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.
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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
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