Largely unnoticed flaws in the fundamentals of depression diagnosis: The semantics of core symptoms

ICD Insight

International diagnostic classification systems risk optimizing the reliability and practicability of diagnostic criteria at the cost of validity. This problem already exists at the level of symptom description. ‘Fatigue or loss of energy’ is one of the diagnostic criteria for a depressive episode in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and one of the three key symptoms according to the International Classification of Diseases, 10th Revision (ICD-10). But the semantically imprecise description of these symptoms undermines the validity of the diagnosis of depression.

Fatigue and the related term tiredness can denote quite different and even opposite psychological and neurophysiological states. It can denote exhaustion in the context of an upregulated brain arousal as observed in major depression (MD). These patients report high inner tension and difficulties relaxing or falling asleep at night as well as during the day. This is related to prolonged sleep onset latencies as assessed in the Multiple Sleep Latency Test, a hyperstable regulation of wakefulness as measured with electroencephalography (EEG) (Vigilance Algorithm Leipzig; Hegerl and Hensch, 2014), or a hyperactivity of wakefulness-promoting brain systems such as the hypothalamic–pituitary–adrenal (HPA) axis or the central noradrenergic system (Hegerl and Hensch, 2014). However, fatigue is also used to denote a state with increased sleep propensity (sleepiness). Patients report difficulties in keeping their eyes open under quiet rest, and short sleep latencies are observed during the day and at night. Based on neurobiological findings, it has been proposed to separate hypoaroused fatigue, as found in chronic fatigue syndrome or fatigue in the context of immunological and inflammatory processes, from hyperaroused fatigue, as typically found in MD (Hegerl et al., 2013).

Loss of energy also mixes up quite different psychological and physiological states. Traditionally, clinicians made the distinction between lack of drive and inhibition of drive. Inhibition of drive, a patient-reported symptom, is typically found in MD. Patients report a high inner tension and a leaden resistance to the initiation of any mental or physical activity. It is evident with experience that this symptom is completely different from anergic, apathetic states with lack of drive, as found for example in the context of immunological and inflammatory processes.

With the terms fatigue and loss of energy as diagnostic criteria, the diagnosis of MD has been erected on sand. Patients from the opposite ends of the arousal regulation dimension are put in the same basket. Bearing in mind the fundamental role of arousal regulation on brain function, these patients are unlikely to show the same pathophysiology and response to psychopharmacological treatments. Patients with an upregulated regulation of arousal, as found in MD, are unlikely to respond to drugs with wakefulness stabilizing properties such as psychostimulants. Indeed, in patients with typical MD, psychostimulants notoriously fail to work as antidepressants (Candy et al., 2008). However, antidepressants, which in a highly consistent manner reduce the firing rate of neurons in the noradrenergic locus coeruleus (West et al., 2009), may partly, through this and other mechanisms (anticholinergic and antihistaminergic effects), counteract the tonic increase of brain arousal (Hegerl and Hensch, 2014). On the other hand, patients with lack of drive and high sleep propensity, as found in fatigue in the context of inflammatory or immunological processes, might respond to psychostimulants, as suggested by several studies and meta-analyses of randomized controlled trials (Minton et al., 2010).

Arousal and regulatory systems are one of the five research areas proposed by the National Institute of Mental Health within the Research Domain Criteria project, which aims at developing a more valid taxonomy of mental disorders. The distinctions between sleepiness versus exhaustion with upregulated arousal, and between lack of versus inhibition of drive, as well as the EEG-based assessment of wakefulness regulation, might provide much needed direction in this context.