Retrospective: Pursuing melancholia – The Australian contribution

The year 1967 in Australia was marked by some sentinel events: Harold Holt disappeared into the surf; Gough Whitlam became leader of the Labor Party; Aboriginal people were, for the first time, counted in the Census; andthe inaugural issue of this journal published an article by John Cade on melancholia.

The Australian & New Zealand Journal of Psychiatry rapidly became a key educational portal, especially for regional psychiatrists. When Editor, I surveyed the membership to determine readers’ needs and was intrigued that the sparring and combative Correspondence section was the most favoured. Now the journal has a more international flavour, and the tone of the correspondence is less disputative, with writers Malhi-fied.

Now let me bring back the biff by reviewing the battle over the melancholia terrain. As an early trainee, I became absorbed by a man in his 40s who lay in his hospital bed for most of the day. When out of bed, he would move slowly and respond monosyllabically to questions, acknowledging a complete lack of pleasure and feeling. Three first-degree relatives had had depression, with one committing suicide. The man was content in his marriage, successful in his career and a proud father, with his first depressive episode emerging without any distinct antecedent stressors. Two consultants offered quite varying formulations. US-trained Dr Unitary was a Meyerian acolyte. He argued that the patient required intensive psychotherapy, even informing the patient that he needed to ‘suffer’ the pain so as to be able to ‘work through it’. Dr Binary had Novocastrian training, noted the failure of antidepressant medication and initiated a course of electroconvulsive therapy (ECT). After eight treatments, the patient’s depression remitted, and he left hospital with the only cloud being on Dr Unitary’s brow.

My point? Severe melancholia has a distinctive phenotype, consistently described since Hippocrates, independent of culture and race, striking in its ‘physicality’, and with its territory richly traversed in psychiatrist Barney Carroll’s (2012) annotated poem as shown.

It strains credulity that melancholic depression lies simply at the more severe end of a depressive spectrum: yet that is the unitary view – and one largely cemented in the International Classification of Diseases, Tenth Edition (ICD-10), the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) and subsequent DSM manuals. Melancholia is, in my opinion, a quintessential psychiatric ‘disease’ – akin to Parkinson’s disease in requiring clinical acumen (in the absence of any definitive laboratory test) to ensure that it is correctly diagnosed and optimally managed.

Melancholia’s ascriptions include a set of distinctive clinical features, genetic rather than psychosocial determinants, biological underpinnings, a minimal response to placebo and a preferential response to medication and ECT than to psychotherapy. Let me overview salient research by Australian psychiatrists.

Aubrey Lewis studied 61 patients and concluded (in his University of Adelaide PhD thesis) that he could not find support from his qualitative analyses for two depressive types (qua melancholic and non-melancholic depression) but noted that future analytic approaches might challenge that view. Following on, Kiloh and Garside (1977) impishly undertook a principal components analysis of Lewis’ own data set and argued that it demonstrated ‘two qualitatively different depr­essive illnesses … (and) that endogenous depression is a categorical illness’. Bob Kendell, an acolyte of Lewis, had claimed that, if the binary view was valid, then any set of depressive features should show a bimodal pattern or ‘point of rarity’ and that no researcher had demonstrated such a pattern. Subsequently, using Kiloh’s data, and limiting Lewis’ clinical features to those that weighted the presence or absence of melancholia’s key characteristic (psychomotor disturbance), our team demonstrated an unequivocal bimodal distribution.

Initially at Newcastle-upon-Tyne and then in Sydney, Kiloh undertook a series of multivariate analyses of depressive symptoms (as did Issy Pilowsky) and maintained that their generated bimodal factor argued for melancholic and neurotic/reactive depressions as differing ‘types’. He successfully extracted sets of ‘endogeneity’ symptoms from the data. Despite three decades of multivariate analyses, however, there had been no distinctive set of clinical symptoms or measure of melancholia sufficiently persuasive to convince the DSM-III architects that melancholia is a categorical disorder with specific features.

We adopted an alternate approach in the 1990s – weighting signs rather than symptoms of psychomotor disturbance – and produced the CORE measure. In our development samples, CORE scores met stringent criteria of being ‘necessary and sufficient’ (i.e. psychomotor disturbance was necessary to indicate the existence of a melancholic depression, and sufficient in and of itself to make such a diagnosis – in that the addition of endogeneity symptoms did not improve differentiation). However, our trials were weighted to older melancholia patients – where psychomotor disturbance is more overt. We reverted to identifying a refined set of symptoms but then established that by adding illness and personality correlates, we could improve the classificatory accuracy of melancholic versus non-melancholic depression from around 70% to 90%. We judge that measure – the SMPI or Sydney Melancholia Proto­typic Index (Parker et al., 2013) – as perhaps as ‘good as it gets’ in terms of diagnostic utility.

In terms of other melancholia ascriptions, we have demonstrated a distinctly higher rate of depression (as well as of suicide) in first-degree and second-degree relatives in those with a melancholic depression, thereby supporting a strong familial loading. In relation to biomarkers, Barney Carroll’s work in Melbourne and later in the United States established the high precision of the dexamethasone suppression test (DST) in differentiating melancholic from non-melancholic depression. The measure’s utility predictably declined when the Americans tested it as a measure of ‘depression’ rather than of melancholia.

In relation to melancholia’s biological underpinnings, we have undertaken functional brain imaging studies and showed impaired functioning in the insula region (fitting when those experiencing a melancholic episode become insular and asocial), and disconnectivity in the sub-genual anterior cingulate cortex and caudate.

Perhaps most importantly we have shown the differential relevance of contrasting treatment strategies, in (1) quantifying distinct superiority of antidepressant medication compared to cognitive behaviour therapy, (2) showing a striking gradient of responses to differing antidepressant classes and (3) advancing augmentation strategies for more treatment-resistant melancholia, including the brief addition of an atypical antipsychotic, and the utility of adding a psychostimulant (the latter, Dr Lord Moran’s strategy for assisting Churchill out of his enervating ‘black dog’ states).

When our group of melancholia mavens pitched melancholia as a specific depressive type to the DSM-5 work group (and published an abbreviated version of our case in the American Journal of Psychiatry), we experienced the totschweigtaktik (death by silence) response. As Gary Greenberg (2013) observed, our arguments offered the ‘APA … at least one opportunity for a slam dunk in the DSM-5 … that, at least in this one case, psychiatrists were real doctors treating real diseases’. However, melancholia failed to be included as a DSM-5 disorder, although the Chair of the DSM-5 Mood Disorders Work Group’s subsequent cri de coeur (Fawcett, 2014) is informative – ‘Right now, with major depression as our target, we are shooting in the dark’. By comparison, the case for melancholia as a categorical disease, with genetic and biological underpinnings and requiring prioritising of physical treatment modalities emerges strongly. It has now moved beyond clinical impression and has been enriched by firm scientific findings. But as Jacob Bronowski observed, no science is immune to the infection of politics.