Helplessness: a systematic translational review of theory and evidence for its relevance to understanding and treating depression.

Helplessness is a major concept in depression and a major theme in preclinical and clinical depression research. For example, in rodents and humans, the learned helplessness (LH) effect describes a specific deficit in behaviour to control aversive stimuli that is induced by prior exposure to uncontrollable aversive stimuli. The LH effect is objective and valid in that the cause of the behavioural deficit, namely uncontrollability, is clear; furthermore, the deficit induced is underlain by emotional, motivational and cognitive processes that are relevant to depression psychopathology. As a further example, helplessness, hopelessness, external locus of control and causal attribution are inter-related and major themes in psychological theories (primarily cognitive theories) of depression. Despite this broad interest in helplessness, it can be argued that its potential usefulness as a scientific and clinical concept has so far not been investigated optimally, including with respect to its application in research aimed at development of improved anti-depressant pharmacotherapy. The first aim of this review was to describe and integrate the psychological evidence and the neurobiological evidence for the LH effect in rodents and healthy humans and for helplessness in depressed patients. The second aim was to conduct three systematic reviews, namely of rodent studies of the LH effect, rodent studies of effects of psychopharmacological agents on the LH effect, and human studies of efficacy of pharmacotherapeutic and psychotherapeutic treatment on helplessness in depressed patients. With respect to the first aim, the major findings are: the specificity of the LH effect in otherwise non-manipulated rodents and healthy humans has been under-estimated, and the LH effect is a specific learned aversive uncontrollability (LAU) effect. There is theoretical and empirical support for a model in which a specific LAU effect induced by a life event of major emotional significance can function as an aetiological factor for generalised helplessness which can in turn function as an aetiological and maintenance factor for depression. However, to date such models have focused on cognitive mediating processes whereas it is emotional-motivational-cognitive processes (as proposed for the LAU effect) that need to be invoked and understood. The evidence is for analogous neural processes underlying the LAU effect in rodents and healthy humans and helplessness in depression, with the ventro-medial prefrontal cortex exhibiting aversive uncontrollability-dependent activity. With respect to the second aim, the major findings are: the LAU effect is demonstrated quite consistently using a number of different paradigms in rat but is poorly studied in mouse. The rat LAU effect can be reversed by chronic administration of monoamine reuptake inhibitors. The effects of antidepressants on human helplessness have been scarcely studied to-date. The major conclusion is that the LAU effect and generalised helplessness constitute major neuropsychological concepts of high value to future translational research aimed at increased understanding of depression and development of novel, improved antidepressant treatments.