An Update on Melancholia

January 20, 2017

Functional vs structural; melancholic vs non-melancholic; and hierarchy of treatment are the focus.

Premiere Date: January 20, 2017
Expiration Date: July 20, 2018

This activity offers CE credits for:
1. Physicians (CME)
2. Other


To understand how melancholia is perceived in this day and age and how it is categorized in DSM-5 and ICD-10.


At the end of this CE activity, participants should be able to:

• Discuss the differences between “functional” melancholia and “structural” melancholia

• Assess melancholic depression versus non-melancholic depression

• Describe the hierarchy of treatment for melancholia-whether mild, moderate, or severe


This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.


CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit ™.


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Gordon Parker, MD, has no disclosures to report.

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Melancholia is variably positioned dimensionally (ie, a severe expression of clinical depression) or categorically (ie, a distinct type). I favor a variant of the binarian model that essentially posits 2 types of depression (melancholic/endogenous vs neurotic/reactive). While viewing melancholia as a categorical biological type, I discount any second “pure” depressive type and view that group as being constituted more by a residual set of non-melancholic conditions that lack any phenomenologically specific features. Their heterogeneity reflects the impact of personality style and psychosocial stressors and differs from normative depressive states along severity, duration, and recurrence dimensions.

Is melancholia a categorical condition?

At the height of the research focus on melancholia (in the 1970s and 1980s), its advocates argued for its categorical status on the basis that it had certain relatively distinct or over-represented features (ie, a phenotypic profile). Its determinants were biological rather than psychosocial (evidencing a strong genetic contribution); it had minimal placebo response; and it showed a preferential response to antidepressant medication and to ECT rather than to psychotherapy. Such a model contrasts with an alternate dimensional model that positions melancholia as simply a more severe type of depression.

Melancholia was viewed more as a movement disorder than a mood disorder for more than 2000 years, reflecting its overt signs of psychomotor disturbance (retardation and agitation as well as compromised cognitive function).1,2 Such consistency of psychomotor disturbance as a phenotypic feature over time-and across contemporary cultures and races-is both striking and at variance with most other psychiatric conditions and again argues for its categorical status.

If melancholia is a categorical condition (qua disease), we might anticipate that it would be defined with some precision on the basis of its clinical features. As one wag noted in another context, just as Michelangelo could see the Pieta in a lump of stone and simply needed to chisel around for a bit to achieve pristine definition, so have workers in the field chipped away in the belief that all (melancholia) would be revealed.

Multivariate analyses in the 1970s and 1980s generated sets of endogeneity symptoms that were viewed as defining the condition. However, while many of those symptoms (eg, fatigue, insomnia, appetite and weight changes, impaired libido) are common in melancholic depression, they are also common in non-melancholic depression and in other psychiatric states and disallow a clear definition of melancholia. Any measure that includes such non-specific symptoms runs the risk of adding “noise” and swamping the capacity of truly differentiating items to define melancholia with any precision.

DSM-5 and ICD-10 criteria

If melancholia is poorly defined and diagnosed, then estimates of its prevalence, cause, and optimal treatment are compromised. This concern holds for DSM-5, which accords melancholia the designation of a “specifier” rather than giving it subtype status; this compromises its differentiation from major depression. An optimal DSM model would be for:

• Major depression to be redefined as a generic “clinical depression” domain (with items that are equally likely to be experienced by those with differing depressive subtypes), and

• Melancholia to be positioned as a subtype and defined by a different set of specific clinical features that show specificity to those that define clinical depression

Five DSM-5 depressive symptoms (psychomotor disturbance, early morning awakening, weight loss, anhedonia, excessive or inappropriate guilt) are criteria for both melancholia and major depression. There is minimal-and if certain symptoms are affirmed, no-differentiation between a diagnosis of major depression with melancholia and a diagnosis of major depression without melancholia. This reality challenges the validity of the DSM approach to defining “true” melancholia, risks over-diagnosing melancholia, and compromises studies that pursue the causes of and optimal treatments for melancholia.

ICD-10 also has logical fallacies. It is underpinned by a dimensional model with 3 depressive episode categories: mild, moderate, and severe. For mild and moderate depression (but paradoxically not for severe depression, in which melancholia might be most expected), a somatic syndrome is included (with somatic joining synonyms such as melancholic, vital, endogenomorphic, or biological depression). An individual who reports a depressed mood, loss of interest, psychomotor disturbance, early morning wakening, appetite disturbance, and a somatic syndrome meets only the ICD-10 listed criteria for mild or moderate depression.

DSM-5 criteria for melancholic features and the ICD-10 somatic syndrome criterion share a similar set of symptom criteria (ie, anhedonia, non-reactive mood, early morning wakening, depression worse in the morning, psychomotor disturbance, loss of appetite and weight) that capture most of the historically favored endogeneity symptoms. But, as no set of endogeneity symptoms has shown accuracy in differentiating melancholic from non-melancholic depression, can classificatory accuracy be improved by alternative paradigms?

Melancholia’s ascriptions and its delineation

We have generated data that support all of melancholia’s historical ascriptions. An MRI study demonstrated that melancholic patients (compared with non-melancholic patients and non-depressed controls) had decreased connectivity from the insula to the fronto-parietal cortex.3 When shown emotionally salient films, patients in the melancholic group exhibited decreased functional connectivity in the subgenual anterior cingulate cortex and caudate, which correlated with anhedonia and a non-reactive mood.4

To determine genetic contribution, we quantified family history rates of depression and found first- and second-degree relatives to be significantly over-represented among those with melancholic features compared with those with non-melancholic depression (92% vs 42%) [G.P., under submission]. Because of melancholia’s greater response to pharmacotherapy than to psychotherapy, a sample of only 29 subjects with melancholia was required to show the significant superiority of antidepressant medication to cognitive behavior therapy at 4 weeks and at 12 weeks in a 3-month trial.5

Respecting the historical observation that melancholia is marked by signs of psychomotor disturbance, the CORE measure was used to assess signs of cognitive disturbance and motor changes (retardation and agitation). CORE signs provided superior differentiation to endogeneity symptoms, were validated against a number of ascriptions to melancholia, and met criteria for necessary and sufficient status.6 That is, all those with clinically defined melancholia showed psychomotor disturbance (the necessary component). Moreover, the addition of endogeneity symptoms to CORE signs did not improve differentiation, which suggests that CORE signs are sufficient in and of themselves to differentiate melancholia. However, there were 2 limitations:

• Valid assessment requires that patients are at or near episode nadir

• Differentiation is less impressive in patients with melancholia who are younger than age 40, and in whom psychomotor disturbance tends to be less overt

Another approach involved the development of a refined set of melancholic or endogeneity symptoms-although in an earlier study with that approach, the overall classificatory accuracy rate was only 68%.7 However, when illness correlates were added to symptoms, the rate increased to 80%.8

On the basis of these findings, we developed the Sydney Melancholia Prototype Index (SMPI), a prototypic approach to assessing symptoms and illness correlates.9 The SMPI has 2 columns; each comprises 12 symptoms and illness correlates that capture melancholic (left column) and non-melancholic (right column) depression. If 4 or more items are rated in the left column than in the right one, the probability of melancholic depression is high and certainly higher than reliance on symptoms alone. Specifically, the SMPI’s sensitivity was quantified as 0.84 and specificity as 0.92; while the positive and negative predictive values were 0.90 and 0.88, respectively, which argues for high differentiation.

The statistically derived cutoff score of 4 or more was confirmed in 2 subsequent independent samples.9,10 In essence, the SMPI operationalizes clinical judgments that seek to determine whether the patient’s pattern matches the prototypic cross-sectional and longitudinal pattern of melancholic depression. The left column has 8 symptoms weighted to melancholia, with all historically supported endogeneity symptoms (ie, non-reactive and anhedonic mood, anergia, diurnal variation with mood and energy worse in the morning, psychomotor disturbance, impaired concentration, and weight loss).

The column also has 4 illness correlates, 2 of which correspond to Newcastle Scale2 illness correlate items (adequate personality and no adequate psychogenesis):

• Early years being no more difficult than for most people in terms of developmental stressors

• Relationships and work performance being unremarkable when euthymic

• Depressive episodes sometimes coming “out of the blue” without any particular reason

• The severity of episodes being worse than expected given the circumstances

While DSM favors a polythetic model (whereby all criteria are essentially viewed as carrying equivalent weight), skilled clinicians operate formally or informally to a prototypic model (employing a pattern analytic approach and asking themselves whether the patient’s clinical features approximate the condition being scrutinized) and a Bayesian model wherein they assign differential weights to different clinical features.


In exploring the likelihood of melancholia, I generally ask the patient to describe key features before moving to closed questions. A list of questions with some justifying comments appears in the sidebar (Box).

In addition to asking such questions, I observe the patient. In severe melancholia, he or she may be monosyllabic and slow to move. In assessing a new patient, I seek information from a corroborative witness-a relative or friend. If the patient has a melancholic pattern, he will be described or acknowledged as insular and asocial during episodes and, often on specific questioning, as “losing the light in his eyes.”

The likelihood of melancholia is increased if there is a family history of depression, bipolar disorder, or suicide; if episodes are likely to “come out of the blue” and are more severe and persistent than expected in relation to any stressors; and if the patient acknowledges a loss of agency (that it feels more like an imposed “disease” rather than a logical reaction to life stressors).



In treating melancholia, there is a need to first distinguish between “functional” and “structural” melancholia. Patients in the former group tend to have late adolescence or adulthood onset and a family history of depression but no distinctive features indicative of an accompanying organic syndrome. In the latter group, onset is more likely at a later age, there is a family history that leans more to cerebrovascular disease than to depression, and there is a base level of cognitive impairment. In addition, an MRI scan will generally show brain hyperintensities and volumetric reduction in the caudate and/or putamen. These patients may initially respond to antidepressant medication or to ECT, but repeated episodes occur after progressively shorter periods, and the degree of improvement lessens. After a period, it becomes evident that the patient has a clear-cut vascular dementia, which the melancholia was simply presaging.

For the majority of individuals with functional melancholia for which there is no organic cause, the first line of treatment is antidepressant medication-although not all antidepressant drug classes have comparable efficacy. For example, SSRIs are generally less effective than the dual-action antidepressants (SNRIs), which in turn are less effective than the TCAs and MAOIs, because of the greater contribution of noradrenaline and dopamine in the latter drug classes.

A meta-analysis showed an 8% to 34% response to SSRIs and a 56% to 63% response to TCAs in patients with endogenous depression.11 In a study that we undertook, patients with melancholia who were younger than 46 years had comparable responses to a TCA or to an SSRI, but the TCA was twice as effective in 46- to 60-year-olds and 4-fold more effective in those older than age 60.12 As psychomotor disturbance becomes more distinct and severe with age, we presume that the phenotypic change reflects more monoaminergic systems being recruited and thus explains the need for broader-action antidepressants.

Augmentation and/or switching to progressively broader-action antidepressants is suggested if there is no response to SSRI therapy after 2 to 4 weeks in an antidepressant-naive young patient with melancholia. While lithium is a commonly recommended augmenting agent, it appears to benefit only 10% to 20% of patients in my practice. I have greater success (on the order of 30% to 40%) in augmenting with low-dose (1.25 to 5 mg) olanzapine and assume that its benefits accrue from its distinct dopaminergic action. If improvement is not evident in the first week, it is discontinued. If treatment is successful, I try to taper and discontinue olanzapine a week after the symptoms remit. If symptom remission is not maintained, I move to a broader-spectrum antidepressant.

In recent years, I have had success with a psychostimulant for melancholia. It can be used to augment all antidepressants other than MAOIs. I favor short-acting methylphenidate, at 10 mg mane, and generally do not need to increase beyond 30 mg daily. While I initially evaluated methylphenidate for treatment-resistant melancholia, its sustained benefit and its relatively low rate of adverse effects have encouraged me to use it relatively early as an augmenting agent.13

If such a regimen fails, if there are higher-order risks, or if the patient has had a previous good response to ECT without ongoing sequelae, I might initiate a trial of ECT. I rarely introduce ECT as an early treatment option in light of the risk (albeit low) of ongoing cognitive effects. Moreover, if successful, ECT does not obviate the need for a medication regimen that will maintain the remission of melancholic symptoms.


Melancholia may be viewed similarly to Parkinson disease-there is no laboratory test or definitive diagnostic strategy for either. The diagnosis relies on skilled clinical assessment. However, in terms of prognosis, we can be far more confident that, unless the melancholia has a structural cause, symptom remission is an achievable clinical objective.



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Dr. Parker is Scienta Professor, School of Psychiatry, University of New South Wales, Prince of Wales Hospital, Randwick, NSW, Australia.


Acknowledgments-The author is grateful for comments to the manuscript provided by Kerrie Eyers. This article was supported by a grant from the National Health and Medical Research Council (NHMRC 1037196).


1. Jackson SW. Melancholia and Depression: From Hippocratic Times to Modern Times. New Haven, CT, and London, UK: Yale University Press; 1986.

2. Parker G, Hadzi-Pavlovic D. Melancholia: A Disorder of Movement and Mood. Cambridge, UK: Cambridge University Press; 1996.

3. Hyett MP, Breakspear MJ, Friston KJ, et al. Disrupted effective connectivity of cortical systems supporting attention and interoception in melancholia. JAMA Psychiatry. 2015;72:350-358.

4. Guo CC, Hyett MP, Nguyen VT, et al. Distinct neurobiological signatures of brain connectivity in depression subtypes during natural viewing of emotionally salient films. Psychol Med. 2016;46:1535-1545.

5. Parker G, Blanch B, Paterson A, et al. The superiority of antidepressant medication to cognitive behaviour therapy in melancholic depressed patients: a 12-week single-blind randomized study. Acta Psych Scand. 2012;128:271-281.

6. Parker G, Hadzi-Pavlovic D, Austin M-P. Sub-typing depression, I: is psychomotor disturbance necessary and sufficient to the definition of melancholia? Psychol Med. 1995;25:815-823.

7. Parker G, Fletcher K, Barrett M, et al. Inching towards Bethlehem: mapping melancholia. J Affect Disord. 2010;123:291-298.

8. Carney MWP, Roth M, Garside RF. The diagnosis of depressive syndromes and the prediction of E.C.T. response. Br J Psychiatry. 1965;111:659-674.

9. Parker G, McCraw S, Blanch B, et al. Discriminating melancholic and non-melancholic depression by prototypic clinical features. J Affect Disord. 2013;144:199-207.

10. Parker G, McCraw S, Hadzi-Pavlovic D, et al. Bipolar depression: prototypically melancholic in its clinical features. J Affect Disord. 2012;147:331-337.

11. Perry PJ. Pharmacotherapy for major depression with melancholic features: relative efficacy of tricyclic versus serotonin reuptake inhibitor antidepressants. J Affect Disord. 1996;39:1-6.

12. Parker G. Differential effectiveness of newer and older antidepressants appears mediated by an age effect on the phenotypic expression of depression. Acta Psychiatr Scand. 2002;106:168-170.

13. Parker G, Brotchie H, McClure G, Fletcher K. Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: a medium term evaluation of cost benefits. J Affect Disord. 2013;151:360-364.