The search for psychosocial factors that contribute to the aetiology and course of coronary heart disease (CHD) has been an energetic, although not always fruitful, pursuit for more than half a century. Around 20 years ago, Appels  identified a prodromal constellation of symptoms, including physical exhaustion and feelings of hopelessness, that preceded major CHD events. It was hypothesized that this syndrome of “vital exhaustion” (VE) was a causal risk factor for CHD events, and several observational studies demonstrating prospective associations between VE and subsequent events have been adduced as supporting the hypothesis , ,  and . In a recent commentary, however, we discussed the difficulties inherent in drawing causal conclusions from observational evidence . Applying general arguments that are by now very well rehearsed  and , we suggested that considerations such as confounding by common antecedents of both VE and CHD and reverse causation could not be readily dismissed and resolution was likely only following experimental studies. For example, an explanation of these prospective associations that regards CHD events as the result of inflammatory processes involved in the progress of atherosclerosis and VE as a consequence of such processes is just as parsimonious as one that regards VE as a causal risk. It is also equally, if not more, plausible biologically; there is now substantial evidence that inflammatory cytokines communicate with the central nervous system contributing to illness behaviour and experience and fostering feelings of depression and fatigue . We also posed the question of what implications do the results of observational studies of VE hold for treatment . Again, we would argue that in the absence of experimental evidence, the implications are extremely limited.