Major running on the spot
Authors: GORDON PARKER
Journal: World Psychiatry (2010)

G. Hasler's overview illustrates the strengths and limitations of recent research into the depressive disorders. Strengths include highly intelligent and assiduously committed researchers. Limitations emerge from the paradigms underpinning our current (DSM and ICD) mood disorder classificatory models. The resulting discordance evokes the old Bavarian proverb: "What's the use of running if you're on the wrong road". I will argue that Hasler's composite review of pathophysiological studies is compromised by a diagnostic paradigm failure. As a consequence, after tasting a large number of appetizers, the reader will be left hungry in the absence of a digestible main course. In reality, major depressive disorder is not an entity and thus not an "it" as described by Hasler, and as positioned and reified by most researchers who wish to have their work published. It is, in essence, a "domain" diagnosis that effectively homogenizes multiple heterogeneous expressions of "depression". It has no more precision, defined boundaries or entity status than, say, "major breathlessness", an analogy worth pursuing. A diagnosis of "major breathlessness" subsumes a number of acute (e.g., asthma, pneumonia, pulmonary embolus) and chronic (e.g., emphysema) conditions, and might risk including transient normative states (e.g., an unfit mountain climber). The DSM criteria for major depression are relatively few and each criterion is operationalized at a low order of inference, generating quite high prevalence estimates and blurring boundaries with "normal depression" 1. A domain diagnosis of "major depression" can be assumed to encapsulate more categorical conditions (e.g., psychotic and melancholic depression) as well as many non-melancholic disorders (e.g., acute and chronic reactive depressive states, depressions secondary to predisposing personality styles). Such constituent domain disorders may have quite different principal causes (e.g., primary biological underpinnings for melancholia; primary social and psychological causes for reactive and personality-based depressions respectively). Such heterogeneity across the domain diagnosis will obscure identification of disorder-specific causal factors and compromise attempts to identify any treatment specificity. Any attempt to study causes of "major depression" should also respect the reality (as for studies investigating "major breathlessness") that findings will be highly dependent on the prevalence of constituent disorders within the "domain diagnosis". Thus, if studies of those with "major breathlessness" were dominated by, say, patients with asthma, then the capacity to identify asthma's causes within a sample dominated by those with respiratory infection would be compromised. As differing depressive disorders will be variably represented across differing samples with quite varying distributions of constituent depressive conditions (e.g., inpatients, psychiatric outpatients, primary practice, community groups), sample selection alone will also influence findings. In essence, if a diagnosis is essentially "non-specific", identification of its causes and treatments will be compromised by that non-specificity, and generate non-specific findings. It would be possible to proceed through Hasler's paper demonstrating non-specific findings in relation to each evidence point but, as this would narrow the focus, one illustration is offered. In the third paragraph — imputing genetic influences — Hasler states that "major depressive disorder is a familial disorder and that this familiarity is mostly or entirely due to genetic factors", referencing a meta-analysis by Sullivan et al 2. Perhaps as a corollary, Hasler states that such findings indicate that parental behaviors and other environmental risk factors are not as important "as previously assumed" and should not be the focus of treatment. However, when the meta-analysis by Sullivan et al is examined, their conclusions were that "environmental influences specific to an individual are also etiologically significant". These two interpretations are somewhat contradictory. Shortly after, Hasler switches emphasis to note a dominance of non-genetic factors, which "suggest that there is a huge potential" for psychosocial interventions to prevent major depression. In two paragraphs, Hasler variably argues for the dominance of genetic factors and then for non-genetic factors. Later, across three consecutive paragraphs, he suggests that environmental factors should not be the main focus of treatment before suggesting that psychosocial interventions focusing on interpersonal difficulties and skills offer "huge potential". The subtitle of Hasler's paper indicates that it is designed to assist clinicians. Again, this objective can be challenged with one illustration. At the end of the "Genes and psychosocial stress" section, Hasler states that "The clinician should be aware that family history will continue to be the most solid source of information to estimate the genetic risk of major depressive disorder". But what does "family history" mean in this context? Does it mean "major depression" or some other psychiatric condition in a family member? Or does it mean a family member being hospitalized for a psychiatric condition, attempting or committing suicide, or receiving treatment by a psychiatrist (all difficult to establish and all likely to have quite varying signal propensities)? Or does it mean less substantive conditions (e.g., being "nervy and a worrier") in a family member. The non-specificity of this "solid source" recommendation challenges the paper's clinical utility. Having posed the question (i.e., is there a solid neurobiological base to "depression"?), Hasler effectively votes against the proposition to conclude that "depression is a clinically and etiologically heterogeneous disorder". Indeed. Should we therefore continue to pursue research into this non-specific domain diagnosis and risk further non-specific findings? Not, in my view, if we wish to stop running on the spot.