Fear-induced bradycardia in mental disorders: Foundations, current advances, future perspectives

Treatment resistance affects 20-60% of patients with psychiatric disorders; and is associated with increased healthcare burden and costs up to ten-fold higher relative to patients in general. Whilst there has been a recent increase in the proportion of psychiatric research focussing on treatment resistance (R2=0.71, p<0.0001), in absolute terms this is less than 1% of the total output and grossly out of proportion to its prevalence and impact. Here, we provide an overview of treatment resistance, considering its conceptualisation, assessment, epidemiology, impact, and common neurobiological models. We also review new treatments in development and future directions. We identify 23 consensus guidelines on its definition, covering schizophrenia, major depressive disorder, bipolar affective disorder, and obsessive compulsive disorder (OCD). This shows three core components to its definition, but also identifies heterogeneity and lack of criteria for a number of disorders, including panic disorder, post-traumatic stress disorder, and substance dependence. We provide a reporting check-list to aid comparisons across studies. We consider the concept of pseudo-resistance, linked to poor adherence or other factors, and provide an algorithm for the clinical assessment of treatment resistance. We identify nine drugs and a number of non-pharmacological approaches being developed for treatment resistance across schizophrenia, major depressive disorder, bipolar affective disorder, and OCD. Key outstanding issues for treatment resistance include heterogeneity and absence of consensus criteria, poor understanding of neurobiology, under-investment, and lack of treatments. We make recommendations to address these issues, including harmonisation of definitions, and research into the mechanisms and novel interventions to enable targeted and personalised therapeutic approaches.

Aversive pavlovian delay conditioning was investigated in a sample of 11 criminal psychopaths as identified by using the Psychopathy Checklist-Revised and 11 matched healthy controls. A painful electric stimulus served as unconditioned stimulus and neutral faces as conditioned stimuli. Event-related potentials, startle response potentiation, skin conductance response, corrugator activity, and heart rate were assessed, along with valence, arousal, and contingency ratings of the CS and US. Compared to healthy controls, psychopathic subjects failed to differentiate between the CS+/CS- as shown by an absence of a conditioned response in startle potentiation and skin conductance measures. Through use of a fear-eliciting US, these data confirm previous findings of a deficient capacity to form associations between neutral and aversive events in psychopathy that appears unrelated to cognitive deficits and is consistent with hypothesized frontolimbic deficits in the disorder. Copyright © 2012 Elsevier B.V. All rights reserved.

Understanding transient dynamics of the autonomic nervous system during fear learning remains a critical step to translate basic research into treatment of fear‐related disorders. In humans, it has been demonstrated that fear learning typically elicits transient heart rate deceleration. However, classical analyses of heart rate variability (HRV) fail to disentangle the contribution of parasympathetic and sympathetic systems, and crucially, they are not able to capture phasic changes during fear learning. Here, to gain deeper insight into the physiological underpinnings of fear learning, a novel frequency‐domain analysis of heart rate was performed using a short‐time Fourier transform, and instantaneous spectral estimates extracted from a point‐process modeling algorithm. We tested whether spectral transient components of HRV, used as a noninvasive probe of sympathetic and parasympathetic mechanisms, can dissociate between fear conditioned and neutral stimuli. We found that learned fear elicited a transient heart rate deceleration in anticipation of noxious stimuli. Crucially, results revealed a significant increase in spectral power in the high frequency band when facing the conditioned stimulus, indicating increased parasympathetic (vagal) activity, which distinguished conditioned and neutral stimuli during fear learning. Our findings provide a proximal measure of the involvement of cardiac vagal dynamics into the psychophysiology of fear learning and extinction, thus offering new insights for the characterization of fear in mental health and illness. Understanding transient dynamics of the autonomic nervous system during fear learning remains a critical step to translate basic research into treatment of fear‐related disorders. Here, using a novel frequency‐based analysis to capture transient changes of heart rate variability, our findings highlight a selective modulation of the high frequency (HF) band of the power spectrum, when facing fear‐relevant stimuli. Crucially, these results reveal specific increased parasympathetic (vagal) activity during fear learning in humans.