T
he statistics
on depres-
sion
are
troubling.
One fifth of
Americans will experi-
ence major depression
or bipolar disorder in
their lifetimes [1]. Yet, less than 40 percent receive any treatment
in the first year, and only about 20 percent receive adequate treatment
[2]. Although death rates are declining for most major illnesses, the
suicide rate has climbed almost 25 percent over the last 15 years.
Depression puts a huge economic burden on society—over 200
billion dollars per year in the USA [3].
With these problems in mind, The University of Louisville (UofL)
Depression Center (http://louisville.edu/depression) has a three-
part mission: 1) treat the most people possible with best practice;
2) perform basic and applied research to find better treatments;
and 3) educate clinicians and the general public on depression
and related conditions. We still have much to do, but are currently
providing over 50,000 treatment visits a year, performing major
research projects with national funding, and delivering a wide array
of educational programs including medical student and resident
training, CME conferences and workshops, and a public presen-
tation series. Together with colleagues in this community, other
universities, and the National Network of Depression Centers,
we are engaged in large-scale projects to improve patient care and
reduce the risk of suicide.
A large number of antidepressants and other therapies are avail-
able for depression, but there are many limitations to present-day
treatment. The remission rate from any single treatment has re-
mained less than 40 percent, depression frequently has a chronic
course, and many persons don’t have access to effective treatment.
This article briefly describes three newer approaches that hold
promise for enhancing treatment outcome or promoting greater
availability of evidence-based therapy.
NOVEL PHARMACOLOGICAL TREATMENTS
Because all currently available antidepressants share a similar mode
of action on monoamines such as serotonin and norepinephrine,
there is great need for medications that work through different
pathways. A recent candidate is ketamine, an antagonist of N-meth-
yl-D-aspartate receptors, which has very rapid antidepressant effects
when given intravenously [4-7]. This drug may be abused because of
psychedelic properties and out-of-body experiences, but it is used
in medical practice in higher doses as an anesthetic [4-7]. Concerns
about a short duration of action, in addition to abuse potential and
dependency, have limited the wide-spread use of this glutamate
MENTAL HEALTH
system modulator for treating depression. Although ketamine has
ultra-short onset of action, with antidepressant responses within
one hour of a single infusion, the antidepressant effect is largely
dissipated by one week after infusion [5]. There are some studies
that have reported a more durable response from repeated injections
[8,9]. However, ketamine apparently does not have the long-term
efficacy of standard antidepressants. Typical side effects are dizzi-
ness, somnolence, distortions of reality, anxiety, nausea, blurred
vision, and headache [10]. These side effects usually diminish or
are eliminated with a series of infusions [10].
Research on ketamine has opened a flood-gate of interest in de-
velopment of other drugs which could impact the glutamate system
while having a longer duration of action, no psychedelic properties
or abuse potential, and an improved side effect profile [9]. No
medications from this pipeline have been approved yet for clinical
use, but there is considerable hope that breakthroughs will result.
Treatment of acute suicidal risk is an especially important potential
application of ketamine or other glutamate system modulators. A
recent meta-analysis of 10 studies found that ketamine has a strong
and rapid effect on reducing suicidal thinking [8]. UofL recently
participated in a multisite study to examine the S-enantiomer of
ketamine (esketamine) in acutely suicidal depressed patients. That
study is now completed, and data analysis is underway. Drs. Rif
El-Mallakh and George Kalayil at the UofL Depression Center are
working on potential applications of ketamine or other glutamate
system modulators [4].
The opiate receptor system is another possible target for the
development of novel drugs for depression. Recent studies with
almost 800 patients at the Massachusetts General Hospital, a part-
ner institution with UofL in the National Network of Depression
Centers, has found that a combination of buprenorphine and sami-
dorphan, which blocks the receptor thought to be largely responsible
for dependence, was significantly more effective than placebo for
treatment-resistant depression [4]. Other positive findings were
that the drug combination was very well tolerated, and there was no
evidence of dependence or withdrawal. The drug is not yet available
for clinical use. However the encouraging results from research at
MGH give hope that we may soon have another powerful option
to use in treating depression.
MEASUREMENT-BASED CARE
UofL has taken a lead along with other National Network of De-
pression Centers members, including the Universities of Michigan
and Iowa, Johns Hopkins and the Mayo Clinic, in implementing
a measurement-based care system into routine clinical practice.
Measurement-based care involves using standardized ratings of
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DECEMBER 2018
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