Posted by jrbecker on May 25, 2004, at 10:52:44
the latest newsletter contains a lot of great feedback from this year's APA conference. To sign up for the free newsletter, go to www.mcmanweb.com
McMan's Depression and Bipolar Weekly
May 26, 2004 Vol 6 No 12Welcome
Lead Story: Mood and anxiety - why we need to think beyond the DSM, plus pathophysiology and treatment strategies.Also in this issue: RIP Serzone, Kids using more meds (but parents uneasy), Most households in contact with a mental health professional, Questionable BP depression treatment, Lexapro-Effexor smackdown, Power meditation, Prisoner abuse at home, Getting smart with brain scans, Early onset BP, BP quality of life, Inositol, Depression drugs in the pipeline, BP drugs in the pipeline, Mailbag, Mickey D's follow-up, McMan's Web, Donations.
Rhymes with Anxious
Feeling a bit on edge? Congratulations, you may be treatment resistant. "I dislike the term," Ellen Frank PhD of the University of Pittsburgh told a symposium at the American Psychiatric Association’s annual meeting held in early May in New York. Treatment resistant, she said, too often applies to patients rather than their disorders, implying the fault is with the patient. Dr Frank prefers using "difficult to treat."
So be it. Difficult to treat it is, and there are a lot of us. The National Comorbidity Survey found that 58 percent of patients with major depression have an anxiety disorder. One’s anxiety, however, need not be full-blown to sabotage recovery. The technical term is "subsyndromal comorbidity," which applies in this context to a mood disorder and under-the-radar anxiety. Two studies by Dr Frank and her colleagues of depressed and bipolar patients found that those with co-occurring panic symptoms experienced significant delays in their weeks to remission. These patients also had higher levels of residual impairment.
We need to think beyond the DSM symptom list, Dr Frank advised. "The DSM has made us less sensitive to our clinical intuition."
At a different APA session, Lori Davis MD of the Tuscaloosa VA Medical Center reported that 42 percent of bipolar patients have co-occurring DSM anxiety, according to a 2001 study by McElroy et al. This breaks down to 20 percent of patients with panic, 16 percent with social phobia, six percent generalized anxiety disorder, seven percent PTSD, and nine percent OCD. (The lifetime figures are much higher, according to National Comorbidity Survey data). High anxious bipolar patients, Dr Davis reported, have more suicide attempts, more alcohol use, less response to lithium, and longer time to remission.
We do not know if co-occurring mood and anxiety are pathologically distinct and happen to overlap by chance or are separate disorders with shared pathophysiology or are part of single disease phenomenon, Dr Davis related. Of the three neurotransmitters most familiar to us, we do know that heightened norepinephrine and dopamine activity figure in mania, panic, and PTSD, and that serotonin dysregulation is implicated in bipolar, panic, OCD, and PTSD.
These three neurotransmitters (monoamines) modulate the fast-acting neurotransmitters, GABA and glutamate, which in turn signal the release of more monoamines and the stress hormone CRF. There is reduced GABA activity and excessive glutamate activity in bipolar, panic, and PTSD. Sensory information about harmful stimuli is processed in the amygdala in the brain. In response, glutamate sets off a cascade that results in the fight or flight response which, over time, can manifest as a mood episode or an anxiety attack or both. GABA, which is supposed to be keeping a lid on this, is largely AWOL - plasma GABA has been found to be low in patients with PTSD.
Stress and trauma may mediate both mood and anxiety. At a session of the APA meeting two years ago, Charles Nemeroff MD, PhD of Emory University commented: ""Is the biology of depression the biology of early trauma?" Last year, he and his colleagues had a second look at a 2000 study that found that more than one half of the depressed subjects in the study had endured some form of early abuse or neglect or trauma. At last year’s APA meeting, Robert Sapolsky PhD of Stanford reported on the mind-boggling work his lab is doing genetically rewiring the amygdala and hippocampi of lab animals. "If anxiety is a crackling, menacing brushfire, depression is a suffocating heavy blanket thrown on top of it," he wrote later that year in Scientific American.
Although mood and anxiety may conspire against many of us, the good news is we’re beginning to make some headway on the treatment front. Dr Frank has developed a form of interpersonal therapy aimed at helping patients resolve personal disputes and manage their anxiety. A small study of patients taking a 16-session course found significantly lower depression and anxiety scores after three months. And Dr Nemeroff’s second-look study found that the abused, neglected, and traumatized patients fared far better on talking therapy than an antidepressant. In the meantime, many of our meds operate as virtual Swiss Army knives for both mood and anxiety. A good clinician can work get you on the right ones, but only after first teasing out often difficult-to-spot anxiety symptoms. Talk to your psychiatrist or therapist like you’ve never talked before.
Treating Mood and Anxiety
At the APA meeting, Dr Davis summarized the data we have on meds and talking therapy for treating bipolar and anxiety:
Lithium: BP mania ++, BP depression +, PTSD +
Anticonvulsants: BP mania ++. BP depression ++, Panic ++, OCD +, Social phobia ++
Atypical antipsychotics: BP mania ++, BP depression ++, OCD +/-, PTSD +/-
SSRIs: BP Depression +, Panic ++, OCD ++, PTSD ++, Generalized anxiety disorder (GAD) ++, Social phobia ++
Benzodiazepines: BP mania +/-, Panic ++, OCD +, PTSD +/-, GAD ++, Social phobia ++
Buspar: PTSD +, GAD ++
Cognitive behavioral therapy (CBT)/Behavioral/Exposure: BP depression +, Panic ++, OCD ++, PTSD ++, GAD ++, Social phobia ++
Proposed treatment strategies include:Concurrent bipolar and panic: Anticonvulsant (Depakote) with SSRI and perhaps CBT.
Concurrent bipolar and OCD: Mood stabilizer with SSRI and perhaps CBT.
Concurrent bipolar and PTSD: Anticonvulsant (Lamictal or Depakote), perhaps with an antipsychotic, perhaps an SSRI, and perhaps CBT.
Concurrent bipolar and social phobia: Mood stabilizer and perhaps Neurontin and/or SSRI and/or CBT.
Concurrent bipolar and GAD: Mood stabilizer and perhaps Buspar or SSRI and perhaps CBT.
Serzone to be Taken off US and Down Under MarketsFor those who didn’t receive last week’s special mailing:
Bristol-Myers Squibb has announced it will take Serzone off the market in the US, effective June 14. Serzone has been linked to a remote risk of liver failure, involving 20 deaths worldwide. The drug has been pulled from Europe and Canada and will be withdrawn from New Zealand and Australia. The drug is still available in generic form. Serzone patients are advised to contact their prescribing physicians immediately.
Kids' Meds Use Skyrocketing ...
According to a Medico Health Solutions analysis of customer data, the use of behavioral drugs for children topped all other areas of drugs in 2003 at 17 percent of total spending. This compared to 16 percent for antibiotics and asthma drugs, 11 percent for skin conditions, and six percent for allergy meds. Antidepressants spending grew by 21 percent over a three-year period and ADHD by 369 (no typo) percent compared to 4.3 percent in the use of antibiotics.
Average monthly spending per child was $12.31 a month compared with $125.58 for those 65 and older.
... But for How Long?
A Columbia University telephone poll of 512 parents of children under 18 conducted in the first week of May (shortly after the FDA antidepressant suicide warning) found that:
Although four in 10 parents believe the benefits of antidepressants among teenagers suffering from depression outweigh the risks associated with their use, six in 10 think either that the risk of suicide makes the risk too high or can’t offer an opinion on the matter.
68 percent fear that antidepressants are being over-prescribed to young people.
31 percent believe that teens are harmed by antidepressants and 31 percent say they are not. Parents who consider anti-depressants harmful cite suicide, brain development and weight gain or loss as possible side effects.
A majority worry that most teens suffering from depression are not receiving treatment Over half of parents believe that many teenagers receiving treatment for depression don't have the disorder.
Only 16 percent consider themselves very knowledgeable about teen depression and only 22 percent strongly agree that they know where to go for reliable information.
Attitudes ChangingAn American Psychological Association survey of 1,000 American adults has found that 48 percent of households have had someone see a mental health professional, with nine of ten likely to consult or recommend one if they or a family member are experiencing a problem. Eighty-five percent think health insurance should cover mental health services. Only 30 percent said they would be concerned about other people finding out they saw a mental health professional and only 20 percent believed there is any stigma associated with therapy.
First Do No Harm
An Eli Lilly review of 1,203 patient records from 1995 to 2002 published at the APA meeting found that only nine percent of patients with bipolar depression began treatment that adhered to APA guidelines and that 16 percent - in direct contradiction of the guidelines - were prescribed an antidepressant as monotherapy initially. Over time, with switches in meds, patients on monotherapy decreased 12 percent and those on four meds or more increased 12 percent.
To My Psychiatrist Readers
I am looking to follow up on the FDA antidepressant suicide warning. I would greatly appreciate anything you can tell me about how the news has affected your practice so far (eg patients going off their antidepressants or not, more referrals from GPs or not, etc). Also, feel free to give your opinion on the FDA action. Please email mcman@mcmanweb.com Confidentiality assured.
Note: I believe there was a technical problem with my email link when I put this notice in Newsletter 6#10. To those who tried to respond, I apologize and ask you to please try again.
Lexapro-Effexor Smackdown
Newsletter 5#32 reported on a Forest Labs study that found its Lexapro to be comparable in efficacy and side effects to Zoloft, which is probably not how the company wanted the study to turn out. A new head-to-head study published at May’s APA annual meeting, this time comparing Lexapro to Effexor XR, yielded results more to their liking, with depression scores slightly better (response 58 percent vs 48 percent) and tolerability showing a significant edge (4.1 percent of the Lexapro patients withdrew from the study due to adverse events vs 16 percent for Effexor).
Power Meditation
"It is certainly not inconceivable that 20 years from now, the US Surgeon General might recommend 60 minutes of mental exercise five times a week." Molecular biologist Eric Lander PhD, one of the leaders of the Human Genome Project, speaking at a Sept 2003 conference at MIT, reported on SiFy News.
At the same conference, neuroscientist Richard Davidson PhD showed brain scans of a Buddhist monk who pushed activity in the left prefrontal cortex - associated with positive emotions - "off the chart" by using compassion mediation, and in a different meditative state suppressed the startle reflex, thought to be impossible to do. Advanced meditators were also able to demonstrate blindingly fast cognition.
The catch is these monks had honed their skills over a lifetime.
Why Isn’t This on the Cover of Newsweek?
When Iraqi prisoners were mistreated by US troops, the world got justifiably outraged. Few, however, shed a tear for the unlucky ones in our midst. From the Miami Herald:
"A year ago, [Raymond Santos] grew so desperate for the voices to shut up that he tried to appease them by taking a large, serrated kitchen knife and digging it four inches into his stomach. Two weeks later, with 31 staples in his abdomen, he landed in Florida's largest psychiatric facility.
"The Miami-Dade County Jail.
"He was locked up in a wing where psychotic inmates sleep on the tile floor or rusted metal bed frames, without sheets, blankets or mattresses. They stay in their cells for 24 hours a day. No books, no TV, no visitors, no toothbrush, no eating utensils, no clothes."
Raymond was one of about 400 mentally ill patients warehoused in unspeakable conditions in the jail. Nearly a year after he stabbed himself, he was finally transferred to treatment.
Getting Smart with Brain Scans - I
A Rotman Research Institute meta-analysis of a seven-region brain model of the PET scans of 119 depressed patients and 42 health controls has found that differences in limbic-cortical and limbic-subcortical connections distinguished responders to meds treatment from nonresponders. Other limbic-cortical and cortical-cortical differences distinguished responders to cognitive behavioral therapy from responders to meds therapy. Concluded the authors of the study: "The creation of such models is a first step toward full characterization of the depression phenotype at the neural systems level, with implications for the future development of brain-based algorithms to determine optimal treatment selection for individual patients."
Getting Smart with Brain Scans - II
A Spanish study of 47 PET scans of meds-free patients with late-onset major depression, meanwhile, found fronto-cerebellar variables to be an accurate predictor of treatment response.
Early Onset, Late Recovery
An analysis of data from the first 1,000 bipolar patients enrolled in the NIMH-underwritten STEP-BD series of ongoing bipolar clinical trials has found that of the 983 in whom age of onset could be determined, 27.7 percent experienced onset of mood symptoms at age 13 or younger, and 37.6 percent experienced onset at ages 13 to 18. Earlier onset was associated with greater anxiety and substance use, more recurrences, shorter periods of not manic or depressed, greater likelihood of suicide and violence, and greater likelihood of being in a mood episode at study entry.
Encouraging News
An Indian study 50 bipolar patients in remission (on lithium) found that their quality of life according to two questionnaires compared favorably to the healthy group.
Jury Still Out on Inositol
A University of Oxford meta-analysis of four trials totaling 141 depressed patients has found that there was no clear evidence of a therapeutic benefit for inositol, a component of the B vitamin complex, though "ongoing studies should reduce this uncertainty."
In the Pipeline
Following is a list of drugs in the developmental pipeline for depression, anxiety, and insomnia, adapted from a list prepared by JR Becker on Neruotransmitter.net, used with his permission.
Some explanations: "Preclinical" refers to testing on animals, "Phase I" to small pilot studies on humans, "Phase II" to slightly larger studies testing for safety, efficacy, and dosing, and "Phase III" to large-scale, rigorously-conducted studies scheduled to be submitted to the FDA for review. "NDA" (new drug approval) refers to a manufacturer's application to the FDA, and "Approvable" means the FDA is ready to clear the drug for sale, pending fulfillment of certain conditions the agency may impose on the manufacturer.
According to the Pharmaceutical Research and Manufacturers of America, it takes 10 to 15 years for a drug to travel from the lab to market. Only five in 5,000 compounds that enter preclinical testing ever make it to human testing, and only one of these five is approved for sale. Last year, Merck pulled its seemingly sure-shot antidepressant, Emend (aprepitant), from FDA consideration after phase III trials failed to replicate earlier successes.
As for types of action, 5HT refers to serotonin, NE to norepinephrine, NK1 to substance P (which Emend and other drugs block), and CRF to a precursor of the stress hormone cortisol. Don't worry about what a melatonin MT1 receptor agonist and the rest are - the point is there is an array of potential new targets that the drug companies are looking at, with the reasonably good prognosis that we will one day have a range of real choices in our meds.
Drug Name
Action
Company
Indication
Phase
Cymbalta (duloxetine)
5HT/NE reuptake inhibitor
Eli Lilly
Depression, Anxiety
Approvable, launch expected 2004
Estorra (eszopiclone)
GABA-A modulator
Sepracor
Insomnia
Approvable, launch expected 2Q04
EmSam (transdermal selegiline)
MAO-B inhibitor, MAO-A [at higher doses]Somerset
Depression
Approvable
Variza (gepirone)
5-HT1A partial agonist
Organon
Depression, Anxiety
NDA submitted, decision expected by 2004
Pregabalin
Voltage-gated calcium channel alpha(2)delta subunit modulator
Pfizer
Anxiety, Pain, Bipolar disorder
NDA submitted, launch expected in 2005
Indiplon
GABA-A modulator (at BZ1 sites)
Neurocrine/DOV
Insomnia
NDA expected 2004
Ambien CR (Zolpidem MR)
GABA-A modulator
Sanofi-Synthelabo
Insomnia
NDA expected mid-2004
CORLUX [C-1073], also known as RU-486 (mifespristone)
Cortisol antagonist
Corcept
Psychotic major depression
Phase III, granted fast track status by FDA
Agomelatine
5-HT2C antagonist, 5-HT2B antagonist, melatonin receptor agonist
Servier
Depression, Anxiety
Phase III
Pagoclone
GABA-A modulator
Indevus
Anxiety
[Renewed]Phase III
SR 58611
beta-3-adrenoceptor agonist
Sanofi-Synthelabo
Depression, Anxiety
Phase III
Nemifitide (INN 00835)
Synthetic peptide (injectable)
Innapharma
Depression
Phase III
TAK-375
Melatonin MT1 receptor agonist
Takeda
Insomnia
Phase III
Ocinaplon
GABA-A modulator
DOV
Anxiety
Phase III
Gaboxadol (aka THIP)
GABA-A agonist
Lundbeck
Insomnia
Phase III
GW353162
Dopamine and norepinephrine, reuptake inhibitor
GSK
Depression, Bipolar disorder
Phase II
GW597599
NK1 antagonist
GSK
Depression, Anxiety
Phase II
CP-122,721
NK1 antagonist
Pfizer
Depression, Anxiety
Phase II
R673
NK1 antagonist
Roche
Depression, Anxiety
Phase II
TAK-637
NK1 antagonist
Takeda/Abbott
Depression, Anxiety
Phase II
ORG 34517/34850
GR antagonist
Organon
Depression
Phase II
LY354740
mGluR2, mGluR3 agonist
Eli Lilly
Anxiety
Phase II – currently on hold
Sonata (extended-release)
GABA-A modulator
King Pharmaceuticals
Insomnia
Phase II
VPI-013 (also known as OPC-14523)
5-HT1A agonist, sigma receptor agonist [also a serotonin reuptake inhibitor at higher doses]
Vela, Otsuka
Depression
Phase II
CX717, other AMPAkine compounds
AMPA receptor modulators
Cortex/Servier/ Organon
MCI, Alzheimer's disease, Depression, ADHD, Schizophrenia
Phase II
SL 65.1498
GABA-A modulator
Sanofi-Synthelabo
Anxiety, muscular contractions
Phase II
SR 46349 (eplivanserin)
5-HT2A antagonist
Sanofi-Synthelabo
Insomnia
Phase II
SR 48968 (saredutant)
NK2 antagonist
Sanofi-Synthelabo
Depression, Anxiety
Phase II
KW-6002
Adenosine A2A antagonist, MAO-B inhibitor
Kyowa Hakko
Parkinson's disease
Phase II
DOV 216,303
DA/NE/5HT reuptake inhibitor
DOV
Depression, Anxiety
Phase II
SEP-174559
GABA-A modulator, nicotinic acetylcholine receptor antagonist, NMDA antagonist
Sepracor
Anxiety
Phase II
AR-A000002
5-HT1B antagonist
AstraZeneca
Depression, Anxiety
Phase II
ORG 4420
NaSSA (noradrenergic/specific serotonergic antidepressants)
Organon
Insomnia
Phase II
RG2133 (triacetyluridine)
Prodrug of uridine
Repligen
Mitochondrial disease, Depression, Bipolar disorder
Phase II
ORG 34167
??
Organon
Depression, Pain
Phase II
R-tofisopam
R-isomer of racemic tofisopam (a 2,3-benzodiazepine)
Vela
Anxiety, IBS
Phase I
GW679769
NK1 antagonist
GSK
Depression, Anxiety
Phase I
MEM 1414/ R1533/R1500
PDE4 inhibitor
Memory Pharm./ Roche
Alzheimer's disease, Depression
Phase I
DOV 21, 947
Dopamine, serotonin, and norepinephrine, reuptake inhibitor
DOV
Alzheimer's disease, Depression
Phase I
PRE703
MgluR agonist
Prescient
Anxiety
Phase I
PRX-00023
5-HT1A agonist, sigma receptor agonist
Predix
Anxiety, ADHD,Depression
Phase I
M-100907
5-HT2A antagonist
Aventis
Insomnia
Phase I
R1204
GPCR modulator
Roche
Depression
Phase I
NGD 96-3
GABA-A modulator
Neurogen
Insomnia
Phase I
SSR149415
V1B antagonist
Sanofi-Synthelabo
Depression, Anxiety, Hyperphagia
Phase I
SB 243213
5-HT2C inverse agonist
GSK
Depression, Anxiety
Phase I
SNAP-7941
MCH antagonist
Synaptic
Depression, obesity
Phase I
NPS-1506
NMDA antagonist
NPS
Depression, stroke
Phase I
CRF1 antagonist
CRF1 antagonist
Neurocrine/GSK
Depression, Anxiety
Pre-clinical
CRF1 antagonist
CRF1 antagonist
Janssen
Depression, Anxiety
Pre-clinical
CRF1 antagonist
CRF1 antagonist
Neurogen/Aventis
Depression, Anxiety
Pre-clinical
CP-448,187
CRF1 antagonist
Pfizer
Depression, Anxiety
Pre-clinical
CP-154-526
CRF1 antagonist
Pfizer
Depression, Anxiety
Pre-clinical
CRF-1 antagonist
CRF1 antagonist
Bristol-Myers Squibb
Depression, Anxiety
Pre-clinical
AZD1134
5-HT1B antagonist
AstraZeneca
Depression, Anxiety
Pre-clinical
R1067
GPCR modulator
Roche
Depression
Pre-clinical
MCH antagonist
MCH antagonist
Neurogen
Depression, Obesity
Pre-clinical
And for BipolarAt the APA annual meeting, Bruce Cohen MD, PhD of Harvard presented a list of drugs and nutrients being tested for bipolar and their mechanisms of action, including:
Xanomeline (muscarinic M1 agonist),
Aricept (donepezil, an Alzeimer's drug that is an anticholinesterase inhibitor)
Mirapex (pramipexole, a Parkinson's drug that is a dopamine3 receptor agonist),
Diprivan (propofol, a sedative that activates GABA-linked calcium channels)
Riluzole (memantine, an ALS drug that is a glutamate NMDA antagonist
Taurine (an amino acid that binds glutamate),
Pyridazines and pyrimidines (enhance mitochondrial function),
Magnesium (alters calcium influx, NDMA receptors, and kinase activity)
Mifespristone (RU-486, the morning after pill that is a cortisol/glucocorticoid antagonist).
Mailbag
Last week’s issue was largely devoted to diet and obesity. Charles writes:
BMI is a farce in that it does not measure the amount of body fat to lean muscle mass. I am 5'11 and I weigh 256 lbs at 10 percent body fat. Men should ideally be in the 12-15 percent range, and single digits is super. Once you reach 10 percent, one starts to see their abs. Women should never strive to go below 10 percent due to the fact that it messes with their hormonal levels and as a result their periods can stop. Their ideal should be 15-18 percent with 15 being the goal. I know plenty of people who are within the BMI and would be considered fat or obese. Anyone hitting in the 20 percent body fat range is obese.
Say It Ain’t So
A follow-up to last week’s "Supersize Me" review: McDonald’s recently introduced a fully-loaded fiesta salad that contains 27 g of total fat and 13 g of saturated fat, more than a quarter pounder. Its ingredients include salad mix, seasoned beef, cheddar/jack cheese, salsa, sour cream, and fried tortilla strips. The Caesar salad without chicken, on the other hand, appears to be a safe bet with 4 g total fat and 2.5 g saturated fat. For obvious reasons, the low fat balsamic vinaigrette is a healthier choice (3 g total fat, 0 g saturated fat) than the ranch (15 g total fat, 2.5 g saturated fat) and the creamy Caesar (18 g total fat, 3.5 g saturated fat).
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.comUpdated: Child Bipolar - Part I, Child Bipolar - Part II
Oldie but goodie: Sylvia Plath - In Her Own Words
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"Knowledge is necessity."Copyright 2004 John McManamy
poster:jrbecker
thread:350429
URL: http://www.dr-bob.org/babble/20040521/msgs/350429.html