Recent Studies of

Alan F. Schatzberg, M.D.

the Biology and Treatment

of Depression
Major depression is one of the most common psychiatric disorders, with lifetime prevalence rates of
over 15%. Recent research provides new insights on which brain regions are affected in the disorder,
underlying biological mechanisms, and possible novel treatments. This review discusses a number of
recent research advances in epidemiology, genetics, imaging, treatment, and pharmacogenetics. It also
outlines issues or questions that still need to be addressed, and it begins to outline a framework for
understanding why and how depression may occur.

EPIDEMIOLOGY AND COURSE
Depression is a common disorder. The National
Comorbidity Survey reported a prevalence rate of
5% for current depression and a lifetime rate of
17% (1). Some investigators have noted that these
rates are higher than those seen in the
Epidemiologic Catchment Area (ECA) survey (2),
suggesting an overinclusion of milder forms of
depression. Indeed, a reassessment and follow-up
study using more clinically relevant definitions of
severity of illness yielded rates of depression sub-
groups that are more consonant with other reports
as well as clinical impressions (2, 3). Still, major
depression is a common disorder not only in the
From the Department of Psychiatry and Behavioral Sciences, Stanford University Medical School,
Stanford, California. Send reprint requests to Dr. Schatzberg, Department of Psychiatry and Behavioral
Sciences, Stanford University Medical School, 401 Quarry Road, Stanford, CA 94305-5717; e-mail,
afschatz@stanford.edu.
Acknowledgment
This paper was supported by grant MH 50604 from the National Institute of Mental Health.
CME Disclosure Statement
Alan F. Schatzberg, M.D., Chairman, Department of Psychiatry and Behavioral Sciences, Stanford
University School of Medicine.
Consultant/Speaker: Abbott, Aventis, Bristol-Myers Squibb, Corcept, Lilly, Forest, GlaxoSmithKline,
Innapharma, Janssen, Merck, Novartis, Organon, Pharmacia, Solvay, Somerset, Wyeth. Grants:
Bristol-Myers Squibb, Lilly, Wyeth. Equity: Corcept, Cypress Biosciences, Elan, Merck, Pfizer. Co-
founder: Corcept Therapeutics. Co-inventor: intellectual property owned by Stanford University.
United States but in all societies, and even milder
forms carry considerable morbidity (3). Indeed, the
World Health Organization/World Bank Study
ranked unipolar depression the fourth highest
cause of morbidity in 1990, with the expectation
that by 2020 it would become the second leading
cause of disability (4, 5).
Several recent studies have explored specific sub-
types of depression. For example, atypical features
as defined in DSM-IV-TR have been a focus of a
number of epidemiological and clinical studies (6,
7). Parker and colleagues (6), in Australia, reported
that the absence of mood reactivity appeared to be
associated with severity of depression and that other
atypical symptoms (e.g., hyperphagia) did not
appear to be related to each other, raising questions
about the validity of the subtype. Others, however,
have observed that atypical features do coalesce (7,
8), so this issue remains subject to debate.
Psychotic major depression was the focus of one
analysis of a large European survey involving some
19,000 subjects in five countries (9). Psychotic fea-
tures were found in nearly 19% of subjects who
met criteria for a major depressive episode (MDE),
a rate slightly higher than the 15% reported in the
ECA study. Psychotic features were most com-
monly seen in individuals who endorsed eight or
nine items of the criteria for major depression
(33%), but they were also seen in individuals with
milder forms of MDE.
Alternative presentations of MDE have increas-
ingly become a research focus, for several reasons,
including the common presentation of MDE as

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physical complaints in primary care and the efficacy
of several psychotropic agents in both mood and anx-
iety disorders as well as chronic pain. Many patients
with MDE in primary care settings present with
complaints of physical symptoms, including pain
(10). Although pain is commonly observed in MDE
in primary care settings, there has been considerable
skepticism about the generalizability to epidemiolog-
ical community samples or to psychiatric practices.
In the large European sample mentioned above,
chronic painful physical symptoms were observed
in 16% of the general population but in 43% of
subjects who met criteria for MDE (11). Less than
half of the respondents who reported MDE and
chronic pain symptoms had an identifiable organic
cause of their pain. Headache (including neck
pain), shoulder pain, and backache were the most
common types of pain. Compared with DSM-IV-
TR criteria for MDE, chronic painful symptoms
were more commonly seen in subjects with MDE
than was guilt, and nearly as commonly as loss of
energy. These data have been recently replicated in
a study in California (unpublished 2004 study of
M. M. Ohayon). Consideration should be given to
including chronic pain symptoms in the criteria for
major depression in future classification schemes.
As more effective medication and psychotherapy
strategies have been developed, greater attention has
been given to the significance of residual symptoms
that do not meet full criteria for MDE; patients
with such residual symptoms have been termed par-
tial responders and their illnesses subsyndromal dis-
orders. Analyzing outcome data from the National
Institute of Mental Health (NIMH) Collaborative
Program on the Psychobiology of Depression
(Collaborative Depression Study), Judd and col-
leagues (12, 13) reported that residual depressive
symptoms are associated with a higher risk of
relapse or recurrence, greater utilization of medical
services, and greater risk of substance abuse. Thus,
increasing attention has been given to maximizing
response to both somatic and psychosocial inter-
ventions (discussed further below).
A number of explanations have been proposed
for the continuation of depressive symptoms
despite treatment. Paykel’s group (14) reported a
decade ago that residual physical symptoms of
depression were associated with a greater likelihood
of relapse or recurrence. More recently, Fava and
associates (15), in a pooled analysis of studies of
duloxetine (a dual norepinephrine/serotonin reup-
take inhibitor), reported that remission of depres-
sive symptoms was highly associated with
improvement in pain symptoms. Thus, focusing on
both physical and emotional symptoms in depres-
sion could provide added benefit. Prospective
focus.psychiatryonline.org
SCHATZBERG
large-scale studies comparing dual uptake agents
and selective serotonin reuptake inhibitors (SSRIs)
in depressed patients with comorbid pain could
help illuminate this area.
Another area that has attracted attention is the
role childhood abuse may have in adult major
depression and response to treatment. Our group
has reported that in chronically depressed patients
with early abuse, a specialized form of psychother-
apy (cognitive behavioral analysis system of psy-
chotherapy—CBASP) was more effective than
nefazodone (16), whereas the opposite was seen in
nonabused patients. Early abuse has also been
reported to be associated with an increased risk of
depression, comorbid pain, and utilization of med-
ical services in health maintenance organization
(HMO) settings (17). Thus, research data appear
to be converging on an important adult medical
phenomenon with roots in childhood.
REVIEW
GENETICS
The genetics of major depression has been a
focus of a great deal of research over the past several
decades. For much of that time, linkage studies
failed to establish clearly any single candidate gene,
which led investigators to argue that depression
represented a complex genetic disorder, to which
many different genes could potentially contribute,
either alone or in combination with other genes or
with environmental factors such as stress. Recently
a number of interesting candidate genes have been
identified, primarily from population-based or
case-control studies. Several of these genes point to
potential interactions with stress.
The short form of the promoter for the serotonin
(5-HT) transporter was reported a number of years
ago to be associated with neurotic traits. Although
subsequent studies did not find a genetic risk of
depression in subjects with a short promoter (18),
the short form has been associated with increased
amygdala activation with stress (19). In the past
few years, the short form has also been reported to
predict poor response or intolerance to SSRIs in
Caucasians in Europe and in the United States (see
Pharmacogenetics below). In a major longitudinal
study in New Zealand that followed subjects from
childhood (18), the short form of the promoter by
itself was again not found to be associated with
increased risk of depression in the absence of stres-
sors; similarly, stressors by themselves did not pre-
dict major depression. However, a significant
gene-by-stress interaction was noted, with s/s
homozygotes for the transporter promoter at
greater risk of developing depression if three or
more stressful life events were encountered. This
FOCUS Winter 2005, Vol. III, No. 1 15
 SCHATZBERG
could be a major lead in our understanding of the
interaction between biological risk and psychosocial
precipitants.
Stress activates both the hypothalamic-pituitary-
adrenal (HPA) axis and the sympathetic nervous
system. The ability to turn off the HPA axis via
feedback mechanisms is widely believed to be a
key feature of healthy adaptation, and individuals
who are less able to moderate their stress response
may be more prone to depression. Feedback inhi-
bition is mediated in part via the glucocorticoid
receptor in the hypothalamus, hippocampus, and
pituitary. This receptor is surrounded by chaper-
one heat shock proteins (HSPs), one of which
(HSP90) has been implicated in increasing the risk
of depressive episode as well as predicting more
rapid response to antidepressant treatment.
Multiple single-nucleotide-polymorphism geno-
types of the FKBP5 gene were explored in two
German cohorts. Patients with the T/T genotype
at rs1360780 demonstrated more than twice as
many depressive episodes as did the C/T or C/C
subtypes (20). This T/T genotype is associated
with increased expression of the FKBP5 protein,
which may result in glucocorticoid receptor insen-
sitivity. However, direct study of patients with the
T/T genotype did not point to their having more
elevated cortisol levels, and they demonstrated
more rapid responses to antidepressant treatment.
Thus, although the exact role of this gene or pro-
tein in depression remains to be elucidated, the
gene is clearly worthy of further study.
Decreased serotonin activity has long been
thought to play a key role in the pathophysiology
of depression and response to treatment. Serotonin
is synthesized from tryptophan via a tryptophan
hydroxylase. Recently Zhang et al. (21) and Patel et
al. (22) elegantly demonstrated that neuronal syn-
thesis of serotonin is controlled largely via trypto-
phan hydroxylase 2 (TPH-2) and not the 1 form,
which was formerly thought to regulate synthesis
in the brain but is now seen to be involved mostly
in the periphery. This observation was recently sup-
ported by a report that a mutation in TPH-2 was
found in some 10% of subjects with unipolar
major depression, compared with 1.5% of control
subjects (23). This mutation was associated with an
80% decrease in serotonin levels when expressed in
a cell line. The variant was not observed in a cohort
with bipolar illness. Thus, at least some depressions
may be due to a gene variant associated with low
serotonin activity. Whether this TPH-2 gene can
be used to predict response to SSRI treatment has
not yet been studied.
In two of the three genes discussed above, stress
could play an important role in interacting with a
16 Winter 2005, Vol. III, No. 1 FOCUS T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I AT RY
genetic risk to lead to a depression. In the third gene,
decreased synthesis of an important brain neuro-
transmitter could reflect a specific genetic variant.
BRAIN IMAGING
STRUCTURAL IMAGING
In the past decade, hippocampal volume has
become a focus of much research in MDE. The
impetus has been the work of Sapolsky and of
McEwen (24, 25) showing that stress and gluco-
corticoids could be neurotoxic and lead to hip-
pocampal neuron loss in lower animals. A related
finding is that antidepressants appear to increase
neurogenesis in the hippocampus, which some
have argued may be a key mechanism of action for
these medications (26, 27).
Smaller hippocampal volume has been reported
in depressed patients in several studies (28–33) but
not others (34–37). A recent meta-analysis sug-
gested that hippocampal volume is lower in depres-
sives if one does not include the amygdala in the
volume analysis (38). The findings of these various
studies are summarized in Table 1.
A number of other factors could also affect volu-
metric differences. Sheline and colleagues reported a
significant negative correlation between hippocam-
pal volume and total duration of depression, but not
age (39). They argued that this finding may reflect
chronic exposure to stress, which is consistent with
basic research suggesting that glucocorticoids could
be neurotoxic. In addition, Vythilingam and col-
leagues reported that depressed patients with a his-
tory of early child abuse had smaller hippocampi
than did healthy controls (32), which is consistent
with an effect of cortisol on hippocampal volume.
This hypothesis has been appealing to many
investigators, but earlier data from Axelson and
colleagues showed no relationship between cortisol
activity and hippocampal volume (40). A number
of other perspectives suggest that lower hippocam-
pal volume could be a risk factor for depression
rather than a result of it (41). For one thing, hip-
pocampal volume is largely genetically determined
(42–44). Our group reported that genetics exerted
a greater effect on hippocampal volume than did
early stress in squirrel monkeys (42). Sullivan and
colleagues (43) and Pitman’s group (44) reported a
significant effect of genetics on hippocampal vol-
ume in twin studies. These three studies all point to
strong genetic influences on hippocampal volume.
Other data point to smaller hippocampal volume
presaging untoward outcomes. First-episode,
younger depressives already had smaller hip-

pocampi than control subjects in a German study
(31). In a Veterans Administration study of post-
traumatic stress disorder (PTSD) in twins (44),
identical twins who were discordant for trauma
exposure had similar hippocampal volumes; sub-
jects with smaller hippocampi were more likely to
develop PTSD if exposed to combat. These data all
suggest hippocampal volume is related to risk of
depression. Indeed, another recent study reported
smaller hippocampi in depressives with l/l genotype
for the 5-HT transporter (45). This finding does
not entirely fit with the Caspi et al. (18) finding
that the s/s form of the gene was associated with risk
of depression in the face of stress. In spite of these
findings suggesting that small hippocampal volume
is a risk factor for MDE, depression and stress could
still result in a further diminution of hippocampal
size. For example, Brown and colleagues reported
that medical patients taking steroids had smaller
hippocampi than did medical control subjects (46).
Debate in this area is likely to continue until longi-
tudinal studies with magnetic resonance imaging
and cortisol status are undertaken with depressed
subjects or their at-risk offspring.
FUNCTIONAL IMAGING
Functional imaging studies suggest that hip-
pocampal activity may be disordered in depres-
sion. A number of groups early on reported verbal
memory impairment in the disorder (47, 48);
however, my colleagues and I reported that gener-
ally nonelderly psychotic depressives—but not
nonpsychotic depressives—demonstrated impair-
ment in verbal memory compared with healthy
controls (49). In the same study, we reported a
marked impairment in an attention/response inhi-
bition task in psychotic depressives—indicative of
prefrontal/anterior cingulate involvement—and
suggested a connection between these deficits.
Bremner and colleagues (50) recently reported
that verbal memory impairment in depression is
associated with difficulty in activating both the
hippocampus and the anterior cingulate using
position emission tomography (PET). They sug-
gested a possible circuit involving the prefrontal
cortex, anterior cingulate, and hippocampus in
depression (50).
Decreased prefrontal activity in depression using
PET is a well-established finding (51–53). Of par-
ticular interest is the work of Drevets and Mayberg
showing that the subgenual cortex (inferior/poste-
rior aspect of the frontal lobe) is activated during
sadness induction in depression, that it may be sig-
nificantly reduced in volume, and that its activity
may change in response to antidepressants (54–56).
focus.psychiatryonline.org
SCHATZBERG
Hippocampal Volume in Major
Table 1.
Depression
1. Several studies demonstrate smaller hippocampal volumes in
patients with major depression (28–33)
2. Others show no differences between patients with major depression
and control subjects (34–37)
3. If the amygdala is included in volume analysis, hippocampal volume
may not measure smaller in depressed subjects (38)
4. Duration of depression may be (39) or may not be (31) associated
with smaller hippocampal volume
5. Early abuse may be associated with smaller hippocampal volume in
subjects with major depression (32)
6. Hippocampal size is strongly influenced by genetics (42–45)
7. Small hippocampal volume may be a risk factor for major depression
or posttraumatic stress disorder (31, 44)
REVIEW
This area is a focus of possible therapeutic interven-
tion using direct activation approaches such as deep
brain stimulation.
PSYCHOPHARMACOLOGY
Just a few years ago my colleagues and I com-
mented in the fourth edition of the Manual of
Clinical Psychopharmacology that the horizon
seemed bright for antidepressant agents with new
mechanisms of action (57). However, a number of
then-promising agents have not received approval
from the Food and Drug Administration (FDA),
and the near-term horizon seems quite a bit dim-
mer. Promising approaches are summarized in
Table 2.
DULOXETINE
The most recently approved antidepressant is
duloxetine, a serotonin/norepinephrine reuptake
blocker with dopamine reuptake effects as well.
Duloxetine has been shown to be significantly
more effective than placebo in major depression in
several studies (58–60). Dosages studied have
ranged from 40 mg/day to 120 mg/day, and the
recommended daily dose is now 60 mg/day.
Duloxetine’s half-life is approximately 14 hours.
There are no data to indicate that doses above 60
mg/day are more effective than the recommended
dose. Although the package insert indicates that
the dosage can be started at 60 mg/day, many cli-
nicians have their patients start with 30 mg/day
and increase the dose to 60 mg/day after approxi-
mately 1 week. This approach can help reduce the
FOCUS Winter 2005, Vol. III, No. 1 17
 SCHATZBERG
Table 2. New Psychopharmacological Agents
Agent Principal Mechanism of Action
Duloxetine Norepinephrine/serotonin reup-
take blocker
Selegiline MAO A and B inhibitor in brain
(transdermal patch)
Aprepitant NK-1 or substance P antagonist
Gepirone 5-HT1a agonist
Mifepristone Clucocorticoid receptor antagonist
Alzheimer’s disease (early)
R121919 CRH antagonist
Olanzapine-fluoxetine Atypical antipsychotic
combination (dopamine/serotonin) antagonist;
serotonin reuptake blocker; pre-
frontal cortex release of norep-
inephrine and dopamine
MAO=monoamine oxidase inhibitor; ADHD=attention deficit hyperactivity disorder; NK-1=neurokinin-1 receptor; CRH=corticotropin-releasing hormone
likelihood that patients will experience duloxetine’s
most common side effect, nausea, which is seen in
as many as 40% of patients begun on 60 mg/day.
Accommodation to nausea often occurs by the end
of the first week. Other common side effects
include dry mouth, constipation, and sedation.
Hypertension is seen relatively infrequently (61).
As noted earlier, major depression is frequently
comorbid with chronic pain, often without
organic cause. Duloxetine appears to improve both
depression and painful physical symptoms, partic-
ularly backache and shoulder pain. It is thought
that descending norepinephrine and serotonin
fibers from the brain via the spinal cord serve to
dampen peripheral pain signals. Increased norepi-
nephrine and 5-HT “tone” may thus simultane-
ously improve mood and comorbid pain. As
mentioned above, Fava and associates (15)
reported that remission of depression is more
likely if pain symptoms are also markedly
improved. My colleagues and I recently reported
that in one study duloxetine was significantly
more effective than placebo in reducing pain in
depressed patients with comorbid pain but that
the drug did not separate from placebo on reduc-
tion of depression (62). These data suggest that the
18 Winter 2005, Vol. III, No. 1 FOCUS T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I AT RY
Possible Indications Status in United States
Major depression Approved for major depression and dia-
Diabetic neuropathic pain betic neuropathic pain; pending
Stress urinary incontinence approval for incontinence
Major depression Approval letter for major depression only
Atypical depression Not under study
ADHD
Major depression Development halted for major depres-
Cisplatin-induced nausea and sion due to lack of efficacy
vomiting Approved for cisplatin-induced nausea
and vomiting
Major depression Nonapprovable letter for major depression
Generalized anxiety disorder
Psychotic symptoms in Phase III for psychotic depression
psychotic major depression
Phase II for Alzheimer’s disease
Major depression Development dropped due to liver toxicity
Anxiety disorders
Bipolar I depression Approved for bipolar I depression
Psychotic major depression One positive trial in psychotic major
Refractory depression depression with no further studies
under way
Phase III program for refractory depression
drug can reduce chronic pain (independent of
effects on depression) and are consistent with pre-
clinical data (63).
Indeed, duloxetine was the first drug approved
for treatment of diabetic neuropathic pain,
although it does not provide acute analgesic effects.
At doses of 60–120 mg/day it is significantly more
effective than placebo in reducing pain in nonde-
pressed patients. Recently the drug has also been
reported to improve pain symptoms in patients
with fibromyalgia, particularly women (64).
Enhanced norepinephrine/serotonin activity
may improve bladder control in women with stress
urinary incontinence disorder (65). Duloxetine has
been approved for this use in Europe, and it is
expected to receive similar approval soon in the
United States.
Abrupt discontinuation of antidepressants is fre-
quently associated with rebound symptoms. This
was originally reported with tricyclics, cessation of
which can cause rebound peripheral cholinergic
symptoms (abdominal cramping, headaches, and
the like); in addition, psychiatric symptoms (hypo-
mania and mania) were reported by our group and
others in the 1980s (57, 66, 67). With the advent of
the SSRIs, discontinuation symptoms were observed

anew, particularly with the short-acting, more
potent 5-HT reuptake blockers (68, 69). Symptoms
include a flulike syndrome with vertigo, nausea,
paresthesias, and mood changes. These symptoms
have also been observed with the mixed reuptake
blockers and have been reported in about 15% of
patients treated with duloxetine in clinical trials.
When discontinuing the agent, a gradual reduction
from 60 mg/day to 30 mg/day for at least 1 week is
recommended.
TRANSDERMAL SELEGILINE PATCH
Selegiline is an irreversible monoamine oxidase
(MAO)-B inhibitor that has long been approved at
low doses (5–10 mg/day orally) for the treatment
of Parkinson’s disease. At oral doses of 20 mg/day
or higher, the drug is an effective antidepressant
agent; however, at these doses it is an inhibitor of
both MAO A and B and hence is prone to interac-
tions with dietary foodstuffs (70). Delivery of
selegiline via a transdermal patch avoids major
inhibitory effects on intestinal MAO-A and thus
obviates the need for dietary restrictions. This is
particularly the case at the lower doses, such as via
a 20 mg or 30 mg patch daily. At 40 mg/day an
interaction is theoretically possible but highly
unlikely. When delivered transdermally the drug
appears to produce both MAO A and B inhibition
in the brain (71), which is somewhat similar to the
action of tranylcypromine. Because of its MAO A
and B effects in the brain, patients need to be
warned about avoiding concomitant use of other
agents, such as meperidine, SSRIs, and so on, even
though diet may not pose a problem.
Selegiline transdermal patch has been shown to
be more effective than placebo in improving
depressive symptoms in patients with either typical
or atypical subtypes of depression. The starting
dose is 20 mg applied daily, with increases to a rec-
ommended maximum of 40 mg/day. At 20 mg/day
the drug is more effective than placebo but not dra-
matically so (72). In a pivotal trial using flexible
dosing of 20–40 mg/day, more dramatic separation
from placebo was seen, suggesting that higher doses
may have greater efficacy.
A principal side effect of selegiline is irritation at
the site of application. In addition, because the drug
is metabolized to amphetamine or d-amphetamine,
it may be quite stimulating, and some patients have
difficulty sleeping. Adjunctive hypnotics may be
required. Finally, there is a small risk of orthostatic
hypotension with the drug.
Selegiline transdermal patch has received an
approvable letter from the FDA, and at the time of
this writing final approval was pending.
focus.psychiatryonline.org
SCHATZBERG
APREPITANT (MK-869)
Substance P binds to the neurokinin-1 receptor
(NK-1) in brain. NK-1 receptors are distributed
across regions that contain norepinephrine and 5-
HT neurons. In lower animals, substance P activa-
tion has been associated with stress responses (73).
Mice in which NK-1 receptors have been geneti-
cally knocked out appear less anxious (74), as do
animals given an NK-1 antagonist (75). These data
suggest that NK-1 antagonists may be helpful in
disorders viewed as untoward stress responses, such
as anxiety and depression.
Aprepitant (MK-869)—a Merck Laboratories
substance P antagonist—was reported to be signif-
icantly more effective than placebo (and compara-
ble to paroxetine) in reducing depression (73). A
second substance P antagonist was also reported to
separate from placebo in melancholic depressives
(76). The manufacturer of both pursued a new for-
REVIEW
mulation of MK-869, which failed to separate
from placebo in five double-blind antidepressant
trials (77). In three of the trials, the active com-
parator paroxetine did separate from placebo.
Merck has halted this development program,
although other companies may still be pursuing
this drug class as an antidepressant.
The drug has relatively little in the way of side
effects and was well tolerated. In a different dosage,
aprepitant is available for limited acute use (e.g., for
2 days around administration of chemotherapy) to
prevent cisplatin-induced nausea and vomiting.
GEPIRONE
Gepirone is a 5-HT1A agonist that has been
under study for many years as an immediate-release
formulation. Most recently, one manufacturer
(Organon) was attempting to develop a long-acting
formulation of the drug as an antidepressant. In
one report, the drug separated from placebo on
Hamilton Depression Rating Scale change scores
from baseline to weeks 3 and 8 (78). In another
analysis, the effects appeared to be more pro-
nounced on symptoms of anxiety, which is consis-
tent with previous observations (79). Side effects
are generally mild and include dizziness, nausea,
and insomnia. However, the file submitted to the
FDA was not strong enough to win approval.
MIFEPRISTONE
Mifepristone is an antagonist for the low-affinity
glucocorticoid receptor as well as a progesterone
antagonist. Two decades ago my colleagues and I
hypothesized that the delusions of psychotic
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 SCHATZBERG
depression and similar states were due to excessive
cortisol activity (80). Clinical data suggested that at
doses of 600 mg/day for 4–7 days, mifepristone
may improve the psychotic symptoms of delusional
depression (81), and two recent double-blind stud-
ies support this observation (82, 83). Mifepristone
is currently in Phase III trials. The drug’s side effect
profile appears relatively benign; rashes are seen in
4%–10% of patients.
CORTICOTROPIN-RELEASING HORMONE
ANTAGONISTS
Several pharmaceutical companies are develop-
ing corticotropin-releasing hormone (CRH) antag-
onists. CRH in the brain is involved in initiating
stress responses. CRH is found in the hypothala-
mus, amygdala, and cortex. One CRH antago-
nist—R121919—has been reported in an
open-label German study to reduce depressive
symptoms in hospitalized MDE patients (84).
However, the drug’s development was discontinued
because of laboratory test abnormalities. This
remains an area of active drug development.
OLANZAPINE-FLUOXETINE COMBINATION
The combination of olanzapine and fluoxetine
has been reported to promote antidepressant
responses in nonresponding depressed patients
(85). The mechanism has been thought to reflect
mobilization of prefrontal dopamine and norepi-
nephrine (86). This strategy has been under further
study. Thus far, the data suggest that atypical
antipsychotics rapidly convert nonresponders to
responders by 1 week but may not offer any advan-
tage at 8 weeks.
A combination product of olanzapine and fluox-
etine has been approved for the treatment of bipo-
lar I depression. In the pivotal trials, both
olanzapine and the combination of olanzapine and
fluoxetine separated from placebo (87). The com-
bination has also been studied in psychotic or delu-
sional depression, where it was more effective than
placebo in one of two pivotal studies (88). An
analysis of the combined data indicated that the
combination, but not olanzapine alone, separated
from placebo. However, separation from placebo
occurred only after 4 weeks. At this point it is not
anticipated that the combination will be developed
further for delusional depression.
PHARMACOGENETICS
Pharmacogenetics is becoming a major focus in
psychopharmacologic research. This approach uses
20 Winter 2005, Vol. III, No. 1 FOCUS T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I AT RY
genetic alterations—often single-nucleotide poly-
morphisms (SNPs)—to assess the likelihood of
response to a particular drug or class of drugs or to
predict side effects. The approach has been used in
various psychiatric disorders, with perhaps the
strongest findings seen in depression. Findings are
summarized in Table 3.
Several years ago the Milan group reported that
a short form of the serotonin transporter was asso-
ciated with poor responses to specific paroxetine
(89, 90). In contrast, the alternate long form pre-
dicted positive responses. This observation has
been confirmed in other studies with Caucasians
(91), but the opposite prediction pattern has been
reported in studies with Asian populations (92).
Recently our group reported that the long form of
the transporter was only a mild predictor of posi-
tive response to paroxetine in geriatric patients
(93). In contrast, the short form of the trans-
porter predicted intolerance to the SSRI paroxe-
tine but not to the 5-HT2 antagonist mirtazapine.
Patients who were s/s tolerated mirtazapine much
better than did l/l patients (93). Our view of pre-
vious studies has been that using last-observation-
carried-forward (LOCF) approaches to analysis of
patients who dropped out may have resulted in a
confusion of intolerance and nonresponse in s/s
patients. At any rate, the data do suggest that in
Caucasians the SSRI response may not be optimal.
The 102 T/C SNP of the 5-HT2A receptor has
been associated with the response pattern to cloza-
pine (94) in patients with schizophrenia. We
explored whether the C/C homozygote for the
receptor—seen in some 25% of the population—
was associated with response to either paroxetine or
mirtazapine in geriatric depressives (95). The C/C
homozygocity predicted intolerance to paroxetine,
with over 40% dropping out because of adverse
events by 8 weeks. In contrast, the C/C form did
not predict intolerance to mirtazapine. Response or
remission to either drug was not predicted by the
5-HT2A variants. The s/s form of the transporter
and the C/C form of the 5-HT2A receptor inde-
pendently predicted intolerance to paroxetine (93).
Thus, these data suggest that alterations in 5-HT
reuptake or 5-HT2A postsynaptic receptor activity
affect the ability to tolerate an SSRI but do not
adversely affect tolerability of a postsynaptic recep-
tor antagonist.
Similarly, allelic variation of the norepinephrine
transporter has been explored as a predictor of
response to the selective norepinephrine reuptake
inhibitor milnacipran in Japanese depressives (96).
The T allele of the T-182C polymorphism of the
norepinephrine transporter predicted positive
response to the drug; the A/A form did not. Allelic

Table 3. Pharmacogenetic Findings in Major Depression
Allele/Gene
s/s form of 5-HT transporter
102 R/C allele for 5-HT2c receptor
182 T/C allele for norepinephrine transporter
APOE-4
rS1360780 gene for FKBPS
(chaperone heat shock protein)
P450 2D6
variation for the serotonin transporter did not pre-
dict response to the norepinephrine agent.
Apolipoprotein E ε4 (APOE-4) has been
reported to be a risk factor for Alzheimer’s disease.
Individuals with this allele may be at increased risk
of greater morbidity after surgery or after head
injury and have an increased risk of obstructive
sleep apnea. In our geriatric study (97, 98), we
explored the hypothesis that APOE-4 alleles were
predictors of poor overall response to antidepres-
sant therapy in geriatric patients. This prediction
was not borne out, but patients with APOE-4 al-
leles were dramatic responders to mirtazapine but
not to paroxetine (98). The explanation is not
entirely clear, but APOE status may be associated
with noradrenergic dysfunction (99) or excessive
cortisol activity (100), both of which are targets for
mirtazapine therapy (100, 101).
Glucocorticoid receptors are nuclear and are sur-
rounded by chaperone heat-shock proteins. As dis-
cussed above, alterations in one HSP have been
reported to be associated with multiple depressive
episodes and rapid response to drug therapy (20).
These alterations may affect the individual’s ability to
halt the stress response. Mirtazapine was frequently
used in this study, and the prediction of rapid
response may have to do with the drug’s ability to
lower cortisol levels (101). Further studies in other
subject populations will help elucidate this issue.
In regard to pharmacokinetics, two major sys-
tems have been the focus of much recent research:
P450 2D6 in the liver and medication-resistant P-
glycoprotein (mr-P-GP), which controls efflux of
drug from the brain. P450 represents a basket of
enzymes found primarily in the liver that metabo-
lize various drugs. The best known is P450 2D6.
focus.psychiatryonline.org
SCHATZBERG
Findings
s/s predicts poor response to SSRIs in Caucasians (89–91)
s/s predicts intolerance to SSRIs (93)
l/l predicts poor response to SSRIs in Asians (92)
s/s predicts tolerability with mirtazapine (93)
C/C predicts intolerance to paroxetine but not to mirtazapine (95)
T allele predicts poor response to milnacipran in Japanese (96)
APOE-4 patients are rapid responders to mirtazapine but not to paroxetine (98)
T/T homozygotes demonstrate rapid response to a number of antidepressants,
particularly mirtazapine and citalopram (20)
In geriatric depression, alleles representing intermediate and slow metabolizers
do not predict higher dropout rates due to adverse events of paroxetine or
mirtazapine; study included few patients with null alleles (95)
REVIEW
Many drugs serve as substrates as well as inhibitors
of P450 2D6, whereas some stimulate activity.
There are numerous alleles for 2D6; some connote
increased clearance or metabolism, whereas others
connote slow metabolism. Slow metabolizers
should be more likely to experience side effects.
Rapid or ultrafast metabolizers may clear the drug
so quickly that they fail to achieve adequate blood
levels and are thus less likely to attain a drug effect.
We explored whether slow metabolizers in a geri-
atric population were more likely to drop out
because of side effects of paroxetine (a substrate
and inhibitor of 2D6) or of mirtazapine (a sub-
strate but not an inhibitor) (93, 97). We did not
observe an effect of 2D6 alleles on dropouts due to
adverse events from either drug, although the num-
ber of very slow metabolizers (i.e., null alleles) was
small. As indicated above, we did observe pharma-
codynamic predictors of SSRI response in this
study (97).
In the past few years greater attention has been
given to mr-P-GP as a predictor of antidepressant
response. In mice, knocking out the gene for the
pump protein points to its role in facilitating the
efflux of both cortisol and antidepressants from the
brain (102–105). In studies to date using knock-
outs, citalopram, amitriptyline, and trimipramine
appear to be transported out of mouse brain by P-
GP (103–104). Alterations in this gene may tell us
more about treatment resistance than does drug
clearance via the liver. However, the significance of
these observations on P-GP in lower animals to the
treatment of depressed patients is unclear, since the
knockout model may not be fully relevant to the
clinic. Still, this is an interesting area that is fast
becoming a focus of pharmacokinetic research.
FOCUS Winter 2005, Vol. III, No. 1 21
 SCHATZBERG
SUMMARY
Recent studies point to key brain areas as having
important roles in depression as well as to specific
genes as risk factors for developing depression, often
in interaction with environmental stress. New anti-
depressant strategies are being pursued, and despite
some recent disappointments in this area, pharma-
cogenetics is pointing to potential tools for selecting
drugs or deciding how to dose them.
DISCLOSURE OF UNAPPROVED, OFF-LABEL, OR
INVESTIGATIONAL USE OF A PRODUCT
APA policy requires disclosure by CME authors of unapproved or investigational
use of products discusssed in CME programs. Off-label use of medications by
individual physicians is permitted and common. Decisions about off-label use
can be guided by the scientific literature and clinical experience. This article
contains discussion of mifepristone for psychotic depression; MK-869 for major
depression; selegiline patch for depression; and R121919 for depression.
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