Melancholy (n) c.1303, condition characterized
by sullenness, gloom, irritability, from Gk.
melankholiasadness, lit. black bile, from melas
black + kholé bile.1
The treatment of depressive mood
disorders is in disarray. Despite a
plethora of medications, novel psychotherapies,
and expert treatment algorithms,
one therapeutic trial after
another fails, patients suffer endlessly,
are labeled therapy-resistant, and
overwhelm our treatment facilities.
A powerful example is the report of
the large government-supported multisite
assessment of antidepressant
medications known as STAR*D.2 After
relief was accorded to 30% of depressed
patients in a primary treatment course
with the selective serotonin reuptake
inhibitor (SSRI) citalopram (Celexa),
a subsequent trial in the remainder with
the antidepressants bupropion
(Wellbutrin), venlafaxine (Effexor), and
sertraline (Zoloft) elicited improvement
in 21%, 18%, and 25% of the
patients, respectively. Sadly, half the
patients failed to obtain relief in the
repeated trials. The study population
met DSM criteria for nonpsychotic
What contributed to the low response
rates? The weak antidepressant efficacy
of the medications is a factor. From 20%
to 40% of similar patient populations
improve with placebo; these rates are
equivalent to those associated with the
Heterogeneity of the population
ensures a low response rate. The DSM
criteria for major depression are imprecise
and fail to distinguish between
those with psychological and social
causes for their illness and those with
a biologic (endogenous) basis. The
severity of the illness in the STAR*D study was moderate (Hamilton
Depression Rating Scale-17 score of
19 ± 7.3). Despite this modest degree
of severity reflected in depression scale
ratings, 17% of the patients reported
suicide attempts, 76% reported recurrent
illnesses, the average duration of
the present episode was 30 months, the
lifelong duration of illness was 17
years, and the patients reported an average
of 7 episodes of illness. Anxious
features were recorded in 44% of the
patients and atypical features in 20%.
Yet, of the patients in this outpatient
population, 53% were employed.
The STAR*D experience reflects
our difficulty in assessing treatments for
a heterogeneous population of major
depressed patients. The difficulty is
similar to that of assessing the effectiveness
of an antibiotic in a population
of city dwellers who, during the winter
season, complain of chest pain, cough,
rhinorrhea, fever, and chills. Heterogeneity
of bacterial and viral causes
would offer the researchers ambiguous
results for an effective antibiotic.
Is there an alternative to the DSM
criteria for major depression that would
ensure more homogeneous population
samples in clinical trials?
In the 1970s, studies that monitored
serum blood levels found a cluster of
depressed patients who failed to
respond to the tricyclic antidepressant
imipramine. The patients' illness did,
however, remit quickly with electroconvulsive
therapy (ECT).4 The presence
of psychosis was the distinguishing
characteristic of the medication nonresponders.
The importance of psychosis as a discriminator for treatment choice
and for clinical outcome in depression
was quickly confirmed and set the stage
for our understanding that patients with
psychotic depression warrant different
treatment algorithms from those effective
in nonpsychotic patients. They
respond best to ECT or to combinations
of a tricyclic antidepressant and
a conventional neuroleptic.5
The syndrome of melancholia
Rooting diagnosis in a definable
psychopathology is essential to replicate
this success. A syndrome of melancholia,
like that of psychosis, is a readily
distinguishable mood disorder that
offers a useful discriminator in depressive
For centuries, physicians and laymen
described an illness of mood and
thought, often of sudden onset, and so
severe as to threaten life by suicide and
debilitation.1 Medieval philosophers,
struggling with concepts of body
humors controlling health and disease,
imagined that an excess of black bile
was the basis for the illness and described
the condition as melancholie. The
syndrome's pathophysiology, rating instruments,
laboratory test abnormalities,
and effective treatment algorithms are
well delineated by many authors.
What is melancholia?
Melancholia is the quintessential
depressive mood disorder. Movement
and thought are slowed; mood is sad
and gloomy; insomnia, anorexia, poor
body care, weight loss, disinterest in sex,
and fears of impoverishment, infidelity,
and hopelessness dominate daily living.
Suicide becomes a logical solution as
pain and distress overwhelm daily life.
The agony and helplessness are excruciatingly
described by such recent writers
as Endler (1982), Styron (1990), Manning (1994),
and Nuland (2003).7
measurable by assessing
for which rating
the Hamilton and
the Montgomery-Asberg depression
rating scales, are useful. These standardized
instruments estimate the severity
of the syndrome and are useful
guides to management.
Hypercortisolemia is one distinction
of melancholia from other mood disorders.
It is a unique pathophysiologic
abnormality that reflects the severity
of the illness and varies with remission
and relapse.8 Hypercortisolemia was
first recognized in patients with pituitary
and adrenal tumors, but even
higher elevations were found in severely
ill psychiatric patients. The finding was
initially a curiosity, but systematic studies
by Carroll and coworkers9 in
Melbourne in the 1970s showed that
serum cortisol levels were elevated in
patients with International Classification
of Diseases-defined melancholic
depression. Patients lacked the normal
diurnal rhythmicity of cortisol, and its
levels were not suppressed with the
administration of the corticosteroid
dexamethasone. These findings were
formalized in the dexamethasone
suppression test (DST).9
In patients referred for ECT, an abnormal
test result was quickly recognized
as a measure of severity of illness. The
test results normalized with remission
and became abnormal again with relapse.
Despite its credibility as a monitor of
clinical status, the DST was rejected by
psychiatric leaders in the mid-1980s on
the grounds that it was not a valid measure
of DSM-III diagnostic criteria.10,11
Although they are less well established,
and thyroid function tests are additional
laboratory tools for measuring the
1. Taylor MA, Fink M. Melancholia: The Diagnosis,
Pathophysiology and Treatment of Depressive
Illness. Cambridge, England: Cambridge University
2. Rush AJ, Trivedi MH, Wisniewski SR, et al; STAR*D
Study Team. Bupropion-SR, sertraline, or venlafaxine-
XR after failure of SSRIs for depression. N Engl
J Med. 2006;354:1231-1242.
3. Khan A, Kolts RL, Rapaport MH, et al. Magnitude
of placebo response and drug-placebo differences
across psychiatric disorders. Psychol Med.
4. Glassman AH, Kantor SJ, Shostak M. Depression,
delusions and drug response. Am J Psychiatry.
5. Crismon ML, Trivedi M, Pigott TA, et al. The Texas
Medication Algorithm Project: report of the Texas
Consensus Conference Panel on Medication
Treatment of Major Depressive Disorder. J Clin
6. Parker G, Hadzi-Pavlovic D. Melancholia: A Disorder
of Movement and Mood. Cambridge, England:
Cambridge University Press; 1996.
7. Fink M. A new appreciation of ECT. Psychiatr Times.
8. Carroll BJ. The hypothalamus-pituitary-adrenal axis
in depression. In: Burrows GD, ed. Handbook of
Studies on Depression. Amsterdam: Exerpta
9. Carroll BJ, Feinberg M, Greden JF, et al. A specific
laboratory test for the diagnosis of melancholia.
Standardization, validation, and clinical utility. Arch
Gen Psychiatry. 1981;38:15-22.
10. Fink M. Should the dexamethasone suppression
test be resurrected? Acta Psychiatr Scand.
11. Fink M. The DST riddle. Psychiatr Times.
12. Fink M, Taylor MA. Catatonia: A Clinician’s Guide
to Diagnosis and Treatment. Cambridge, England:
Cambridge University Press; 2003.
13. Caroff SN, Mann SC, Francis A, Fricchione GL,
eds. Catatonia. From Psychopathology to
Neurobiology.Washington, DC: American Psychiatric
14. Dhossche D, Wing L, Ohta M, Neumärker K-J,
eds. Catatonia in Autism Spectrum Disorders.
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