New Treatment Algorithms For Depression
McMAN'S DEPRESSION AND BIPOLAR WEEKLY
May 1, 2002 Vol 4
No 16
Note: This
excellent newsletter is available weekly from:
http://mcmanweb.com/newsletter1.htm
ROLLING OUT THAT ALGORITHM
Newsletter 3#48 reported on algorithms, which essentially seek to answer "What
next?" when initial treatment fails. Algorithms represent an attempt to replace
shoot-from-hip psychiatry with step-by-step guidelines representing expert
consensus, though they are not meant to replace empirical clinical judgment.
Algorithms were pioneered by the Texas Medication Algorithm Project (TMAP),
which issued its first guidelines for bipolar in 1998, with a revision in June
1999. In Oct 2001, TMAP came out with the "roll out phase" of its bipolar
algorithm, Texas Implementation of Medical Algorithms (TIMA), involving the
wide-scale training of clinicians for use in the public sector.
As an illustration of what a difference two years make, 1999's algorithm listed
a choice of Depakote or lithium for patients presenting with mania or
hypomania, and Tegretol or Depakote for mixed episodes or cycling. It was a
full five stages down, at desperation level, just before ECT was considered as
an option, that an atypical antipsychotic such as Zyprexa was first mentioned,
and only as an add-on. By contrast, TIMA has Zyprexa right at the top, as a
first choice stand-alone treatment for either euphoric mania/hypomania, mixed
or dysphoric mania/hypomania, or psychotic mania.
The new guidelines also give first-time recognition to Lamictal, for treating
bipolar depression, and to Trileptal, similar chemically to Tegretol but with
fewer side effects. Significantly, TIMA lists its goals as "symptomatic
remission, full return of psychosocial functioning; and prevention of relapses
and recurrences," all which imply there are smarter ways to use the medications
available to us.
The TIMA project is headed up by Trisha Suppes MD, PhD and Ellen Dennehy PhD,
both who were lead authors in the earlier TMAP algorithm. In addition, a report
on TIMA in April's Journal of Clinical Psychiatry lists an all-star roster of
authors including Alan Swann, Charles Bowden, Joseph Calabrese, Robert
Hirschfeld, Paul Keck Jr, Gary Sachs, M Lynn Crismon, Marcia Toprac, and Steven
Shon. Owing to this and to the fact that a bipolar algorithm is about to be
applied on a significant scale for the first time, this Newsletter will take an
extended look at the new TIMA guidelines, bearing in mind the recommendations
are no substitute for what you and your psychiatrist may decide:
MANIA/HYPOMANIA
TIMA stresses the primacy of the mania/hypomania algorithm, even when bipolar
depression is involved. For patients presenting with euphoric mania/hypomania or
psychotic mania, the choice is between lithium, Depakote, or Zyprexa. For mixed
or dysphoric mania, Depakote or Zyprexa are the two options. TIMA distinguishes
between divalproex and valproic acid, recommending the former due to
"significantly better tolerability." (Abbott Laborories' Depakote is divalproex
sodium.)
For a partial response with good tolerance, the recommendation is to move to
combination therapy with two of the following: lithium, Depakote, or Trileptal,
or one of the same three mood stabilizers plus either Zyprexa or Risperdal. For
stage three, the physician is asked to keep one agent from the previous
combination and change to a different drug out of the same group. In stage four,
Seroquel and Geodon are added as options (as part of a two-med cocktail), and in
stage five we graduate to a three-med combination, with lithium plus one of the
anticonvulsant mood stabilizers plus one of the atypical antipsychotics. At
stage six, the option is ECT or adding Clozaril.
At stage seven, the algorithm begins to lose clarity with "other" options as
add-ons, including Lamictal, Topamax, and conventional antipsychotics. Lamictal
has its function on the depression side of the equation, but why Topamax is
relegated to the bottom is not discussed.
BIPOLAR DEPRESSION
TIMA's emphasis is on treating the patient for hypomania and mania, using its
depression algorithm as a concomitant treatment strategy. Accordingly, stage one
for both the mania/hypomania and depression algorithms are the same, using a
mood stabilizer or Zyprexa. Stage two adds an SSRI, Wellbutrin, or Lamictal to
the existing medications. TIMA implicitly concedes it is stepping out on a limb
for its stage one and stage two recommendations by acknowledging that stage
three "begins to rely more heavily on clinical consensus and expert opinion."
Even so, "there is only limited data on treatment of bipolar depression
following failure in stage two." Stage three offers the choice of adding lithium
or switching to an alternate antidepressant including Effexor or Serzone or
adding an antidepressant (for a double combination). The double combination
extends into stage four, with Lamictal considered an antidepressant for TIMA's
purposes. In using a combination, TIMA suggests antidepressants from different
classes (eg an SSRI plus Wellbutrin). Stage five involves switching to an MAOI
or adding an atypical antipsychotic. Stage six represents the kitchen sink,
from ECT to tricyclics to omega 3 to acupuncture to hormones. Why tricyclics
should be brought in at this late stage (and after MAOIs are tried) is not
explained.
DECISION POINTS
Week two into treatment involves the first critical decision point for
physician (and presumably the patient), building up to weeks six and eight,
where moving to the next phase of treatment needs to be considered should
symptoms persist. TIMA recommends that if a medication is to be discontinued,
the new medication should be started and brought to a therapeutic level, then
the medication to be discontinued should be gradually tapered over a period of
at least one month (unless the side effects from the first drug increases, in
which case, according to TIMA, the taper should begin earlier).
SIDE EFFECT MANAGEMENT
GI upset: Take medication with food and large amounts of liquid; consider
lowering the dose; use sustained release preparations when available; use
histamine blockers such as Tagamet and Zantac.
Mild tremor: Decrease dose; add 20-30 mg propranolol (a beta-blocker).
Parkinsonian tremor: Decrease dose, divide dosing; add one to two mg
benztropine, 100 mg amantadine (both anti-Parkinson's), or 25-50 mg Benadryl.
Sedation: Change dosing schedule
Extrapyramidal (tics, tremors, etc): Reduce dose; 20-30 mg benztropine, amantadine,
or Benadryl for akathisia, or clonidine (an anti-hypertensive) or lorazepam;
one mg benztropine for preventing or managing dystonia or one mg lorazepam for
managing dystonia.
Tardive dyskinesia: Lower dose; vitamin E in high doses (1,000 units/day) may
help.
Insomnia: Change dosing schedule; add 5-10 mg Ambien, 10 mg Sonata, or
benzodiazepine.
Sexual dysfunction: Use 4-7.5 mg yohimbine three times a day, 4-8 mg cyproheptadine
(a hay fever drug) shortly before sexual intercourse, or 75-300 mg/day
Wellbutrin.
THE CONTINUATION PHASE
Mania/Hypomania: TIMA recommends simplifying the medication regimen, with
gradual tapering, though it notes "little is scientifically known about the
relative need for combined mood stabilizers long term." Continuation with mood
stabilizers is recommended for those who underwent ECT in the initial phase of
treatment. TIMA recommends a lifetime regimen of mood stabilizers for those who
have had two manic episodes, or one severe episode with a family history of
bipolar or major depression. For a patient with one episode and no family
history, medication and tapering may be considered six months into remission
(allowing for individual circumstances).
Bipolar depression: Here TIMA enters into potential controversy by recommending
tapering and discontinuing antidepressants one to three months after full
remission for first-time depression patients. The recommendation squares with
The Expert Consensus Guidelines for the Treatment of Bipolar Disorder published
in 2000 (Gary Sachs MD of Harvard lead author), but goes against the grain of
research conducted by Michael Thase MD of the University of Pittsburgh showing
that discontinuation of an antidepressant leads to high relapse rates.
Moreover, there is increasing recognition by bipolar experts of the depressive
side of the illness. As Ross Baldessarini MD of Harvard put it at last week's
DRADA conference in Baltimore, bipolar depression "has been raised on my list
to public enemy number one." TIMA concedes it may be on shaky ground by
acknowledging that "guidelines are limited due to few scientific studies on the
long-term management of antidepressants in bipolar patients."
DRUG INTERACTIONS
TIMA goes into considerable detail, noting that caffeine is one of the drugs
that may lower lithium levels. This report will restrict itself to the
depression and bipolar drugs that may interact with each other, including:
* Depakote: Increases Lamictal levels, may increase tricyclic levels and
possibly SSRIs. May be decreased by Tegretol. May be increased by SSRIs.
* Tegretol: Can induce the metabolism of Lamictal, Depakote, benaodiazepines,
and tricyclics. Trycyclics may decrease Tegretol levels. Using Tegretol with Clozaril
is not recommended.
* Zyprexa: Elevated levels when used with Luvox. Fifty percent increase in
clearance from the system when used with Tegretol.
* Clozaril: Luvox and Serzone may raise levels and inhibit its metabolism.
* Seroquel: Luvox and Serzone may increase blood levels. Tegretol may
decrease blood levels.
* Geodon: Tegretol will decrease levels.
* Topamax: Can potentially decrease Depakote levels. Depakote and Tegretol
appear to decrease Topamax levels.
* Lamictal: Depakote inhibits its metabolism; therefore Lamictal should be
increased slowly when these medications are combined. Tegretol induces the
metabolism of Lamictal; therefore higher doses of Lamictal are required when
used with Tegretol.
* Prozac: Results in increased concentrations of tricyclics, antipsychotics,
and Tegretol. Should not be taken with MAOIs or in a patient who has recently
discontinued an MAOI.
* Paxil: Causes increased tricyclic levels.
* Zoloft: Causes increased tricyclic levels.
* Wellbutrin: Should not be given with MAOIs.
* Serzone: Can increase plasma concentrations of MAOIs, Haldol, and
benzodiapines.
FURTHER READING
You can check out the complete TIMA bipolar algorithm at:
http://www.mhmr.state.tx.us/CentralOffice/MedicalDirector/TIMABDman.pdf
SEGUE
And now back to normal programming ...
GEODON
Pfizer has slightly revised its letter to health providers, its labeling, and
package insert to warn that Geodon should not be taken with a number of drugs
that prolong the QT interval, including Thorazine. For more information,
please go to:
http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#geodon
DOING THE RIGHT THING
This week President Bush came out strongly on the side of mental health parity
by urging Congress to act. Standing alongside Senator Pets Domenici (R-New
Mexico), a co-author of the mental health parity bill before Congress, Bush
told a gathering at the University of New Mexico: "Mental disability is not a
scandal. They deserve a health care system that treats their illness with the
same urgency as a physical illness ... We are determined to confront the hidden
suffering of Americans with mental illness."
The President's actions were praised by the Mental Health Association and other
mental health groups. A US Senate vote is expected in a few weeks.
DOING THE WRONG THING
The Washington Times uncritically published an analysis from a so-called
handwriting expert who claims the individual who mailed anthrax to US Congress
is white, middle-aged - and has bipolar.
LITHIUM
"Despite declining use, especially in the United States, the evidence base
supports the view that lithium should be the first choice prophylactic drug
for most patients with bipolar disorder. To date the alternative mood
stabilizers have not been as extensively investigated. Valproate [Depakote] or
carbamazepine [Tegretol] should be confined to second line use in those who do
not respond to lithium, or who have significant and unacceptable side effects
due to lithium, and in patients with a history of rapid cycling."
From an editorial in the British Medical Journal.
http://bmj.com/cgi/content/full/324/7344/989
OMEGA-3
A NY TIMES interview with Dr Joseph Hibbeln of the NIH, a champion of omega-3,
notes:
* Infant monkeys fed baby formula supplemented with omega-3 are stronger and
more alert even at less than a week than monkeys given standard baby formula.
* Depression is 60 times higher in New Zealand, where the average consumption
of seafood is 40 pounds a year vs Japan, where a person consumes nearly 150
pounds of seafood a year.
* Postpartum depression is 50 times more common in countries with low levels of
seafood consumption. During pregnancy, a woman's body becomes depleted of fatty
acids, which are transferred to the fetus.
* Omega-3 seems to be critical to the growth and maintenance of brain cells,
especially cell membranes.
* When omega-3 is not available, the body uses omega-6, which produces cell
membranes less able to cope with neurotransmitter traffic.
* And of course the famous 1999 Harvard pilot study.
http://199.97.97.16/contWriter/yhd7/2002/04/18/medic/9159-0014-pat_nytimes.html
LIGHT THERAPY
A Yale University study of 16 pregnant women with depression has found three
weeks of light box therapy improved depression symptoms by 49 percent. Those
who continued the treatment for five weeks experienced a 59 percent
improvement.
http://my.webmd.com/content/article/1663.52988
SEXUAL SIDE EFFECTS
An earlier Newsletter reported on a University of Virginia study of sexual
dysfunction side effects in antidepressants. That study (funded by Wellbutrin
manufacturer GlaxoSmithKline) has now been published in the Journal of
Clinical Psychiatry. The study, which surveyed 6,297 patients, found patients
taking Wellbutrin and Serzone had a "statistically lower" prevalence of sexual
dysfunction than those on Prozac, Paxil, Zoloft, or Effexor. Those taking
Wellbutrin also fared better than those on Celexa or Remeron. Prozac patients
did better than those on Paxil. Otherwise, there were no statistically
significant differences.
http://www.psycport.com
LOW DOSE LEXAPRO
A University of Nebraska eight-week study of 491 patients with major depression
has found Lexapro, an isomer of Celexa, efficacious at 10 mg/day, the lowest
dosage of any SSRI. "This may help reduce patient discontinuation rates,"
according to the study's lead author, William Burke MD. Lexapro at 10 and 20
mg/day showed greater results after eight weeks than 40 mg/day of Celexa. Four
percent discontinued 10 mg Lexapro vs 8.8 percent taking 40 mg Celexa.
http://www.docguide.com/news/content.nsf/news
FOLIC ACID
A Massachusetts General Hospital open trial of 12 patients with major
depression were treated with leucovorin (a folic acid) as a supplement to
SSRIs. After eight weeks, only 31 percent of the completers achieved a
response (19 percent achieved remission), leading the study's authors to
conclude: "Leucovorin appears to be modestly effective as an adjunct among
SSRI-refractory depressed individuals with normal folate levels."
http://ipsapp009.lwwonline.com/content/getfile/4464/9/3/abstract.htm
ST JOHN'S WORT
Add another one to the many drug interactions with St John's wort: According to
a Dutch study, St John's wort reduces blood levels of irinotecan (CPT-11) used
treating advanced colorectal cancer.
http://www.medscape.com/viewarticle/431592
SUICIDE AND DIET
Two studies:
A Northeastern University study has found women with anorexia nervosa are 57
times more likely to commit suicide than other women. Of 246 women with eating
disorders who were studied over 8.6 years, 58 reported suicide attempts. Four
anorexia subjects died by suicide during the course of the study.
http://www.nupr.neu.edu/04-02/eatingdisorders.html
A Cornell/NIH study has found that youths from homes where there is not enough
to eat are five times more likely to attempt suicide and four times more likely
to suffer from dysthymia. One in five American children live in poverty, the
highest level of childhood poverty among developed nations.
http://www.news.cornell.edu/releases/April02/hunger.kids.ssl.html
DOWN IN THE MOUTH
One more thing to be depressed about: A University of North Carolina study has
found that depressed patients have twice the odds of sub-optimal outcomes for
periodontal treatment. The study's lead author John Elter speculated a number
of possible factors, including poor compliance, smoking, and impaired immune
system.
http://healthnewsdigest.com/news/hlth_teeth-27.html
RIGHT TO DIE
Previous Newsletters have reported on Diane Pretty, the terminally ill UK
mother who unsuccessfully sought a court order that would have allowed her to
commit suicide with her husband's aid. Diane is paralyzed from the neck down.
On Monday, the European Court of Human Rights ruled that the UK had violated
none of her human rights, thus exhausting her final appeal.
MCMAN'S WEB
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