotional facial expressions, and memories also are reliable and relatively specific neuropsychological findings of MDD (Watkins et al, 1996; Murphy et al, 1999), and have been found in remitted depressed subjects suggesting some state-independence (Hammen et al, 1985; Koschack et al, 2003). Experimental depletion of central serotonin led to the emergence of mood-congruent memory bias (Klaassen et al, 2002), and physiological activation of the brain regions that have been found to be involved in mood-congruent information processing (Elliott et al, 2002) is thought to play a key role in MDD (Drevets et al, 1997), thus implicating good biological validity. Attentional and mnemonic biases in depression have high clinical relevance because they are related to cognitive-behavioral theories of depression, upon which treatment strategies have been based (Beck, 1967). However, there is only preliminary data on the heritability of mood bias: recurrent thoughts of death and suicide appeared to be a specific characteristic of familial MDD (Kendler et al, 1999).
Anhedonia (Impaired Reward Function)
Loss of interest, lack of reactivity, and anhedonia also constitute core features of major depression (Nelson and Charney, 1981), and these symptoms represent key diagnostic criteria for the DSM-IV melancholic subtype of major depression. Anhedonia seems to be a relatively specific feature of depression (Fawcett et al, 1983), and even in patients with schizophrenia, anhedonia has been related to the depressive syndrome rather than to the deficit syndrome (Loas et al, 1999). Associations between dysfunctions of the brain reward system and anhedonia are the basis of the biological plausibility of anhedonia-related endophenotypes. Specifically, neurotrophic factors including cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) and the transcription factor delta-FosB may represent molecular mechanisms involved in long-term alterations of the brain reward system (Nestler et al, 2001; 2002). Enhanced rewarding effects of dextroamphetamine found in patients with MDD may represent hypofunction of the dopaminergic system associated with anhedonia (Tremblay et al, 2002). Preliminary evidence for the potential heritability of these findings includes a functional polymorphism of the catechol-O-methyltransferase (COMT) gene that has been associated with the individual variation in the brain response to dopaminergic challenge (Mattay et al, 2003).
Epidemiological research provides clues for state-independence, heritability, and familial association of dysfunctions of the brain reward system as endophenotype for MDD. For example, anhedonia symptoms often precede the onset of MDD (Dryman and Eaton, 1991) and seem to be relatively stable over time (Oquendo et al, 2004). A sib-pair study showed that the personality construct 'reward dependence' has trait-like characteristics related to the familiality of major depression (Farmer et al, 2003). Given the extensive evidence for associations between impairments of brain reward pathways and addiction (Nestler et al, 2002), familial coaggregation and lifetime comorbidity of substance use disorders and MDD (Kendler et al, 1997; Brook et al, 2002) also suggest persistent familial abnormalities of brain reward pathways in MDD.
Impaired Learning and Memory
Diminished ability to attend or concentrate is a diagnostic criterion of DSM-IV major depressive episode, which reflects cognitive impairments including learning and long-term memory, and deficits in working memory (short-term memory) and selective attention (Burt et al, 1995; Landro et al, 2001). These impairments are not specific for depression, although the pathophysiological mechanisms underlying these features of depression may differ from those in other psychiatric disorders (Berman et al, 1993; Barch et al, 2003). Specifically, abnormal reduction of CBF and metabolism in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex (ACC) might explain diminished ability to attend and concentrate in MDD (Drevets and Raichle, 1998), thus providing some evidence for the biological plausibility of this putative endophenotype for MDD.
Impaired concentration and attention were found to be frequent and early prodromal signs of depression (Dryman and Eaton, 1991; Hagerty et al, 1997), and recovered patients sometimes continue to show memory impairment (Roiser et al, 2003). However, at the symptom level, these deficits have been found to be relatively unstable over the course of depressive illness (Oquendo et al, 2004). Some authors suggest that working memory deficits in depression are due to persistent deficits in selective attention (state-independence) assessed by the Stroop paradigm that have been related to persistent abnormalities in the prefrontal cortex (Trichard et al, 1995; Blumberg et al, 2003). In contrast, deficits in long-term storage and retrieval of declarative memory have been associated with number of depressive episodes, stress, hypercortisolemia, and hippocampal volume reduction found in major depression (MacQueen et al, 2002; 2003), thus suggesting that these memory symptoms are rather a consequence than an etiologic factor of depression.
There is a wealth of knowledge on the genetics of working memory in mice providing converging evidence that glutamate, acetylcholine and dopamine receptors, calcium/calmodulin kinase II and protein kinase C gene families play roles in short-term information processing (Luciano et al, 2003). In healthy humans and schizophrenic patients, a functional polymorphism of the COMT gene appeared to explain some of the individual variance in working memory performance (Egan et al, 2001; Malhotra et al, 2002). However, there is a lack of information on the heritability, familial association, and cosegregation of learning and memory symptoms related to MDD.
Neurovegetative Signs
Although appetite and weight change are not specific symptoms of major depression (Nelson and Charney, 1981), there is some evidence that the direction of appetite and weight change may be useful as a marker of depressive subtypes. The direction and extent of weight change was found to be consistent across episodes of MDD (Stunkard et al, 1990) suggesting some state-independence, although a recent study did not show any correlation between Hamilton depression scale appetite measures across episodes (Oquendo et al, 2004). Evidence for heritability and familial association comes from studies in identical twins showing that melancholic and atypical depressive subtypes independently aggregate in families and are at least in part genetically determined, and that these subtypes are most clearly distinguished by a different pattern of appetite and weight change (Kendler et al, 1996). Finally, appetite-associated endophenotypes for depression seem to be biologically plausible given that brain monoamines and peptides that play major roles in major depression, such as serotonin, norepinephrine, dopamine, neuropeptide Y, and corticotropin-releasing hormone, also play important roles in the regulation of food intake and body weight (Gillard et al, 1993; Meguid et al, 2000; Wang et al, 2001).
More than 90% of depressed patients complain about impairments of sleep quality, and insomnia was found to be a prominent risk factor for subsequent development of depression. However, sleep disturbances including morning awakenings are not specific for major depression and co-occur with a wide range of physical and psychological symptoms. In addition, studies comparing subtypes of depression such as unipolar, melancholic, and bipolar depression failed to find consistent differences in nocturnal sleep patterns (Riemann et al, 2001). However, due to the availability of sophisticated examination methods such as polysomnography, sleep pathophysiology may be well suited to discover endophenotypes for major depression (see below).
Diurnal Variation
Some symptoms of MDD may show diurnal variations (mood, psychomotor activity, accessibility of memories of positive and negative experiences), and a subgroup of patients with MDD may have a circadian rhythm disorder (Bunney and Bunney, 2000). In healthy young subjects, moderate changes in the timing of the sleep-wake cycle had specific effects on subsequent mood (Boivin et al, 1997). The association between phase advance of the sleep-wake cycle and phase advances in nocturnal cortisol secretion, and the effect of antidepressants on circadian rhythms of behavior, physiology, and endocrinology contribute to the biological plausibility of this putative endophenotype (Duncan, 1996; Bunney and Bunney, 2000). Because manipulations of the circadian rhythms (light therapy, sleep deprivation, phase advance treatment) can have antidepressant efficacy, circadian abnormalities have been hypothesized to be etiologically associated with major depression.
There is strong evidence for a genetic control of the human circadian clock (Linkowski et al, 1993), and a familial variant of human sleep behavior has been attributed to a mutation in a human clock gene (Toh et al, 2001). The influence of a functional polymorphism within the angiotensin I-converting enzyme (ACE) gene on partial sleep deprivation in patients with MDD is probably mediated by dopaminergic neurotransmission (Baghai et al, 2003). A functional polymorphism within the promoter of the serotonin transporter gene has been related to sleep deprivation's efficacy and suggests an involvement of the central serotonergic system in the regulation of circadian rhythms (Benedetti et al, 1999).
Further epidemiological research is needed to determine state-independence, heritability, and familial aggregation of circadian abnormalities associated with MDD.
Impaired Executive Cognitive Function (Response Speed)
Impairments of executive cognitive function in depressed subjects refer to abnormalities in cognitive behaviors that control and integrate neural activities including selecting strategies, planning, and monitoring performance. These impairments are not specific for MDD and usually recover to normal levels in remission. However, response speed has been found to be unrelated to concurrent depressive symptoms and to remain impaired in fully recovered depressed patients off medication (Roiser et al, 2003) (state-independence). Specifically, inspection time, a measure of speed of information processing that does not require a speeded motor response, has been found to be slower in subjects with unipolar major depression than in age-, sex-, and IQ-matched controls independent of current mood (Tsourtos et al, 2002). The cholinergic basis of inspection time (Nathan and Stough, 2001) paralleling the hypothesis of a cholinergic dysfunction in major depression (Riemann et al, 1994) lends biological plausibility to this putative endophenotype. Twin studies demonstrated heritability for inspection time, sharing a substantial genetic relationship with performance IQ (Luciano et al, 2003).
Psychomotor Change (Retardation, Agitation)
Psychomotor retardation and agitation are included in the DSM-IV diagnostic criteria of major depression and have been shown to reliably differentiate depressed patients from psychiatric and normal comparison groups (Sobin and Sackeim, 1997). Moreover, psychomotor disturbance has been proposed as a marker of an underlying neuropathological process specific for the melancholic depressive subtype (Parker, 2000). The biological and clinical plausibility for this putative endophenotype includes associations between psychomotor disturbances and hypothalamic-pituitary-adrenocortical (HPA) axis dysfunction in depressed subjects (Mitchell et al, 1996), and Parkinsonian movement deficits in melancholic patients (Rogers et al, 2000), consistent with a potential dopaminergic dysfunction related to depression (Nestler et al, 2002). Unfortunately, information on state-independence, heritability, familial association, and cosegregation of specific psychomotor disturbances are lacking.
Increased Stress Sensitivity (Gender Specific)
The heritability of major depression being estimated to range between 31 and 42% emphasizes the relative importance of environmental factors (Sullivan et al, 2000). Given the lack of specificity between stressors and psychopathological outcomes (McMahon et al, 2003), one may hypothesize that gene-stressor interactions account for outcome specificity. Therefore, psychopathological constructs reflecting gene-environment interactions might be among the most specific and most useful endophenotypes for major depression. Caspi et al (2003) have shown in a representative prospective study that 5-HTT genotypes moderate the influence of stressful life events on major depression, thus successfully using a gene-environment interaction as phenotype.
Gender differences have appeared as a specific characteristic of stress sensitivity in humans. Men and women are, in general, equally sensitive to the depressogenic effects of stressful life events, but their responses vary depending upon the nature of the event itself. Men are more likely to have depressive episodes following divorce, separation, and work difficulties, whereas women are more sensitive to events in their proximal social network, such as difficulty getting along with an individual, serious illness, or death (Kendler et al, 2001).
Diathesis-stress theories of depression predict that genes influence individuals' sensitivity to stressful events (Costello et al, 2002), consistent with a potentially important role of gene-by-environment interactions played in the etiology of depressive psychopathology. A diagnostic construct consistent with these theories is the personality concept 'neuroticism' defined as general vulnerability to anxiety and depressive symptoms under stress. Neuroticism was found to be reasonably invariant during adulthood (Costa and McCrae, 1988), although depressive state features may have a considerable impact on neuroticism scores (Griens et al, 2002). There is consistent evidence of gender-specific heritability and familial association and cosegregation for neuroticism as putative endophenotype for MDD: neuroticism has been associated with gender-specific genetic factors, and a high degree of overlap between genes influencing neuroticism and major depression within the genders has been demonstrated (Fanous et al, 2002); the reported heritability of neuroticism is equal or greater than heritability estimates for MDD (Jang et al, 1996); and neuroticism has been successfully used as phenotype for genetic studies (Sen et al, 2003).
The biological plausibility of stress-related endophenotypes for MDD can be derived from biological correlates of increased stress sensitivity including an excessive activation of the HPA axis that is frequently found in patients with MDD (see below). Sex differences in the response of the HPA axis to stress appeared to be important: overall, women showed a greater stress responsiveness than men, consistent with the greater incidence of major depression in women (Young, 1998); moreover, men showed greater cortisol responses to achievement challenges, whereas women showed greater cortisol responses to social rejection challenges (Stroud et al, 2002).
Although the concept of gene-environment interactions may be most closely related to the concept of major depression, psychometric difficulties, and the complexity and temporal structure of its underlying molecular mechanism complicate its practical use. It is particularly noteworthy that recent studies have demonstrated nongenomic transmission across generations of not only maternal behavior but also stress responses (Francis and Meaney, 1999). This has clear parallels in clinical population. For example, environmental events (for example, early childhood stressors) correlate with the development of psychiatric disorders in adults (Heim and Nemeroff, 2001). Indeed, as witnessed by multiple studies of discordant monozygotic twins where one has the disorder and the other does not, epigenetic mechanisms must be operative to control behavior in genetically identical populations (Petronis et al, 2003). A critical question involves the mechanism by which early life events regulate long-term changes in behavior and sustained differences in gene expression.
In most areas of the brain, neurons are not replaced; thus, permanent and semipermanent modifications that occur in early life, which alter gene transcription, could have downstream effects that may be temporally distant from the initial event. These nongenetic (epigenetic) mechanisms of gene regulation likely play a role in the formation of cellular memory and the modulation of neural circuitry in a manner that alters lifetime cellular and behavioral responses in an organism. The true extent of the dynamic mechanisms responsible is unknown and is an active area of research. However, it is known to involve the interplay of transcription factors interacting with covalent DNA modifications, such as cytosine methylation, and the accessibility of DNA that is regulated by histone acetylation (Petronis, 2001; Geiman and Robertson, 2002). These mechanisms are likely involved in modulating how previous experience may regulate subsequent behavioral responses.
BIOLOGICAL ENDOPHENOTYPES
The number of genes involved in a phenotype is thought to be associated with both the complexity of the phenotype and the difficulty of the genetic analysis (Gottesman and Gould, 2003). Assuming a large number of genes involved in the pathogenesis of major depression, and assuming that disease progression and medication may alter the clinical phenotype, defining endophenotypes for depression by narrow psychopathological definitions such as circadian abnormalities and direction of vegetative symptoms, by personality constructs such as neuroticism and reward dependence, or by neuropsychological tests including inspection time and the Stroop paradigm may still require relatively large samples to detect the effect of a single genetic polymorphism. One emerging strategy that may circumvent some of these difficulties is the use of quantitative biological markers, which are associated with disease and may be closer to single gene effects than clinical phenotypes (Almasy and Blangero, 2001). The ideal biological endophenotype would be a biological marker that is easy to assess and that reflect the action of a single gene.The use of biological endophenotypes has been successful in locating genes for nonpsychiatric disorders. For example, some of the multiple genes involved in cardiac arrhythmias were identified using an ECG endophenotype. Initially, a prolonged QT interval on the electrocardiogram was found in some patients with familial cardiac arrhythmia. Subsequent discovery of an increased prevalence of a prolonged QT interval among healthy relatives of arrhythmic patients than among unrelated controls suggested heritability of this ECG trait in these families. Finally, using QT interval elongation as endophenotype allowed for successful genetic linkage studies (Keating et al, 1991; Keating and Sanguinetti, 2001).
In the following, we will present biological correlates for major depression that meet some of the endophenotype criteria.
REM Sleep
Reduced REM latency, higher REM density, and more REM sleep in adolescents turned out to be specific and predictive for unipolar major depression, whereas none of these signs were found in adolescents who later switched to bipolar disorder and in those who remained free from psychopathology at follow-up (Rao et al, 2002). Early changes of REM sleep parameters, especially REM latency and percentage amount of REM during the sleep period, have been found in patients with acute and remitted major depression (Giles et al, 1993) (state-independence). The first-degree relatives of unipolar depressed patients showed a significantly higher REM density than controls, suggesting that genetic factors contribute to these REM sleep alterations (Giles et al, 1998; Modell et al, 2003). Nearly all effective antidepressant medications have shown a pronounced inhibition of REM sleep (Murck et al, 2003), and the serotonergic and cholinergic neurotransmitter systems have been implicated in both REM sleep regulation and MDD, thus providing evidence for the clinical and biological plausibility of this putative endophenotype.
Several candidate genes may be considered for REM sleep-related endophenotypes. The CREB gene has been implicated in the regulation of REM sleep (Graves et al, 2003), memory consolidation, and major depression (Zubenko et al, 2002). The effect of the muscarinic cholinergic 2 receptor gene that has been implicated in MDD in women (Comings et al, 2002) may conceivably be mediated by REM sleep disturbances. Finally, genes associated with neurological disorders affecting REM sleep characteristics such as narcolepsy may contribute to REM sleep disturbances in MDD: the HLA class II allele DQB1*0602, genes for the hypocretin receptors, and polymorphisms in genes of the COMT and the tumor necrosis factor system (Taheri and Mignot, 2002).
Abnormalities in Brain Structure and Function
The identification of pathologic lesions in specific regions of the central nervous system has importantly contributed to the rapid progress in the understanding and treatment of neurological disorders including Parkinson's and Alzheimer's disease. Neuropathological findings are extremely useful to define nosological subtypes reflecting different underlying disease states that may be related to genetic vulnerability factors. For example, clinical features alone can only be used to diagnose parkinsonism; postmortem examination is needed for the definite diagnosis of the underlying disease including classic Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and frontotemporal dementia (Giasson and Lee, 2003).
Although there is no consensus in the field about the site of pathology in major depression, functional, structural, and molecular brain mapping in major depression have the potential to bridge the gap between clinical depressive features and genes. Since approximately 70% of all genes are expressed in the brain, many functional gene polymorphisms can potentially influence how the brain processes information. Since functional imaging has the capacity to assay within individuals information processing in discreet brain circuits, it has the potential to provide endophenotypes for MDD (Hariri and Weinberger, 2003). For example, significant differences have been reported between s/s and l/l genotypes of the 5-HTT promoter gene regarding the amygdala response to fearful faces measured by functional MRI in the absence of behavioral differences (Hariri et al, 2002). Furthermore, growing evidence suggests that major depression travels with brain structural changes mediated by hypercortisolemia, glutamate neurotoxicity, stress-induced reduction in neurotrophic factors, and stress-induced reduction in neurogenesis (Sheline, 2003). Therefore, advanced imaging technology might describe subtle changes in brain structures that are associated with specific pathophysiological processes and genes. Finally, in vivo molecular imaging opens up the potential to connect findings in genetic neuroscience obtained from animal experiments and postmortem human studies to clinical characteristics of depressed subjects by defining endophenotypes at the molecular level (eg receptors, transporters, and enzymes).
Functional imaging A series of studies have consistently found that the resting CBF and glucose metabolism in the amygdala in subjects with familial pure depressive disease and the melancholic depressive subtype is increased (Drevets, 2000). Elevation of resting amygdala CBF and metabolism may prove specific to primary mood disorders, insofar as this abnormality has not been reported in obsessive-compulsive disorder, panic disorder, phobic disorders, schizophrenia, or other neuropsychiatric conditions (Charney and Drevets, 2002). Although the magnitude of the amygdala activity in depression is partly modulated by illness severity, preliminary data suggest that left amygdala activity is abnormally elevated in remitted depressed patients off medication with a family history for affective disorders (Drevets et al, 1992). Moreover, one study showed that increased amygdala activity predicted return of depressive symptoms in remitted MDD subjects on medication following tryptophan depletion (TD; Bremner et al, 1997). The associations between elevated amygdala activity and vegetative depressive symptoms, plasma cortisol (Drevets et al, 1992), and REM sleep (Nofzinger et al, 1999) underline the plausibility of this biological marker for MDD. However, whether elevated amygdala activity meets the endophenotype criteria heritability, familial association, and cosegregation has not yet been determined.
In the subgenual prefrontal cortex, decreased CBF and metabolism have been consistently implicated by numerous studies in MDD (Drevets, 2000; Kegeles et al, 2003). Dysfunction of this brain region has been associated with blunted hedonic response and exaggerated stress responsiveness (Pizzagalli et al, 2004), and functional alterations in this region have been observed following serotonergic challenge (Kegeles et al, 2003), induced sadness (Mayberg et al, 1999), and treatment with a serotonin reuptake inhibitor (Buchsbaum et al, 1997). In remitted depressed patients, mood provocation produced a CBF decrease in brain regions connected with the subgenual prefrontal cortex (Liotti et al, 2002). Although information about this finding in healthy subjects at risk for MDD is lacking, it represents another promising imaging endophenotype.
Structural imaging Volume reductions in the ACC located ventrally ('subgenual') and anterior ('pregenual') to the genu of the corpus callosum have been implicated by numerous studies of mood disorders (Drevets, 2001). Specifically, a volume reduction in the left subgenual ACC has been associated with familial affective disorders by MRI-morphometric measures (Drevets et al, 1997; Hirayasu et al, 1999) and by postmortem neuropathological studies, which have shown glial reduction in the corresponding gray matter (Öngür et al, 1998). This reduction in volume exists early in the illness (state-independence), but appears to become more pronounced following illness onset, based upon preliminary evidence in twins discordant for MDD (Botteron et al, 1999). Humans with lesions that include the ventral ACC show abnormal autonomic responses to emotional stimuli, an inability to experience emotion related to concepts, and inability to use information regarding the probability of aversive social consequences vs reward in guiding social behavior (Damasio et al, 1990). In rats, left-sided lesions of the ACC increase sympathetic arousal and corticosterone responses to restraint stress (Sullivan and Gratton, 1999). The mechanisms and genes underlying volume loss in the ACC have not yet been determined. Preclinical studies on the role and genetics of neurotrophic factors and the signaling cascade neurotrophic factor/MAP kinase/bcl-2 involved in the fine balance maintained between the levels and activities of cell survival and cell death factors (Manji et al, 2003b) may inform clinical studies associating ACC volume loss to genes.
Reductions in hippocampal volumes associated with MDD have been consistently reported. However, this structural abnormality is not a specific sign of MDD (ie it has been found in patients with PTSD, schizophrenia, and epilepsy) and only occurs in a subgroup of MDD patients (Sheline and Mintun, 2002). In some studies, the volume loss appears to have functional significance with an association between acute depression and abnormalities of declarative memory (Burt et al, 1995) as well as associations between depression in remission and lower scores on tests of verbal memory (Sheline et al, 1999). The pathogenesis of hippocampal volume reduction seems to overlap with depressive pathophysiology, given its association with early-life stress, stress hormones, and duration of depressive illness (McEwen, 1999; Brunson et al, 2001; MacQueen et al, 2003). A study in monkeys suggests that hippocampal volume also reflects an inherited characteristic of the brain associated with increased cortisol response to stress (Lyons et al, 2001). Preliminary results on the genetics of the hippocampal function suggest that the BDNF val66met polymorphism may influence the development of memory deficits associated with psychopathology (Egan et al, 2003), and targeted disruption of mineralocorticoid receptor (MR) genes resulted in impaired hippocampal neurogenesis (Gass et al, 2000).
The literature is in disagreement regarding amygdala volumes in mood disorders, possibly due to technical limitations such as low reliability and validity of amygdala volume measures. However, a recent study using high-resolution 3T MRI has consistently found decreased amygdala volume in symptomatic and remitted mood disorders (Drevets et al, 2004). Amygdala volumes have been negatively associated with amygdala activity, suggesting that amygdala hyperactivity could be a factor in amygdala volume reductions in MDD (Siegle et al, 2003). This association and the high clinical plausibility of neuropathological abnormalities of the amygdala as endophenotype for MDD encourages further investigation on the consistency, specificity, familiality, and heritability of these findings.
Receptor pharmacology Decreased 5-HT1A receptor binding potential has been consistently found in multiple brain areas of patients with MDD (Drevets et al, 1999; 2000). This abnormality is not highly specific for MDD and has been found in patients with panic disorder (Neumeister et al, 2004) and temporal lobe epilepsy (Toczek et al, 2003), and may explain the considerable comorbidity among these conditions. The lack of effect of selective serotonin reuptake inhibitor treatment and hydrocortisone challenge on 5-HT1A receptors in recovered patients with MDD suggests state-independence of this abnormality (Bhagwagar et al, 2003; 2004). Unfortunately, no information is available on the heritability, familial association, and cosegregation of 5-HT1A receptor binding potential. However, a recent report suggests that a polymorphism associated with 5-HT1A receptor transcription is more common in MDD than in controls (Lemonde et al, 2003).
There is growing evidence from animal studies for the biological plausibility of this putative endophenotype for stress-related disorders. Mice with mutation in the 5-HT1A receptor gene have been consistently found to display increased stress-like behaviors and to express decreased activity toward a novel object (Bakshi and Kalin, 2002). However, the use of a tissue-specific, conditional rescue strategy revealed that the expression of the 5-HT1A receptor in the hippocampus and cortex (but not in the raphe nuclei) during the early postnatal period (but not in the adult) is sufficient to rescue the normal behavioral phenotype of the knockout mice (Gross et al, 2002), suggesting that stimulation of the 5-HT1A receptor during the postnatal period leads to long-lasting changes in the brain structure that are necessary for normal affective behavior throughout life.
Serotonin, Dopamine, and Norepinephrine
Alterations in noradrenergic and serotonergic function in the brain have been implicated in the pathophysiology of depression and the mechanism of action of antidepressant drugs (Charney, 1998), although dysfunctions within the monoaminergic neurotransmitter systems are not likely to play primary roles in the pathophysiology of depression but rather represent the downstream effects of other, more primary abnormalities (Manji et al, 2003b). Because depletion of catecholamines or serotonin induces significant depressive symptoms in remitted depressed subjects, depressive reactions in response to lowering of brain monoamine neurotransmitters has been proposed as an endophenotypic vulnerability marker for major depression (Berman et al, 1999).
Serotonin Major depression has been associated with abnormally reduced function of central serotonergic systems by abundant evidence from biochemical, challenge, imaging, and postmortem studies (Coppen et al, 1973; Charney et al, 1981; Lopez et al, 1998; Drevets et al, 1999). TD is an instructive paradigm for investigating the relationship between serotonergic function and depression. This paradigm involves the mood response to serotonin depletion, achieved by oral loading with all essential amino acids except the 5-HT precursor, tryptophan. The transient reduction in plasma tryptophan concentrations, cerebral serotonin synthesis, and central 5-HT concentrations resulting from this dietary manipulation is associated with redevelopment of depressive symptoms in remitted depressed patients who are either off medication (Delgado et al, 1994) or medicated with selective serotonin reuptake inhibitors (Delgado et al, 1999).
TD-induced depressive symptoms show a relatively high specificity for major depression (Bell et al, 2001). The presence of this diagnostic sign in remitted patients suggests state-independence. TD-induced depressive symptoms seem to be heritable: in remitted depressed patients, the long allele of the serotonin transporter gene promoter polymorphism predicted depressive response to TD (Moreno et al, 2002), while, in healthy women, the s-allele of this functional polymorphism and a positive family history of depression represented additive risk factors for TD-induced depressive symptoms (Neumeister et al, 2002). There is also evidence for familial association and cosegregation: never-depressed subjects with a positive family history of depression have also been shown to experience mood symptoms following TD that were smaller than in remitted depressed patients but different from subjects without familial risk who showed no effect following TD (Benkelfat et al, 1994).
In vulnerable individuals, TD induces mood-congruent memory bias (Klaassen et al, 2002), alters reward-related behaviors (Rogers et al, 2003), impairs memory consolidation (Riedel et al, 2002), slows responses to positive stimuli, and disrupts inhibitory affective processing (Murphy et al, 2002). These TD-induced changes are comparable with those occurring in major depressive episodes, thus implicating clinical plausibility. Acute severe serotonin depletion leads to biological changes associated with MDD, including enhanced norepinephrine transporter mRNA levels and reduced serotonin transporter mRNA levels (Koed and Linnet, 2000), increased number of MR binding sites (Semont et al, 1999), and altered BDNF gene expression in the dentate gyrus (Zetterstrom et al, 1999), thus implicating biological plausibility.
Norepinephrine/dopamine MDD has been associated with noradrenergic and dopaminergic dysfunction. Findings implicating catecholaminergic dysfunction in the pathophysiology of depression include studies about neurotransmitter synthesis and neurotransmitter storage, showing that reduction of catecholamine stores results in an exacerbation of depressive symptoms (Mendels and Frazer, 1974).
An instructive paradigm for investigating the relationship between catecholaminergic function and depression has involved the mood response to catecholamine depletion (CD), achieved by the administration of the tyrosine hydroxylase inhibitor -methylparatyrosine (AMPT). Mood responses to CD in healthy subjects are usually not significant (Salomon et al, 1997). Among untreated, symptomatic depressed patients prior to initiation of an antidepressant treatment CD failed to exacerbate depression (Miller et al, 1996b). This finding may be due to the brain catecholamine function being already maximally dysfunctional in symptomatic depressed patients (ceiling effect) (Lambert et al, 2000). Among treated depressed patients, CD reversed the antidepressant effects of antidepressants, in particular of catecholamine reuptake inhibitors (Miller et al, 1996a) and light therapy (Neumeister et al, 1998).
Because CD has not been systematically used in high-risk subjects and across different neuropsychiatric disorders, there is a lack of information on the specificity, familial association, and cosegregation of CD-induced symptoms for MDD. The presence of CD-induced depressive symptoms in unmedicated remitted patients with MDD suggests state-independence of this biological marker (Berman et al, 1999).
The depressive symptoms evoked by CD were often similar to those the patients had experienced during their depressive episode, suggesting clinical plausibility. There is also evidence for biological plausibility: the CD-induced return of depressive symptoms has been associated with decreased brain metabolism in orbitofrontal and dorsolateral prefrontal cortex; increased resting metabolism in prefrontal cortex and limbic areas have been found to increase vulnerability to CD-induced depressive exacerbation (Bremner et al, 2003).
HPA Axis and CRH
Altered HPA axis physiology and dysfunctions of the extrahypothalamic CRH system have been consistently found in humans with major depression. There is accumulating evidence that altered stress hormone secretions in depression are more than epiphenomenal, and that antidepressants may act through normalization of these changes. Given the potentially causal role of HPA axis and CRH system dysfunctions in depressive pathophysiology, and the involvement of cortisol and CRH in a variety of biological and behavioral components of major depression, indicators of these dysfunctions are likely to be useful as endophenotypes for major depression.
Cortisol Negative feedback regulation of the HPA axis occurs through a dual-receptor system of MRs and glucocorticoid receptors (GRs). Decreased limbic GR receptor function (Modell et al, 1997; Mizoguchi et al, 2003) and increased functional activity of the MR system (Young et al, 2003) suggest an imbalance in the MR/GR ratio in stress-related conditions such as MDD. The possible antidepressant properties of GR antagonists also appear compatible with the corticoid receptor hypothesis (Belanoff et al, 2002).
The neuroendocrine function test that measures dysfunctional cortisol responses in major depression most sensitively combines the dexamethasone suppression test and the CRH stimulation test (dex/CRH test) (Heuser et al, 1994). The specificity of this test is high to discriminate between healthy subjects and psychiatric patients including patients with panic disorder, mania, and schizophrenia, and its sensitivity for MDD is above 80%, depending on age and gender; however, its specificity for MDD with regard to other psychiatric disorders is low (Heuser et al, 1994). Abnormal cortisol responses in MDD patients, MDD high-risk probands, and healthy controls were found to be surprisingly constant over time (Modell et al, 1998), and independent of the actual depressive state (Zobel et al, 1999), suggesting that this marker is state-independent. Findings in healthy subjects at high familial risk for affective disorders (Holsboer et al, 1995) suggest familial association and cosegregation.
Interactions between cortisol and its receptors and neurotransmitters, neuropeptides, and brain circuits associated with depressive symptomatology suggest biological plausibility of the dex/CRH test as endophenotype for MDD. Specifically, the MR system seems to control the sensitivity of the CRH-1 system (de Kloet, 2003), which is thought to be altered in MDD, and to be the primary mediator of 5-HT1A downregulation after chronic stress (Kuroda et al, 1994), whereas the GR seems to be the primary receptor involved in stress-related 5-HT2A receptor upregulation (Karten et al, 1999).
Depression-like alterations of functions of the prefrontal cortex such as inhibitory control, attention regulation, and planning following cortisol administration, and the bidirectional associations between amygdala activity and cortisol levels (Gold et al, 2002) suggest clinical plausibility of cortisol-related endophenotypes for MDD. Furthermore, elevated cortisol may mediate between major depression and its medical long-term consequences such as coronary heart disease, type II diabetes, and osteoporosis.
Finally, there is some preliminary evidence for the heritability of GR/MR system functions. Some humans manifest a relative glucocorticoid resistance caused by GR gene mutations (Koper et al, 1997). In mice, conditional GR overexpression has been suggested as a model for increased anxiety-related behavior not secondary to altered levels of stress hormones (Muller et al, 2002). Targeted disruption of MR genes resulted in impaired hippocampal neurogenesis (Gass et al, 2000). Genetic factors most probably act in concert with environmental factors: an increase in hippocampal MR levels has been shown after exposure to psychological stress (Gesing et al, 2001).
Corticotropine-releasing hormone The evidence for the specificity, and clinical and biological plausibility of endophenotypes related to dysfunctions of the hypothalamic and extrahypothalamic CRH system for MDD is abundant: Levels of CRH in the CSF are elevated in some depressed subjects (Nemeroff et al, 1984), while the pituitary response to CRH appears appropriate given the high cortisol levels (Gold et al, 1986); the number of CRH-secreting neurons in limbic brain regions is increased (Raadsheer et al, 1994); the number of CRH binding sites in the frontal cortex is reduced, possibly as a compensatory response to increased CRH concentrations (Nemeroff et al, 1988); CRH produces a number of physiological and behavioral alterations that resemble the symptoms of major depression including decreased appetite, disrupted sleep, decreased libido, and psychomotor alterations (Nemeroff, 1996); and anxiety and depression scores have been reduced following CRH-1 receptor blockade (Zobel et al, 2000).
One of the strongest models of environmental regulation of the development of responses to stress is the postnatal handling research. The central CRH system is seen as the critical target for these environmental effects (Francis and Meaney, 1999). Postnatal maternal separation increases CRH gene expression in the paraventricular nucleus and alters systems involved in the regulation of the CRH system (eg the noradrenergic system); these effects may become permanent. Additionally to these environmental regulations, genetic factors have to be taken into account: reports on mouse mutants where CRH receptors were genetically inactivated suggested that CRH-R1 mediates anxiety-like behavior (Timpl et al, 1998); the CRH binding protein gene has been found to be involved in the vulnerability for MDD (Claes et al, 2003).
Although the CRH system is among the most promising to provide clinically and biologically plausible endophenotypes for MDD, few studies have investigated the temporal stability, heritability, familial association, and cosegregation of the CRH system in relation to major depression. One reason for the lack of such studies is the lack of PET ligands for CRH receptors, which can permit noninvasive assessments of CRH system dysfunction in vivo in humans.
Intracellular Signaling Molecules (a Perspective)
Neurotrophic factors The prominent cognitive deficits and brain volumetric changes in depression give additional weight to the contention that severe mood disorders arise, at least in part, from impairments of cellular plasticity and resilience (Manji et al, 2001; Manji and Duman, 2001). Endogenous neurotrophic factors such as BDNF are necessary for growth, survival, and functioning of neurons. They increase cell survival by providing necessary trophic support for growth, and also by exerting inhibitory effects on cell death cascades. There is emerging evidence, primarily from postmortem studies, that supports a role for abnormalities in neurotrophic signaling pathways in depression. Decreased levels of CREB, BDNF, and the TrkB receptor have been reported in suicide victims (Odagaki et al, 2001; Dwivedi et al, 2003).
As discussed already, genetic abnormalities in CREB and BDNF may also occur in depression. Substantial evidence indicates that CREB is a core component of the molecular switch that converts short- to long-term memory. A growing body of evidence suggests that antidepressants may regulate neurotrophic signaling cascades. Antidepressant treatment in rats increases CREB phosphorylation and CREB-mediated gene expression in mice limbic brain regions. More evidence that relates upregulation of these pathways and antidepressant utilization comes from antidepressant-like performance in behavioral models. Thus, it was observed that CREB overexpression in the dentate gyrus or BDNF injection results in an antidepressant-like effect in the learned-helplessness paradigm and the forced swim test model of antidepressant efficacy in rats (Chen et al, 2001; Shirayama et al, 2002). Together, the data suggest that alterations of neurotrophic signaling cascades may underlie the pathophysiology and treatment of depression. Because of the potential genetic underpinnings of abnormalities of these neurotrophic pathways, they may provide biological endophenotypes for major depression.
Ubiquitous signaling cascades It is now clear that genetic abnormalities in signaling components are often fully compatible with life, and in many instances, despite the often-ubiquitous expression of the signaling protein, these abnormalities are associated with circumscribed clinical manifestations (Manji et al, 2003a). These overt, yet relatively circumscribed, clinical manifestations are believed to ultimately arise from vastly different transcriptomes (all of the transcripts present at a particular time) in different tissues because of tissue-specific expression, haploinsufficiency, genetic imprinting, alternate splicing, varying stoichiometries of the relevant signaling partners in different tissues, and differences in the ability of diverse cell types to compensate for the abnormality (either autocrine or paracrine). Moreover, there is preliminary evidence that abnormalities in shared signaling cascades may even play a role in the growing appreciation that 'comorbidities' of major depression including cardiac disease, migraines, atopic disease, type II diabetes, and anxiety disorders appear to be the rule rather than the exception. There is no question that some medical illnesses (eg osteoporosis) represent the secondary sequellae of the biochemical changes (eg hypercortisolemia, sympathetic hyperarousal) of depression; however, some comorbidities may arise because the signaling cascade (eg cAMP cascade) also plays a role in the pathophysiology of these other disorders (eg vascular reactivity in migraine). In support of such a contention, Bondy et al (2002) investigated the ACE ID and the G-protein beta3-subunit (Gbeta3) C825T polymorphism in 201 patients with major depression and 161 ethnically and age-matched controls. Both gene variants have earlier been implicated in cardiovascular disease or affective disorders, making them good candidates for a combined analysis. Analyzing the data for both genes, they found that the combined actions of ACE and Gbeta3 genotypes accumulate in carriers of the ACE D allele (ID and DD) and Gbeta3 TT homozygotes, with ID/DD-TT carriers showing a more than five-fold increase in risk for major depression. These intriguing findings suggest that heritable biological makers of common medical conditions may turn out to be useful endophenotypes for major depression.
CONCLUSIONS
Table 1 shows an overview of putative psychopathological and biological endophenotypes for MDD, indicating estimates of evidence for each putative endophenotype with respect to the endophenotype criteria (Tsuang et al, 1993).
Table 1
Evaluation of Putative Endophenotypes for Major Depression
Anhedonia-related endophenotypes showed good evidence regarding endophenotype criteria including specificity. These endophenotypes parallel Klein's 'endogenomorphic' depressive subtype reflecting 'inhibited pleasure mechanisms' as psychopathological core feature (Klein, 1974). However, longitudinal and high-risk studies using specific anhedonia measures and tasks that estimate abnormalities of the brain reward system are necessary to further evaluate the applicability of anhedonia-related endophenotypes for major depression.Increased stress sensitivity also met most of the endophenotype criteria. Particularly, the familial coaggregation with MDD makes this phenotypic construct qualified for genetic studies; however, its use is limited by low specificity for MDD and by psychometric issues: the genetics of the partly state-dependent construct 'neuroticism', which can easily be assessed by a questionnaire, may be as complex as the genetics of MDD, and a potentially more reliable and more valid assessment of stress sensitivity by measuring stress levels and stress symptoms over time by means of a prospective community-based study is extremely costly and time-consuming.
Among the biological endophenotypes, TD showed evidence for all of the endophenotype criteria including specificity, state-independence, and familial association, thus encouraging the use of TD to identify a potentially homogenous depressive subtype associated with serotonergic dysfunction. Unfortunately, the complexity of TD including the use of a pharmacological challenge, the clinical observation of the research subject over many hours, and the exclusion of patients with symptomatic depression reduce the usefulness of this endophenotype, particularly in epidemiological research. The dex/CRH test, being somewhat easier to apply than TD, also showed good evidence across various endophenotype criteria. The low specificity for MDD, however, represents a major limitation to the use of this biological marker as MDD endophenotype.
The large sample sizes of MDD patients needed to perform genetic association studies on subsamples stratified according to endophenotypes is a general limitation to the endophenotype approach. In addition, using PET or fMRI endophenotypes may not be practical given the huge costs to obtain a sample size with sufficient power for genetic studies. The systematic evaluation of combinations of related psychopathological and biological endophenotypes (eg attentional bias toward negative stimuli combined with functional/structural abnormalities in the subgenual prefrontal cortex) expands the scope of this review.
FUTURE DIRECTIONS
Given the relative scarcity of well-designed twin, family, and prospective studies evaluating putative psychopathological and biological endophenotypes (see Table 1), future research has the potential to improve considerably the phenotypic definition of MDD. Progress in developing economical and easy-to-apply neurobiological markers may considerably facilitate the discovery of biological endophenotypes. Moreover, in the long term, the development of a new diagnostic system that includes psychopathological and biological endophenotypes will be necessary to improve the power of genetic studies by systematically defining relatively homogenous depressive subtypes.The Framingham Heart Study, designed as a large community study with a long-term follow-up, helped to identify biological and behavioral risk factors for cardiovascular disease and to establish diagnostic criteria for nosological entities such as arterial hypertension. Likewise, prospective longitudinal studies that collect comprehensive phenotypic data of psychiatric disturbances (eg the Zurich Cohort study; Angst et al, 1984; Hasler et al, 2004) are required. These studies are very different from the conventional phenotypic data collection (DSM-disease present or absent); it is rather a systematic effort to quantify the manifestations that compose the overall phenotype. In addition, these long-term follow-up studies are also required to identify environmental modifiers and precipitants that may alter clinical and biological phenotypes. The definition of endophenotypes in a way that takes developmental and environmental factors into account to detect vulnerability genes (Caspi et al, 2002; 2003) is an exciting model for future epidemiological research in depression.
Neuroimaging, postmortem, and preclinical studies are required to discover neurobiological endophenotypes bridging the gap between behavioral phenotype and genotype. Specifically, postmortem studies on gene variation conducted in families or populations may prove very useful in studying many facets of the gene or genes in question. By linking gene and gene expression (mRNA) to brain structure and function, postmortem research can be used to identify genetically relevant disease subtypes and to validate neuroimaging findings. New PET ligands that have specificity for receptors implicated in the pathophysiology of major depression, which are sensitive to dynamic neurotransmitter function, are needed to associate baseline levels of receptor occupancy as well as receptor displacement in response to pharmacological and behavioral challenges to both behavioral phenotypes and genotypes. Dramatic progress in the development of MRI-based methods will help to reliably identify subtle abnormalities of neural structures, connectivity, and function in depressed subjects and healthy subjects at familial risk that may be used as endophenotypes for genetic studies (Charney et al, 2002). Finally, longitudinal neurobiological studies are required to elucidate impairments of neuroplasticity and cellular resilience in major depression (Manji and Duman, 2001).
Taken together, reducing phenotypic heterogeneity is crucial for the identification of vulnerability genes for major depression, and, therefore, the development of a new classification system is badly needed. We propose to dissect the behavioral phenotype into key components, and integrate specific environmental risk factors and neurobiological endophenotypes into the new classification system. We hope and expect that advances in epidemiology, neurobiology, and genetics will result in ongoing improvements of the phenotypic definition of major depression based on etiology and pathophysiology.
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Posted by SLS on July 12, 2004, at 21:55:33
In reply to Re: Neuropsychopharmacology article link, posted by jrbecker on July 12, 2004, at 20:12:35
Posted by SLS on July 13, 2004, at 7:34:08
In reply to Re: McMan's Depression/Bipolar Weekly: Genetics, posted by jrbecker on July 12, 2004, at 14:12:59
Hi JB.
Thanks for everything.
Right now, I'm in a bad place regarding my outlook for my own case. The more I learn about the degenerative nature of bipolar disorder, the contribution of stress, and the damage that begins in early childhood and extends throughout a chronic and unremitting depressed state (age 17-44), the less I think are my chances for getting well. It is only logical. The only ray of hope I have to hold on to is the fact that I have had several brief (less than a week) remarkable improvements in response to changes made in medication over this last year.
> By the way, some of this new research is being put into practice in early drug treatments (e.g., PDE4 inhibitors...
There is a drug called rolipram that has been used in Japan to treat depression for many years. It is also a PDE4 inhibitor. Do you know anything about this? This might be a stretch, but how might this tie in to caffeine and cGMP? Caffeine is one of the few substances that I can rely on to give me an energy boost - more so than amphetamine.
Sometimes I feel truly stupid for having hope. I feel like one of P.T. Barnum's suckers.
- Scott
Posted by jrbecker on July 13, 2004, at 14:50:58
In reply to Re: McMan's Depression/Bipolar Weekly: Genetics » jrbecker, posted by SLS on July 13, 2004, at 7:34:08
cheer up Scott. Being bipolar is not a slow death sentence. Remember that the >psychological< is just as important as the psychiatric component of our illness. Outlook counts for a lot in our mood state. I'm sure you're familiar with the model of learned helplessness, right? Get angry, get pumped, or whatever it takes, but take charge of your attitude and stay optimistic. Believe that you're the one in control of your illness. Make sure you're doing all you can do on your own to make yourself better. In my case, I truly believe that my regimen of consistent exercise accounts for at least 75% of my ability to feel better. The meds are just icing on the cake really. Make sure you're exploiting any and all forms of treatment!
As for the PDE4 inhibitors...
PDE4 inhibitors have been used for asthma/COPD in the past. However, in recent years, there's been quite a bit of interest in its antidepressant effects. PDE4 inhibitors directly stimulate cAMP and thus the CREB cycle and BDNF. Thus, their potential as antidepressants are quite promising. And yes, you're right about rolipram. It went through a few trials a long time ago for depression. Unfortunately, it has fairly bad side effects of emesis and sedation. Luckily though, there's been a lot of work to discover more about the subreceptors of PDE4 in recents years to increase efficacy and reduce the side effects. A few more PDE4 inhibitors [still for asthma/COPD, are being developed...one called Ariflo is hitting the market quite soon]. However, two companies are currently studying PDE4 for major depression, alzheimers, and inflammatory conditions: Memory Pharmaceuticals and Neuro3d. The latter has just initiated phase I trials.
As for the caffeine connection, well, caffeine does have neurotrophic properties, but it also acts on adenosine, thus affecting DA/NE, so it's hard to parse out what's actually causing the effect for you.
here's a few links and more to read on pde4's:
http://www.neuro3d.fr/news.html
http://biz.yahoo.com/prnews/040601/ukf004_1.html
http://www.memorypharma.com/p_pde4.html
Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4)Trends in Pharmacological Sciences
Volume 25, Issue 3 , March 2004, Pages 158-163
Copyright © 2004 Elsevier Ltd. All rights reserved.James M. O'Donnell and Han-Ting Zhang
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Abstract
Despite initial promise, the development of type 4 phosphodiesterase (PDE4) inhibitors as antidepressants has not advanced significantly. This is due to an incomplete understanding of the functional importance of PDE4 subtypes and high-affinity and low-affinity inhibitor-binding conformers. However, recent developments have rekindled interest in the therapeutic potential of PDE4 inhibitors. First, PDE4 has been shown to be involved in cAMP signaling pathways that are affected by antidepressants. Second, data obtained using mouse knockout lines indicate that PDE4D and PDE4B mediate antidepressant effects. Third, it appears that the interaction of inhibitors with the high-affinity binding conformer of PDE4 is particularly important for antidepressant efficacy. These developments highlight the difficulties of dissociating the actions of PDE4 inhibitors and provide a guide for future research.
Article Outline
1. The PDE superfamily and PDE4
2. Antidepressant effects of PDE4 inhibitors
3. PDE4 in antidepressant-sensitive signaling pathways
4. PDE4 subtypes in the mediation of antidepressant effects
5. Inhibitor binding to conformers of PDE4
6. Future directions
Acknowledgements
References
Research by Helmut Wachtel at Schering AG Pharmaceuticals over 20 years ago demonstrated that the then-novel compound rolipram, as well as other inhibitors of cAMP phosphodiesterase (PDE), have CNS activity [1]. Subsequently, it was demonstrated that its pattern of effects is indicative of antidepressant efficacy [2], which was borne out later in a clinical trial [3]. Examination of the neuropharmacological actions of rolipram showed that it is a potent, highly selective inhibitor of type 4 PDE (PDE4), one of the 11-member superfamily of cyclic nucleotide PDEs [4]. These findings led to the suggestion that inhibitors of PDE4 might represent a novel class of antidepressant drugs, the potential of which is also being investigated for the treatment of inflammatory and immunological disorders [5 and 6]. Several factors have prevented the realization of the initial promise of therapeutic utility in depression. These include the lack of highly selective inhibitors of the four PDE4 subtypes, little knowledge of the involvement of each subtype in the signaling pathways that are involved in mediating antidepressant effects, and an incomplete understanding of the nature and consequences of two distinct PDE4 conformers with which inhibitors interact, termed the high-affinity and low-affinity rolipram-binding sites (HARBS and LARBS, respectively) [7]. However, recent developments have rekindled interest in the potential of PDE4 inhibitors as antidepressant agents.1. The PDE superfamily and PDE4
PDE enzymes comprise an eleven-family group (PDE1–PDE11); there are multiple isoforms in each family, caused by multiple genes and alternative splicing [8 and 9]. The PDE families differ in their primary structure, ability to hydrolyze cAMP and cGMP, tissue and intracellular distribution, and sensitivity to modulators (e.g. Ca2+, calmodulin and cGMP) and pharmacological inhibitors.The PDE4 enzyme family, which also is referred to as the low Km, cAMP-selective PDE and the rolipram-sensitive PDE, consists of four, independently coded subtypes (PDE4A–PDE4D) [10]. Of these, PDE4A, PDE4B and PDE4D are widely, but differentially, expressed throughout the brain, whereas the PDE4C subtype is expressed only minimally. Importantly, PDE4 is present in brain regions that are thought to be involved in reward and affect [11 and 12].
The PDE4 enzymes have been divided into three groups: the long form, short form and super-short form (Figure 1) [10]. The long-form PDE4s, consist of a subtype-specific C-terminus, a catalytic region that is highly conserved across subtypes and two conserved regions in the N-terminus, termed the upstream conserved region 1 (UCR1) and UCR2. Differential splicing results in distinct N-termini for the PDE4 enzymes; for example, the N-terminal region of PDE4D4 is distinct from that of PDE4D5. The N-terminal region of long-form PDE4s contains a conserved phosphorylation site for protein kinase A, which is involved in regulation of hydrolytic activity, as well as domains involved in protein-protein interactions. The short-form PDE4s and super-short-form PDE4s lack the UCR1 and the UCR1 plus a portion of the UCR2, respectively. The catalytic region of several PDE4 enzymes contains a phosphorylation site for extracellular-signal-regulated kinase that regulates hydrolytic activity in a variant-specific manner [13].
(17K)Figure 1. Type 4 phosphodiesterase (PDE4) enzymes are encoded by four genes, PDE4A, PDE4B, PDE4C and PDE4D, 19 variants of which are expressed by alternative splicing. Based on their primary structure, these variants are classified as long-form, short-form and super-short-form (s-short) PDE4s. Each PDE4 subtype has a unique C-terminus. Alternative splicing at the N-terminus results in unique N-terminal regions for each splice variant of PDE4. The N-terminus contains the upstream conserved region 1 (UCR1) and UCR2, and sites for phosphorylation and interactions with other proteins. The C-terminus contains an extracellular signal-regulated kinase (ERK2) phosphorylation site, which is located in the catalytic C-terminal regions.
2. Antidepressant effects of PDE4 inhibitors
Rolipram and other PDE4 inhibitors [e.g. Ro201724 (see Chemical names) and ICI63197] produce antidepressant-like effects in several preclinical models. They reduce the time of immobility in the forced-swim test, decrease response rate and increase reinforcement rate under a differential-reinforcement-of-low-rate schedule, reverse the effects of chronic, mild stress, normalize the behavioral deficits observed in Flinders sensitive-line and olfactory-bulbecomized rats, antagonize the effects of reserpine, and potentiate yohimbine-induced toxicity [2, 14, 15, 16 and 17]. These effects are typical of antidepressant drugs. PDE4 also appears to be involved in the CREB (cAMP response element-binding protein)-mediated induction of neurogenesis in the hippocampus [18] and the ability of antidepressant drugs to induce neurogenesis appears to be important in mediating late-developing effects on behavior [19].
1. Chemical names
ICI63197: 2-amino-6-methyl-4-propyl-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one
Ro201724: 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone
The results of clinical studies also indicate that PDE4 inhibitors have antidepressant efficacy, although only a small number of compounds have been evaluated [20, 21 and 22]. It is clear from these studies that the side-effect profile of rolipram, notably its emetic and sedative actions, limits its clinical utility. This has led to attempts to dissociate the antidepressant effects of rolipram from the more troublesome side-effects, which appear to be, at least in part, mediated centrally [23 and 24]. This effort has focused on the subtypes (PDE4A, PDE4B and PDE4D) and the binding conformers of PDE4 (i.e. the HARBS and LARBS).
3. PDE4 in antidepressant-sensitive signaling pathwaysIn general, clinically used antidepressants enhance noradrenaline-mediated and serotonin (5-HT)-mediated neurotransmission, either by inhibiting reuptake catabolism or by blocking inhibitory, presynaptic -adrenoceptors (either autoreceptors or heteroreceptors) [25]. Thus, it was of interest to determine whether PDE4 is involved in signaling mechanisms that are associated with these two neurotransmitters ( Figure 2). PDE4 was found to be either the predominant or exclusive PDE that mediates the hydrolysis of cAMP formed by stimulation of -adrenoceptors in rat cerebral cortex [26]. Furthermore, it appears that PDE4 is regulated via changes in noradrenaline-mediated activity. Using 6-hydroxydopamine to induce noradrenergic lesions reduces both PDE4 activity and the expression of PDE4A and PDE4B subtypes. By contrast, enhancing noradrenaline-mediated activity by repeated administration of the reuptake inhibitor desipramine markedly increases the expression of these two PDE4 subtypes [27]. In addition, PDE4D regulates phosphorylation of the -adrenoceptor by interacting with arrestin [28 and 29]. Overall, these data indicate that PDE4 is a regulated component of cAMP signaling mediated by -adrenoceptors. Inhibition of PDE4 might produce antidepressant effects in part by altering noradrenaline-mediated neurotransmission.
(26K)Figure 2. Type 4 phosphodiesterase (PDE4) is a component of -adrenoceptor-mediated and NMDA-receptor-mediated signaling, and might also be involved in 5-HT-receptor-mediated signaling. Both the intracellular localization and the function of PDE4 are affected by its interaction with other proteins, including receptors for activated C kinases 1 (RACK1) and A-kinase-anchoring proteins (AKAPs), and proteins that contain SH3 domains. Inhibition of PDE4 increases cAMP-mediated signaling in these pathways, an effect that is similar to that expected following administration of the antidepressants desipramine and fluoxetine, which inhibit noradrenaline transporters (NATs) and 5-HT transporters (SERTs), respectively, and following stimulation of NMDA receptors. Some actions of PDE4 inhibitors, such as antidepressant and memory-enhancing effects, might be mediated via these signaling pathways and involve specific PDE4 subtypes and binding conformers, such as the high-affinity rolipram-binding sites (HARBS) and low-affinity rolipram-binding sites (LARBS). Abbreviations: AC, adenylyl cyclase; CaM, calmodulin; PKA, protein kinase A.
Less is known of the involvement of PDE4 in 5-HT-mediated neurotransmission. However, some 5-HT-receptor subtypes are coupled positively to adenylyl cyclase, and so it is possible that PDE4 inhibitors enhance aspects of 5-HT-mediated neurotransmission that involve cAMP. Consistent with this suggestion, repeated treatment with an inhibitor of 5-HT reuptake such as fluoxetine increases the expression of PDE4A and PDE4B in rat cerebral cortex and hippocampus [30, 31 and 32]. It is unclear whether the antidepressant-induced increase in the expression of PDE4A and PDE4B, but not PDE4D, indicates that the two former subtypes are more involved in the signaling pathways that mediate the effects of antidepressants or whether the expression of PDE4D in the brain is less susceptible to regulation. PDE4D activity is particularly affected by phosphorylation, which indicates that this, rather than altered expression, might be its primary mode of regulation in the brain [33 and 34]. However, it should be noted that PDE4D has been shown to be regulated at the expression level in several cell types [35 and 36].
A third pathway that is implicated in antidepressant actions and involves PDE4 is NMDA-receptor-mediated signaling (Figure 2). The role of NMDA receptors in mediating antidepressant effects is not well understood. NMDA antagonists such as MK801 (dizocilpine) are reported to produce antidepressant-like effects on behavior [37 and 38]; however, this interpretation has been questioned [39]. Also, rolipram has been shown to reverse memory deficits that result from dizocilpine treatment, which indicates that the role of PDE4 in NMDA-receptor-mediated signaling might be related more to cognitive deficits that occur in depression [40]. Regardless of the exact nature of the functional role of PDE4 in NMDA receptor-mediated signaling, it does seem to be an important factor. Stimulation of NMDA receptors in primary cultures of rat cerebral cortical neurons increases intracellular concentrations of cAMP and cGMP. These neurons express enzymes from different PDE families, but the cAMP formed by NMDA-receptor stimulation is hydrolyzed exclusively by PDE4; the cGMP that forms is hydrolyzed by PDE2 only [41]. At present, it is not known which PDE4 subtypes are components of NMDA-receptor-mediated signaling in neurons.
4. PDE4 subtypes in the mediation of antidepressant effects
As yet, no highly selective inhibitors of the PDE4 subtypes have been developed; available compounds are only about 10-fold selective, which limits their utility for studies in vivo. The most-studied inhibitors, such as rolipram and Ro201724, are equipotent at inhibiting the four PDE4 subtypes. Thus, it is necessary to examine the behavioral phenotype and pharmacological sensitivity of mouse lines that are deficient in a particular subtype to assess the relative roles of the PDE4 subtypes in the mediation of antidepressant effects. At present, constitutive, PDE4B-knockout and PDE4D-knockout lines have been established [42].PDE4D-deficient mice exhibit an antidepressant-like profile in the forced-swim and tail-suspension tests [43], evidenced by reduced immobility relative to wild-type controls. This reduced immobility is similar to that observed if the mice are administered proven antidepressants or the putative antidepressant rolipram. A further reduction in immobility in the forced-swim test is observed when the antidepressants desipramine and fluoxetine are administered to PDE4D-deficient mice. By contrast, rolipram causes, at best, a minimal, additional reduction in the time of immobility in PDE4D-knockout mice. This reduced effect of rolipram indicates that its actions are mediated to a significant degree by the PDE4D subtype. Consistent with this, the ability of rolipram to enhance -adrenoceptor-mediated cAMP formation in the cerebral cortex also is diminished in PDE4D-deficient mice [43]. Interpretation of the effect of desipramine and fluoxetine is less obvious. Although, it might mean that PDE4D is not involved in their actions, this might not be the case. If the monoamine-uptake inhibitors produce their effects by increasing receptor-mediated cAMP formation, then loss of the PDE4 subtype in the affected pathway would either enhance the effects of desipramine and fluoxetine or increase the potency of these drugs. At present, pharmacological analyses sufficient to detect a change in sensitivity have not been carried out.
Much less is known about the role of the PDE4B subtype in the mediation of antidepressant effects. Preliminary results indicate that PDE4B-deficient mice also exhibit an antidepressant-like profile in the forced-swim test and rolipram causes no significant, additional reduction in immobility (H-T. Zhang and J.M. O'Donnell, unpublished). However, unlike PDE4D-deficient mice, desipramine produces no further antidepressant-like effects in PDE4B-deficient mice. This indicates an important difference between the roles of PDE4B and PDE4D in signaling pathways affected by antidepressant drugs. It remains to be determined whether this difference is observed with 5-HT-reuptake inhibitors.
Although the subtype involved in mediating the antidepressant-like effects of PDE4 inhibitors is by no means resolved, particularly because PDE4A-deficent mice have not been examined, results obtained to date do indicate an important role for the PDE4D subtype. This raises two issues. First, it contrasts with data obtained in rats, which shows that repeated treatment with antidepressants from different pharmacological classes increases the expression of PDE4A and PDE4B but not PDE4D [30 and 31]. Second, it is important to know to what degree the side-effects of emesis and sedation are related to inhibition of PDE4D. The first issue indicates either a species difference (i.e. that rats and mice utilize different PDE4 subtypes in particular signaling pathways) or that PDE4D might be regulated differently to PDE4A and PDE4B (e.g. by phosphorylation rather than altered expression). The second issue is somewhat more troubling. PDE4D appears to be expressed highly in the area postrema, an emetic-trigger zone [44], but its relative contribution to overall hydrolysis of cAMP in this region is not known. However, data obtained using a surrogate model that appears to be related to emetic potential, also indicate a role for PDE4D [45]. Obviously, this issue needs to be clarified if we hope to dissociate the antidepressant and emetic effects of PDE4 inhibitors.
5. Inhibitor binding to conformers of PDE4
Another level of complexity in understanding the actions of PDE4 inhibitors concerns the high-affinity and low-affinity binding conformers (the HARBS and LARBS). The first indication that rolipram binding might be somewhat complex was the finding that whereas [3H]-rolipram binds with high affinity to brain membranes (Ki=1–10 nM), little high-affinity binding is detected in preparations of peripheral organs [46]. A systematic analysis of binding using a technique that assesses both high-affinity and low-affinity interactions to recombinant PDE4A, showed that [3H]-rolipram binds with two distinct affinity states that differ ~500-fold in their apparent Ki values [7]. Both high-affinity and low-affinity interactions require the catalytic site; the N-terminal region of PDE4 stabilizes the high-affinity component of rolipram binding. Because both components of rolipram binding are to the catalytic site, they are described more accurately as distinct affinity states or conformers, rather than independent sites [47]. It should be noted that the HARBS and LARBS refer specifically to rolipram; some drugs exhibit high, equal affinity for both affinity states (e.g. piclamilast).The issue of high-affinity and low-affinity binding sites for rolipram is not just an esoteric aspect of the pharmacology of PDE4. It appears to have important functional consequences because binding to each affinity state mediates a unique range of pharmacological effects. The order of potency of PDE4 inhibitors for producing some effects, such as induction of head twitches and tremor in mice, and emesis in ferrets, correlates with affinity for the HARBS; other effects, including inhibition of mast cell degranulation and antigen-induced T-cell proliferation in guinea-pigs appear to be more closely related to the LARBS [16, 48, 49, 50 and 51].
Interestingly, the HARBS appears to be present in brain, but not in peripheral tissues [46 and 52]. PDE4 is expressed throughout the body, and so it is likely that this observation results from differences in the intracellular environment rather than an intrinsic difference between PDE4 in brain and peripheral tissues. Several factors affect the affinity of inhibitors for PDE4. These include the phosphorylation state of PDE4 and its interaction with proteins such as A-kinase-anchoring proteins (AKAPs), receptors for activated C kinases 1 (RACK1) and proteins that contain SH3 domains [53, 54, 55 and 56]. Data obtained to date support the suggestion that the CNS effects of PDE4 inhibitors are mediated by the HARBS. Saccomano and co-workers [16] found that the relative potency of a series of inhibitors in reducing immobility of mice in the forced-swim test (an index of antidepressant efficacy) correlates with that of inhibition of [3H]-rolipram binding (an index of interaction with the HARBS). Similar data have been obtained recently using the forced-swim test in rats (Y. Zhao et al., unpublished).
In addition, repeated treatment with either desipramine or fluoxetine, antidepressants that exert their antidepressant effects primarily via noradrenaline-mediated and 5-HT-mediated actions, respectively, increases the HARBS but not the LARBS in rat cerebral cortex and hippocampus [57]. If this increase in binding is a simple reflection of the overall increase in PDE4 expression that is observed [30 and 31], then an increase in binding to both conformers would be expected. The selective increase in inhibitor binding to the HARBS, together with the finding that this increase occurs in membrane but not cytosolic fractions, indicates that the antidepressants alter components of signaling pathways that involve PDE4. It appears that these antidepressant effects are secondary to enhanced noradrenaline-mediated and 5-HT-mediated neurotransmission, because prior lesion of these systems blocks the ability of desipramine and fluoxetine to increase binding of inhibitors to the HARBS [57].
6. Future directions
Much has been learned in the past several years about the mechanisms that mediate the antidepressant actions of PDE4 inhibitors. However, several areas need to be addressed more fully. First, the field would be advanced significantly by the development of highly subtype-selective PDE4 inhibitors. This has proved difficult because the catalytic site to which PDE4 inhibitors bind is highly conserved across subtypes [10]. However, as understanding of PDE4 structure and inhibitor binding increase, aided by the publication of the crystal structure of the core, catalytic region [58 and 59], some progress in this area might be realized.Second, although the understanding of the involvement of PDE4 in signaling pathways that are affected by antidepressants has improved, it is essential that these systems are defined more fully. For example, it is known that PDE4 is the predominant PDE involved in the -adrenoceptor-linked adenylyl cyclase pathway [26], but which subtype and splice variants are particularly important in individual brain areas is unknown. Less is known about the involvement of PDE4 in 5-HT-receptor-mediated signaling and other signaling pathways affected by antidepressants.
Last, the concept of high-affinity and low-affinity binding conformers for PDE4 inhibitors (i.e. the HARBS and LARBS) has to advance from phenomenology to a fuller mechanistic understanding. Given that the HARBS is present in brain but not peripheral tissues in appreciable numbers [52], it is likely that the intracellular milieu of CNS neurons (and, possibly, glia), results in a unique inhibitor-binding profile. Although many factors affect the binding of inhibitors to PDE4, including the phosphorylation state and several protein-protein interactions, as yet, none have been linked causally to the HARBS in vivo. Because factors that influence binding affinity of inhibitors often affect catalytic activity, they could provide a means to alter cAMP hydrolysis in specific signaling pathways independent of overt pharmacological inhibition. This might indicate novel ways to alter PDE4-related CNS function, including mediation of antidepressant activity.
Acknowledgements
Research in our laboratory was supported by research grants and an Independent Scientist Award from the National Institute of Mental Health.
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> Hi JB.
>
> Thanks for everything.
>
> Right now, I'm in a bad place regarding my outlook for my own case. The more I learn about the degenerative nature of bipolar disorder, the contribution of stress, and the damage that begins in early childhood and extends throughout a chronic and unremitting depressed state (age 17-44), the less I think are my chances for getting well. It is only logical. The only ray of hope I have to hold on to is the fact that I have had several brief (less than a week) remarkable improvements in response to changes made in medication over this last year.
>
> > By the way, some of this new research is being put into practice in early drug treatments (e.g., PDE4 inhibitors...
>
> There is a drug called rolipram that has been used in Japan to treat depression for many years. It is also a PDE4 inhibitor. Do you know anything about this? This might be a stretch, but how might this tie in to caffeine and cGMP? Caffeine is one of the few substances that I can rely on to give me an energy boost - more so than amphetamine.
>
> Sometimes I feel truly stupid for having hope. I feel like one of P.T. Barnum's suckers.
>
>
> - Scott
This is the end of the thread.
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