Melancholy (n) – c.1303, “condition characterized by sullenness, gloom, irritability,” from Gk. melankholia“sadness,” 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(Drug information on citalopram) (Celexa), a subsequent trial in the remainder with the antidepressants bupropion (Wellbutrin), venlafaxine (Effexor), and sertraline(Drug information on 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 major depression.
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 medications studied.1,3
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(Drug information on 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 mood disorders.1,6
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), Rosenberg (2002), and Nuland (2003).7
Melancholia is measurable by assessing symptoms, for which rating scales, especially 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(Drug information on 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, sleep electroencephalography and thyroid function tests are additional laboratory tools for measuring the syndrome’s severity.1
