Mar c h 1, 2005 www. e i nt e r na l me di c i ne news .

c om Psychiatry Clinical Rounds 31

Genetic Defect May
Raise Depression Risk
A
recently discovered genetic mutation that caus-
es dysfunction in the synthesis of serotonin
might explain why some depressed patients are re-
sistant to drug treatment, researchers say.
Xiaodong Zhang, M.D., and colleagues at Duke
University, Durham, N.C., screened 87 adults with
unipolar major depression, 60 adults with bipolar
disorder, and 219 controls for a mutant allele known
as 1463A in an enzyme that helps direct synthesis
of serotonin known as human tryptophan hydrox-
ylase 2 (hTPH2).
Overall, 10% of patients with major depression
had the gene mutation, compared with 1% of the
controls. None of the individuals with bipolar dis-
order had the mutation (Neuron [online]
2004;45:www.neuron.org).
Seven of the nine depression patients with the
hTPH2 mutation had a family history of mental ill-
ness or drug and alcohol abuse, six had either at-
tempted suicide or shown suicidal behavior, and
four had generalized anxiety symptoms. In addi-
tion, seven of the patients with the mutation
showed a lack of responsiveness to an SSRI, and the
other two responded only to high doses.
Communication among neurons may stall if
serotonin levels are low, as they often are in people
with depression. Additional larger studies are need-
ed to confirm these findings and to explore the re-
lationship between the genetic mutation and de-
pression, the researchers said.
Heidi Splete
St. Johns Wort Equals Paroxetine in New Study
BY NANCY WALSH
Ne w York Bureau
EX E TE R, ENGL AND A proprietary
formulation of St. Johns wort was equiv-
alent in efficacy to paroxetine for moder-
ate to severe depression in a prospective,
randomized, multicenter study, Stephan
Klement, M.D., reported at a symposium
on alternative and complementary thera-
pies sponsored by the universities of Ex-
eter and Plymouth.
A group of 101 German patients whose
Hamilton Rating Scale for Depression
(HAM-D) scores exceeded 22 points were
randomized to receive standardized hy-
pericum extract WS 5570 (Dr. Willmar
Schwabe Pharmaceuticals, Karlsruhe, Ger-
many) in an initial daily dose of 900
mg/day, or paroxetine (Paxil) in an initial
dose of 20 mg/day.
Patients whose initial response was in-
sufficient could increase the dose of hy-
pericum extract to 1,800 mg/day or of
paroxetine to 40 mg/day. Response was
considered to be a reduction of 50% or
greater on the HAM-D, and remission
was defined as a HAM-D end point total
score below 10, said Dr. Klement of
Schwabe Pharmaceuticals.
In a preplanned interim analysis at 6
weeks, response rates were 60% in the hy-
pericum group and 63% in the paroxetine
group, while remission rates were 46.6%
with hypericum and 42.9% with paroxe-
tine. The rates in the two groups were
comparable, Dr. Klement said in a poster
session.
Adverse events when calculated as inci-
dence densities were 0.039/day of expo-
sure for hypericum and 0.056/day of ex-
posure for paroxetine. This represents a
43.6% advantage for hypericum based on
ratio, he said.
These findings differ from those seen in
another randomized trial that compared a
different extract of St. Johns wort (LI 160,
Lichtwer Pharma, Berlin) with sertraline
and placebo. In that study, performed in
the United States by the Hypericum De-
pression Trial Study Group, neither ser-
traline nor the hypericum extract was sig-
nificantly different from placebo in a
group of 340 patients with major depres-
sion ( JAMA 2002;287:1807-14).
The major differences between the two
trials can be attributed to different patient
populations and the missing assay sensi-
tivity in the [JAMA] trial, Dr. Klement
told INTERNAL MEDICINE NEWS.
Patients in the American trials were re-
cruited from tertiary care clinics, and pa-
tients who had not responded to adequate
trials of two antidepressant trials were in-
cluded. The depressive episode had already
persisted for more than 2 years in roughly
one-third of patients, and for between 6
months and 2 years in a further third. This
suggests that many of the patients were
chronically depressed and some may have
been treatment resistant, Dr. Klement said.
In the German study, patients were lim-
ited to only one previous adequate anti-
depressant therapy trial, probably limit-
ing the number of treatment-resistant
patients, he said. The mean duration of
the current depressive episode was signif-
icantly shorter in the German trial, sug-
gesting that fewer patients were chroni-
cally depressed, and patients had sought
care spontaneously in primary or sec-
ondary care settings.
The major drawback of the American
study was its lack of assay sensitivity, Dr.
Klement said. Sertraline, a proven syn-
thetic antidepressant, served as a positive
control to check the sensitivity of the
study. Neither St. Johns wort extract nor
sertraline differed significantly from place-
bo in the primary target criteria, which
were reduction of the Hamilton depres-
sion total score and the number of patients
showing complete remission.
The trial therefore did not have the as-
say sensitivity to document an antide-
pressant drug effect and thus does not ap-
pear to be useful for estimating the
therapeutic potential of either St. Johns
wort or sertraline, he said.
In the German study, no placebo group
was included as it would have been un-
ethical to give placebo to patients suffering
from severe depression, a potentially life-
threatening condition, Dr. Klement said.
But this trials assay sensitivity is sup-
ported by the observed treatment effect
for paroxetine, which is in line with pre-
viously published data from trials against
placebo and synthetic antidepressants, he
said. I
Visits, Calls May Help Elderly Depression
BY DAMI AN Mc NAMARA
Mi ami Bureau
FORT MY ERS , FL A. Home visits and follow-up tele-
phone calls improved elderly depression in a program that
used existing community services for seniors in Seattle, ac-
cording to a presentation at the annual meeting of the
Academy of Psychosomatic Medicine.
Rates of depression are higher in older adults who are
socially isolated, have high medication comorbidity, or are
homebound. About one-fifth to one-sixth of elderly indi-
viduals in the United States have clinically significant de-
pression. They are more likely to have minor depression
or dysthymia, compared with their younger counterparts.
A 12-month, randomized, controlled trial showed the
Program to Encourage Active, Rewarding Lives for Seniors
(PEARLS) effectively improved depression among older
adults at higher risk, specifically those who are physically
impaired, socially isolated, and/or of lower socioeco-
nomic status.
It is home based, so in a way it is a systematized, styl-
ized way to do house calls, but a postmodern version done
by social workers, not doctors, Paul Ciechanowski, M.D.,
explained. Its amazing how much extra information you
get by observing and visiting patients in their own homes,
said Dr. Ciechanowski of the University of Washington,
Seattle. The university runs PEARLS in collaboration with
Senior Services Seattle/King County, Aging and Disabili-
ty Services, and Public Health Seattle King County. The
study was funded by the Centers for Disease Control and
Prevention.
There were 138 participants, 99 referred from agencies
and 39 who were self-referred. About half were diagnosed
with dysthymia, the other half with minor depression. The
mean age was 73 years, 79% were female, and the major-
ity had a mean annual income of less than $10,000. At base-
line, 35% were taking antidepressants. People were ex-
cluded if they had major depression or another psychiatric
disorder, substance abuse, or a cognitive disorder.
After randomization, there were 66 patients in a routine
care group and 72 in an intervention group. Routine care
included referral and communication between the pa-
tients primary care physician, the community agency so-
cial worker, and University of Washington researchers. The
intervention included a mean of 6.6 1-hour problem-solv-
ing treatment (PST) sessions in the home over 19 weeks.
PST is effective, nonpsychiatric, and consistent with other
modern self-management strategies in medical disease, Dr.
Ciechanowski said. We define and break down problems,
establish realistic goals, and take small, incremental steps.
They begin to feel empowered.
The intervention also included one or more of the fol-
lowing: problem-solving counseling sessions, social activa-
tion, physical activity, and/or prescription of antidepressants.
If there was not a 50% improvement in depression
scores, it was a red flag. The PEARLS staff would then con-
sult with the patients primary care physician about initi-
ation or adjustment of medication. I ended up calling 52
people, mostly providers, about drug therapy and other pa-
tient factors, Dr. Ciechanowski said. Seven in the inter-
vention group started an antidepressant versus four in the
controlso not a big difference or change.
A meeting attendee asked Dr. Ciechanowski how par-
ticipants reacted to the PEARLS intervention. Most peo-
ple loved it. These were lonely people. The challenge was
to talk about PST and not everything else. I
I
NTERNAL MEDICINE NEWS asked
David Spiegel, M.D., to comment on
the new hypericum trial.
Dr. Spiegel, the Jack, Lulu, and Sam
Willson Professor in the School of
Medicine and associate chair of psychi-
atry and behavioral sciences, Stanford
(Calif.) University, had this to say:
This is an interesting study, well
conducted but with the obvious
drawbacks that it has no placebo con-
trol group. Also, it is always harder to
prove statistically the absence of a dif-
ference (between hypericum and
paroxetine) than the presence of a
difference.
The author is right that the JAMA
study suffered because placebo pa-
tients actually did slightly better than
those randomized to either hypericum
or sertraline. Unfortunately, they used
rather low doses of sertraline (50 or
100 mg) when one can prescribe up to
200 mg. Thus, neither treated group
did especially well. They might have
been treatment resistant, as the author
suggests.
This new study does provide sug-
gestive, but not definitive, evidence
that hypericum works as well for mild
to moderate depression as paroxetine,
but it does not rule out the possibility
that this group of patients had tran-
sient depressive symptoms that are re-
ally responding to a placebo effect or
the passage of time.
Sizing Up the Clinical Trial Findings