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CanJPsychiatry 2013;58(4):183189

In Review

A Case for Reprising and Redefining Melancholia


Gordon Parker, MD, PhD, DSc, FRANZCP1
1

Scientia Professor of Psychiatry, University of New South Wales, Sydney, Australia. Correspondence: Black Dog Institute, Prince of Wales Hospital, Randwick, NSW 2031, Australia; g.parker@blackdog.org.au.

Key Words: melancholia, nonmelancholic disorder, depression, classification Received January 2012, revised, and accepted July 2012.

Objective: To identify limitations to severity-based classifications of depression, and to argue for positioning melancholia as a distinct melancholic subtype. Method: An overview of relevant literature was conducted. Results: First, dimensionalizing depressive disorders effectively aggregates multiple heterogeneous depressive types and syndromes, and thus limits, if not prevents, identification of differential causes and treatments. Second, the melancholic depressive subtype can be defined with some relative precision, and that as it shows quite distinct differential treatment responsiveness, identification should be a clinical priority. Conclusion: Melancholia can be positioned and classified as a distinct depressive subtype. WWW

Une raison de revoir et de redfinir la mlancolie


Objectif : Identifier les limites des classifications de la dpression selon la gravit, et discuter du positionnement de la mlancolie en tant que sous-type mlancolique distinct. Mthode : Un survol de la littrature pertinente a t men. Rsultats : Premirement, la dimensionnalisation des troubles dpressifs regroupe effectivement de nombreux types et syndromes dpressifs htrognes, et limite ainsi ou mme prvient lidentification des causes diffrentielles et des traitements. Deuximement, le sous-type dpressif mlancolique peut tre dfini avec une prcision relative, et puisquil dmontre une sensibilit distincte au traitement diffrentiel, lidentification devrait en tre une priorit clinique. Conclusion : La mlancolie peut tre positionne et classe comme sous-type dpressif distinct.

his article argues for positioning melancholia as a distinct depressive subtype, principally based on its phenomenology and differential treatment response implications. Such an argument essentially reprises the longstanding binary modela paradigm contrasting 2 depressive disorder typesbut, here, revisionist in arguing for delineating melancholia from multiple residual heterogeneous nonmelancholic conditions (as against any imputed second pure type). Significant challenges to the binary model emerged almost a century ago, but the alternative unitarian (compared with binarian) view (that is, clinical depression merely varies dimensionally) was consolidated during the last 3 decades following the introduction of DSM-III1 and ICD-10.2 Those classificatory systems effectively differentiated clinical depression into 2 respective severity-based categories: major, compared with minor; and severe, moderate, and mild. The argument for a revisionist binary view has 2 key struts utility and validity. Before making a case for melancholia as a valid and distinct depressive syndrome, let me first highlight the nonspecificity integral to the unitarian model
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and in its applicationwhere, for example, a diagnosis of major depression provides no information about cause, natural history, or differential treatment response.

Limitations to the Unitary View and How Melancholia Had Its Specificity Attenuated

The unitary view essentially positions depression as a single condition varying by severity. If invalid (that is, there actually are meaningfully different depressive conditions), their dimensionalizing effectively risks obscuring their integral differences. Before focusing on major depressionas it provides the major exemplar of such homogenizationlet us consider an analogy, major breathlessness. The latter can be normal and transient (a consequence of excessive exertion) or acute or chronic, and reflect multiple pathological conditions (for example, asthma, pneumonia, and pulmonary embolus). Such a diagnosis alone provides minimal information about cause or treatment. Let us narrow the analogy. Figure 1 considers 4 differing chest infections, which, while all
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In Review

capable of producing major breathlessness, reflect differing pathologies and benefit from quite differing management priorities. For example, an antibiotic that would not be recommended for the common cold may be beneficial in certain circumstances for those with influenza, and be the preferential treatment for pneumonia, while a rare pneumonia may need either a broad-spectrum or a quitespecific antibiotic. In essence, cause and pathology shape treatment choice and response, not a generic domain diagnosis of major breathlessness. Theoreticallyalthough the case will be advanced shortlywe could assume similarly differing depressive states: 1. Normative depressed moods likely to be transient and self-remitting, and not requiring any AD. 2. Nonmelancholic depressive disorders that may benefit from ADsas well as from a range of nondrug strategies. 3. Melancholic depression, where an AD is the treatment of choice. 4. Psychotic depressionwhere meta-analyses3 indicate quite distinct superiority to AD plus antipsychotic, compared with AD or antipsychotic alone. Returning to the unitarian model, the first problem is what rules dictate cut-off scores to distinguish normal from clinical depression, or major from minorand how valid are they? As an example, let us consider a putatively severe conditionmajor depressionfirst introduced by the DSM-III classification.1 A read of its descriptive features1, p 210211 suggests a weighting to historically ascribed features for melancholia, however the actual diagnostic criteria effectively attenuated classification to a melancholia lite profile (Bernard Carroll, personal communication). The mandatory Criterion A defines a dysphoric mood, while 4 of 8 Criteria B symptoms raise conceptual and clinical concerns, several being relatively slight and nonspecific (even to depressive status). For example, experiencing loss of appetite, sleep disturbance, fatigue, and self-reproach would allow a person to meet Criterion B status, with the DSM-III Introduction acknowledging that such features are described at the lowest order of inference.1, p 7 Such attenuation of depressive symptom signals, and the limited criteria set, have contributed to increasing concerns about Abbreviations
AD DSM ECT ICD PMD RCT SSRI TCA antidepressant Diagnostic and Statistical Manual of Mental Disorders electroconvulsive therapy International Classification of Diseases psychomotor disturbance randomized controlled trial selective serotonin reuptake inhibitor tricyclic AD

Clinical Implications
A diagnosis of melancholia has clinical implications in favouring physical (drug and [or] ECT) therapy above psychotherapy, and in suggesting that broad-spectrum ADs may be more efficacious than narrow-action ones. Positioning melancholia along a dimension of depression severity risks false weighting of potential causal factors in addition to compromising treatment. Currently, there is no acceptable measure or laboratory test for pristinely delineating melancholia as an entity and categorically distinct from nonmelancholic disorders. Limitations to defining melancholia may remain distinct if melancholia is a neurocircuit disorder as disruptions across differing sites of the neurocircuit may generate differing clinical features.

Limitations

psychiatry pathologizing normal sorrow and sadness into depressive disorders such as major depression,4 let alone delineating clear-cut boundaries with the less severe minor depressive conditions. Thus the rules for identifying clinical depression and its severity-based subsets appear arbitrary within a unitary model. Positioning and reifying major depression as a categorical entity ignores the reality that it is a severity-based pseudoentity subsuming a varied collection of depressive disordersranging across melancholic, reactive, anxietybased, and personality-based depressive conditions, as well as more normative adjustment disordersall with differing etiological weightings and likely differential treatment responsiveness trajectories. Logically, as for major breathlessness, homogenizing subsumed conditions into a domain diagnosis will compromise research attempts to delineate differential causes and treatment outcomeboth of one treatment against another and even of treatments against placebo, risking the phrase evidence-based psychiatry being an oxymoron. As reviewed elsewhere,5 meta-analyses of old ADs, new ADs, psychotherapy, and even of St Johns Wort demonstrate comparable and nondifferentiating response rates in relation to major depression. Further, meta-analyses show minimal differentiation of AD from placebo in studies evaluating treatments for major depression. For example, Khan et al6 examined data submitted to the US Food and Drug Administration from 52 pivotal placebo-controlled studies of new ADs and quantified that, in only 52%, the AD showed superiority to placebo. Kirsch et al7 undertook a meta-analysis of 35 published and unpublished RCTs and quantified improvement scores of 9.6 for people receiving an AD, compared with 7.8 for those receiving a placebo. While the so-called evidence-based psychotherapies are invariably included in guidelines for managing major depression, similar levels of nondifferentiation or minimal differentiation from placebo are evident in trials of cognitivebehavioural therapy and interpersonal psychotherapy8 when those psychotherapies are compared with a credible placebo in studies of people with major depression.
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A Case for Reprising and Redefining Melancholia

Figure 1 How respiratory and depressive states can be dimensionalized along with severity parameters or subtyped respecting condition status and (or) cause. Which model is valid and has the greatest utility for the depressive disorders?

Rare pneumonia

Psychotic depression

Pneumonia

Melancholia

Influenza

Nonmelancholic depression
moderate or severe (disabling)

Viral URTI (common cold)

mild nonmelancholic depression (nondisabling)

Depressed mood

URTI = upper respiratory tract infection

Such findings are usually interpretedor rejectedat face value, but are likely to reflect several conceptual and methodological problems that should concern researchers and practitioners. First, the nature of the standard RCT, where people with the most severe (and suicidal) depressive disorders are excluded (effectively excluding those with psychotic and melancholic conditions), while other exclusion criteria (for example, drug and alcohol problems, personality problems, and anxiety disorders) and recruitment practices (often selection from the general community) put RCTs at risk of being undertaken in samples of relatively pristine people who, as oranges, do not compare with the apples observed in clinical practice. Further, recruitment generally weights people likely to have a spontaneous remissionwith 1 study quantifying response rates in RCTs (whether receiving drug or placebo) increasing by 8% per decade during 3 decades.9 The high spontaneous remission rate (rare in melancholic depression) alone acts like noise to narrow, if not prevent, any true drugplacebo difference from emerging. The second principal contribution to nonspecific treatment findings emerges from testing treatments nonspecifically (as if they have universal application) across a nonspecific domain (that is, major depression). Imagine if a highly
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effective antiasthma drug was tested in a sample of people with major breathlessness (but where only 5% to 10% of sample members had asthma, while the others had a range of acute and chronic respiratory conditions). As there would be few people with the signal disorder, it would be impossible to quantifyif not demonstratethe efficacy of the condition-specific treatment. If a trial diagnosis of major depression subsumes subset conditions that are each selectively and differentially responsive to ADs or to psychotherapy, then their respective representation alone will shape study findings or, more commonly, the lack of specific findings. Similarly, the representation of differing constituent disorders within major depression shapes and obfuscatesfindings toward differential biological, psychological, and social cause contributions. Thus I argue that severity-based categorical domain diagnoses, such as DSMs major depression and dysthymia, and the severity-based ICD-10 categories, are without intrinsic meaning. If we are to reject this model, there are predictable and immediate problems in arguing for an explanatory alternate subtyping modelreflecting the reality that depression can reflect numerous normative, disorder, syndromal, and disease categories. Respecting that reality, options are to
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In Review

seek to define the meaningfully differing clinical conditions (a task risking idiosyncratic decision making) and (or) to limit initial consideration to explicating the most categorical clinical disease statesand here psychotic depression and melancholic depression suggest themselves. Respecting history, a case will be made for positioning melancholia as a distinct mood disorder, as referenced in a brief submission by numerous melancholia mavens to the relevant DSM-5 committee.10 Melancholia has a long history as a constructalbeit narrated via many synonyms and pseudonymsand with recent historical accounts provided by Jackson,11 Parker and Hadzi-Pavlovic,12 and Taylor and Fink.13 While its recognition goes back some 3000 years, and melancholia was defined by Hippocrates in the 5th century bc, one of the most interesting historical delineations was provided by St Paul (in Corinthians) in contrasting depressions that either came from God or were of the world. In essence, the inexplicability (at face value) of the first type was distinctive (and later led to the term endogenous), while the contrasting nonmelancholic (or reactive) depressions were clearly interpreted as explicable reactions to secular stresses. While melancholia has been variably described as endogenous, endogenomorphic, autonomous, type A, psychotic, and typical depression, it has generated and accrued numerous consistent ascriptions over time. First, that it has a relatively distinct phenotype (of symptoms and signs). Second, genetic and other biological factors are more salient to its onset and persistence than developmental factors. Third, it is selectively responsive to physical treatments (that is, ADs and ECT). Regarding its phenotypic picture, the most consistent defining marker has been PMD, and it is, therefore, interesting to note Berrios statement14 that, in classical antiquity, melancholia was defined in terms of overt behavioural features [and] that symptoms reflecting pathological affect . . . were not part of the concept. As reviewed,1,2 historical descriptions of melancholia longweighted PMD, albeit interpreted according to the prevailing Zeitgeist. Thus some sought to explain PMD as reflecting blood being thicker than usual, circulation being sluggish, body fluids being acidic and fixed, aetherial nerve fluids being irregular, or that there was too little nervous fluid and that such depleted states explained the observable anergic behaviour. The historical weighting to signs of overt PMD (both retardation and agitation) was somewhat diffused in the 1950s and 1960s by concentrated attempts to define and distinguish melancholic and (or) endogenous depression from reactive and (or) neurotic depression by so-called endogeneity symptoms. In retrospect, there were numerous distinct limitations to this methodological approach. First, symptomsbeing subjectiveare subject to a range of self-report biases, while alternate rating strategies (for example, presence, compared with absence, severity, and persistence) can all
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MelancholiaSome History

influence analytic attempts. Further, the broadness and actual nonspecificity of many of the suggested endogeneity symptoms compromised attempts at differentiating melancholic and nonmelancholic depressive subtypes, as did the actual multivariate analyses. Most involved factor or principal component analyseswhich were largely inappropriate techniques, designed to identify dimensions rather than categories or types. Second, Kendell15 delivered a coup de grce to findings from such studies. He emphasized that bimodality or a point of rarity in clinical feature scores was required to demonstrate natural boundaries between different depressive syndromes,15, p 310 but that such bimodality had not been demonstrated in studies of endogeneity symptoms over 2 decades, and firming a default unitarian positionbut not the end of the story. Kendells mentor, Aubrey Lewis, had undertaken a doctoral thesis seeking to identify qualitative distinctions between 61 depressed patients, and concluded16 that he could find no evidence to support separate depressive subtypes. Subsequently, Kiloh and Garside17 extracted data on 58 variables from Lewis published papers and we (see Parker and Hadzi-Pavlovic18) then undertook latent class analyses of those extracted data. When we plotted the distributions of all 42 clinical features considered by Lewis, the distribution of scores was unimodal, arguing against a binary model. By contrast, when we limited consideration to 14 items weighting PMD disturbance, a striking bimodal distribution was demonstrated, allowing 2 conclusions. First, bimodality (at least in this historical data set) was evident. Second, the differing analyses explained why bimodality had been obscured in many previous studiesin that inclusion of any clinical feature not specific to melancholia effectively swamps the capacity of truly differentiating items to demonstrate their specificity. Therefore, we should suspect that many DSM-IV criteria for melancholia are similarly sufficiently nonspecific so as to compromise true identification of melancholia. DSM-IV rules19 allow that melancholia can be a subset diagnosis once the diagnosis of major depression has been derived. However, there is little differentiation between the criteria sets for major depression and those for melancholia, with 5 of the 8 melancholic criteria corresponding to DSM-IV criteria for major depression. Second, some of the DSM symptoms of melancholia lack precision. One (excessive or inappropriate guilt19, p 384) allows a positive rating to be returned for people experiencing the normal self-absorbed guilt felt by those with clinical depression and who judge that they are not meeting family or work responsibilities as well as guilt manifested as an overvalued idea or as a delusionand so excising any specificity of melancholianuanced guilt. Another criterion (distinct quality of depressed mood19, p 384) is defined as differing from feelings experienced after the death of a loved one,p 384 which is a negative definition without any positive defining features, akin to defining ice hockey as not baseball. As a consequence of such lack of specificity, of the potential inclusion of many noise-producing, nonmelancholic items and of the distinct
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A Case for Reprising and Redefining Melancholia

overlap between melancholia and major depression, DSM criteria effectively overdiagnose true melancholia. Equally important, in failing to validly differentiate melancholic from nonmelancholic major depression, they compromise studies seeking to identify differential causes or treatments, further marginalizing melancholia and ensuring a selffulfilling prophecy that such a diagnosis is of no importance, and that a retreat to a unitarian model is appropriate.

retardation, agitation, and loss of the light in the eyes). We have recently reported21 on a refined measure (the Sydney Melancholia Prototype Index or SMPI) differentiating melancholic and nonmelancholic depression based both on clinical features and on illness correlates, with the clinicianrated version showing a high level of differentiation and superior to the self-report version. Our studies overviewed to here have progressively identified a refined set of symptoms and signs of melancholia, but neither we nor any other research group have identified a set providing absolute distinction of melancholic and nonmelancholic depression. This could allow the default position to be assumed (that is, that depression is simply a single condition varying by severity), but we still embrace melancholia as a distinct depressive subtype with a relativelybut not absolutelydistinct phenotype. This is not inconsistent with other exemplars from medicine. For example, Parkinson disease lacks absolutely characteristic symptoms. Instead, it comprises a constellation of features (for example, tremor, rigidity, and bradykinesia) that may be quite variably manifested by people with that conditionand there is no laboratory or other benchmark test. A diagnosis of Parkinson disease is based essentially on clinical assessment. It is not always easy to distinguish it from other neurological conditions, but this does not stop neurologists from regarding Parkinson disease as an important syndrome for diagnosis (particularly in light of treatment implications), and we would argue that this model should hold for melancholia. To the degree that the model is valid, it also explains some of the limitations to trying to delineate melancholia with absolutely discriminatory symptoms. If melancholia is a neurocircuit disorderwith such circuits linking the basal ganglia, and the prefrontal cortex being variably perturbed at differing sitesthen this could account for patients variably weighting quite differing symptoms (for example, some weighting anhedonia, others abulia), a model that could be advanced by correlating individually weighted prototypic symptoms with a persons neuroimaging profile. Therefore, we now argue that definition of melancholia and its delineation from nonmelancholic conditions requires multiple approaches (for example, symptoms, signs, and clinical correlates), as was the model for the Newcastle definition of endogenous depression22 and the DSM-III-R23 criteria set for melancholia. Just as global navigational systems rely on a minimum of 3 satellites (triangulation), it appears preferable for melancholia to be defined by multiple strategies (for example, clinical features, illness correlates, and biological markers), and clearly there is a need to advance study into efficiently discriminating biological markers.

In our early studies (see Parker and Hadzi-Pavlovic12), we quantified that many of the so-called endogeneity symptoms lacked specificity, being equally likely to be affirmed by people with melancholic or nonmelancholic disorders. By contrast, when we focused on PMD signs, we were able to differentiate between melancholic and nonmelancholic patients with relatively clear separation, allowing us to position observable PMD as both necessary and sufficient for the definition of melancholia. We validated that approach to diagnosis by showing that people assigned as having melancholia by our CORE measure of PMD had slower reaction times, higher dexamethasone suppression test (commonly referred to as DST) nonsuppression rates, and, in line with ascriptions about melancholia, were more likely to respond to TCAs and to ECT. However, we progressively learned that our relatively pristine model was advanced by the older age of our melancholic subjects, with subsequent clinical observations (supported by some empirical studies) suggesting that overt PMD is not so evident in younger people with true melancholia. We suspected that this phenotypic change reflected more monoaminergic systems being recruited with age in people with melancholia, an explanation that also assists to interpret why response to differing ADs (particularly narrow-action SSRIs) changes over timeas detailed later. Thus, as PMD is not necessarily necessary and sufficient in younger melancholic patients, we returned to analyses of symptoms, but first focused on their prototypic status. As detailed recently,20 distinction based on prototypic status was comparable with their severity statusand with moderate overall classification rates being returned. However, when we (see Parker et al20) added a set of clinical correlates (that is, older age at initial episode, fewer developmental stresses, fewer proximal stresses, less personality disturbance, and lower prevalence of anxiety disorders) to the symptom variables, the overall classificatory rate improved to 80%, and the plotted scores showed clear evidence of a bimodal distribution. Symptoms that we now weight as the most useful clinical signals of melancholia include anergia (whereby a person finds it extremely difficult to get out of bed and get going); an anhedonic and nonreactive mood; mood and energy showing diurnal variation, being worse in the morning; reporting impaired concentration (such as, brain feeling foggy and thoughts slowed down, rather than the distractible thoughts associated with anxiety) and overt PMD (for example,
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What Clinical Features Best Define Melancholia?

A key argument for positioning melancholia as a separate depressive type10 is demonstration of its differential response to differing treatments. If demonstratedin the
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Does a Diagnosis of Melancholia Have Treatment Implications?

In Review

absence of evident differentiation treatment impacts for major depressionthen management recommendations can be refined, treatment response rates should be improved, and the simple unitarian model of depression dispatched to historys dustbins. There are several key problems in overviewing this key question. First, there is little such applied researchas a consequence of melancholia withering. Second, most researchers used formalized diagnoses of melancholia. If, as indicated, the DSM-IV definition of melancholia is invalid, then a lack of treatment differentiation would be expected in relation to DSM diagnosesand alone could destroy the argument for defining melancholia as a distinct type. One of the ascriptions to melancholia is that it has a low placebo response rate and that melancholia responds preferentially to physical treatments as against psychotherapies. Regarding the first component, Fairchild et al24 quantified a 6% response to placebo by people with endogenous depressioncompared with a 54% placebo response by those with a nonendogenous depression. Regarding the second component, there are no RCTs examining any of the evidence-based psychotherapies against AD therapy as treatments of melancholia, so that this sectional overview is limited to consideration of AD effectiveness. Despite distinct limitations to DSM-IV melancholia criteria, we can still observe signals. Assigned melancholic subjects in the Sequenced Treatment Alternatives to Relieve Depression (commonly referred to as STAR*D) study25 had lower response and remission rates to the initial 12-week trial of the AD citalopram than those not meeting DSM-IV criteria for melancholia. When other definitions of melancholic depression are used, more distinctive treatment gradients are evidentif not striking. For instance, Perry26 undertook a meta-analysis and quantified a 57% response to TCAs, compared with 18% for SSRIs, for subjects with endogenous depression. We have undertaken retrospective and prospective studies (see Parker27 and Parker et al28) of large samples of depressed patients. In essence, while response to a broadaction AD (that is, a TCA) does not appear to differ from that of a narrow-action AD (that is, an SSRI) for patients with a nonmelancholic depression, those with melancholia showed a distinct gradient favouring the TCAand with the gradient increasing with age, reflecting the SSRI response rate declining. In 1 of our studies,27 we established that TCAs were 4 times more effective than SSRIs in people over the age of 60and, as noted earlier, this differential age-based treatment response may reflect greater monoaminergic recruitment with ageas signalled by age changes in the phenotype. Such datasuggesting that SSRIs may be less effective than dual-action drugs, which, in turn, may be less effective than broad-action ADs (TCAs and monoamine oxidase inhibitors) and broad-action strategies (for example, an atypical antipsychotic plus an AD)respect a model
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implicating greater involvement of dopaminergic and noradrenergic systems (than serotonergic systems alone) in melancholiaand increasing with age. They also provide a logic for a stepped model for managing melancholia,3 whereby if a patient does not respond to a narrow-action AD, then a set of progressively broader-action ADs would be implemented.

Conclusions

In arguing a case for melancholia, limitations to the unitarian view are first emphasized to set the stage for defining depressive subtypes that evidence causal, phenomenological, and treatment differentiation. Melancholia advances itself as such a candidate and would benefit from concentrated studies to improve its clinical distinction and causal nuances.

Acknowledgements

This paper reflects research funded by a National Research and Medical Council Program Grant (510135). Dr Parker has received funding for talks and served on boards of several pharmaceutical companies, for example, Eli Lilly, Pfizer, Servier, Lundbeck, and AstraZeneca. Manuscript assistance by Karlyn Greenshields is appreciated. I thank Bernard Carroll for permission to quote a personal communication. The Canadian Psychiatric Association proudly supports the In Review series by providing an honorarium to the authors.

References

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10. Parker G, Fink M, Shorter E, et al. Issues of DSM-5: whither melancholia? The case for its classification as a distinct mood disorder. Am J Psychiatry. 2010;167(7):745747. Editorial. 11. Jackson S W. Melancholia and depression: from hippocratic times to modern times. New Haven (CT): Yale University Press; 1986. www.LaRCP.ca

A Case for Reprising and Redefining Melancholia


12. Parker G, Hadzi-Pavlovic D. Melancholia: a disorder of movement and mood. A phenomenological and neurobiological review. New York (NY): Cambridge University Press; 1996. 13. Taylor MA, Fink M. Melancholia. The diagnosis, pathophysiology, and treatment of depressive illness. Cambridge (GB): Cambridge University Press; 2006. 14. Berrios GE. Melancholia and depression during the 19th century. Br J Psychiatry. 1988;153:298304. 15. Kendell RE. Clinical validity. In: Robins LN, Barrett JE, editors. The validity of psychiatric diagnosis. New York (NY): Raven Press; 1989. p 305323. 16. Lewis AJ. 1931. A clinical and historical survey of depressive states based on the study of 61 cases [doctoral thesis]. [Adelaide (AU)]: University of Adelaide. 17. Kiloh LG, Garside RF. Depression: a multivariate study of Sir Aubrey Lewiss data on melancholia. Aust N Z J Psychiatry. 1977;11:149156. 18. Parker G, Hadzi-Pavlovic D. Old data, new interpretation: a re-analysis of Sir Aubrey Lewis MD thesis. Psychol Med. 1993;23:859870. 19. American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): APA; 1994. 20. Parker G, Fletcher K, Barrett M, et al. Inching towards Bethlehem: mapping melancholia. J Affect Disord. 2010;123:291298. 21. Parker G, McCraw S, Blanch B, et al. Discriminating melancholic and non-melancholic depression by prototypic clinical features. J Affect Disord. 2102;144:199207. 22. Carney MWP, Roth M, Garside RF. The diagnosis of depressive syndromes and the prediction of ECT response. Br J Psychiatry. 1965;111:659674. 23. American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders. 3rd ed. Revised. Washington (DC): APA; 1987. 24. Fairchild CJ, Rush AJ, Vasavad N, et al. Which depressions respond to placebo? Psychiatr Res. 1986;18:217226. 25. McGrath PJ, Khan Ahsan Y, Trivedi MH, et al. Response to the selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report. J Clin Psychiatry. 2008;69:12. 26. Perry PJ. Pharmacotherapy for major depression with melancholic features: relative efficacy of tricyclic versus selective serotonin reuptake inhibitor antidepressants. J Affect Disord. 1996;39:16. 27. 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;106:168170. 28. Parker G, Roy K, Wilhelm K, et al. Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study. J Clin Psychiatry. 2001;62:117125.

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