Neuropsychopharmacology of Auditory Hallucinations

Insights From Pharmacological Functional MRI and Perspectives for Future Research

Erik Johnsen; Kenneth Hugdahl; Paolo Fusar-Poli; Rune A Kroken; Kristiina Kompus


Expert Rev Neurother. 2013;13(1):23-36. 

In This Article

Abstract and Introduction


Experiencing auditory verbal hallucinations is a prominent symptom in schizophrenia that also occurs in subjects at enhanced risk for psychosis and in the general population. Drug treatment of auditory hallucinations is challenging, because the current understanding is limited with respect to the neural mechanisms involved, as well as how CNS drugs, such as antipsychotics, influence the subjective experience and neurophysiology of hallucinations. In this article, the authors review studies of the effect of antipsychotic medication on brain activation as measured with functional MRI in patients with auditory verbal hallucinations. First, the authors examine the neural correlates of ongoing auditory hallucinations. Then, the authors critically discuss studies addressing the antipsychotic effect on the neural correlates of complex cognitive tasks. Current evidence suggests that blood oxygen level-dependant effects of antipsychotic drugs reflect specific, regional effects but studies on the neuropharmacology of auditory hallucinations are scarce. Future directions for pharmacological neuroimaging of auditory hallucinations are discussed.


Auditory verbal hallucinations (AVHs) are experiences of hearing voices, which are independent of the physical external environment.[1–3] Auditory hallucinations are a major diagnostic criterion of schizophrenia. However, recent research and clinical evidence has highlighted that subtle psychotic symptoms can be present in subjects at high clinical risk (HR) for psychosis and even in the healthy population (psychotic-like experiences [PLEs]).[4,5] Auditory hallucinations with negative, threatening or commanding content are a significant stressor, adding to the burden of illness in schizophrenia patients and diminishing their quality of life.[6] Consequently, developing reliable treatment and intervention options is of utmost importance in psychiatric research; however, it is complicated owing to limited understanding of the neural mechanisms by which auditory hallucinations are triggered and maintained.[7]

Current neuroimaging methods, for example functional MRI (fMRI) and PET, have made it possible to examine the neural mechanisms underlying subjective mental states with a wealth of data on different aspects of mental processing, such as memory, consciousness and emotional states. Although there are several imaging studies of patients with auditory hallucinations,[8–10] the results are complicated and not always easy to interpret. This is at least partly due to the practical challenges of imaging subjective experiences which may occur relatively rarely and usually unpredictably, as well as requiring active collaboration from the subject in reporting these. To have the patients reporting the onset and offset of symptoms while in the scanner may also be a challenge, and with a great deal of uncertainty regarding the true time course of such events during scanning. Another major caveat is that the neurophysiological investigation of auditory hallucinations is often hampered by brain functional and structural changes associated with illness chronicity or antipsychotic treatment.[11] In particular, there is evidence that antipsychotic treatment can affect brain structures that are fundamental in the development of the illness.[12,13] The impact of antipsychotic medication on brain function is even less clear as well as their role in affecting the experience of auditory hallucinations, including the nature and content of hallucinations in patients with schizophrenia.

A more recently developed field in psychiatric neuroimaging is pharmacological imaging,[14,15] which concerns the effects of pharmacological compounds on neuronal activation observed during functional neuroimaging. Pharmacological neuroimaging may therefore aid in pinpointing the mechanisms of drug action and thereby assist in developing drug intervention strategies. It may, moreover, bridge the gap between mechanisms of drug action and the occurrence of AVHs. By combining imaging of specific psychiatric symptoms and imaging of the effects of specific pharmacological interventions, new insights can be gained regarding the therapeutic potential and limitations of CNS drugs, such as antipsychotics.

The aim of the present work was thus to review the contributions from pharmacological fMRI to the understanding of how antipsychotic drugs affect auditory hallucinations, and how future studies can address issues such as more individualized antipsychotic drug therapy and prediction of treatment response. The review should be considered as a selective review of the available literature, driven by an ambition to critically evaluate and discuss the contributions of functional neuroimaging to understand the effects of antipsychotic medication on auditory hallucinations. Thus, the current review does not provide the kind of quantitative comparisons as seen in, example, a meta-analysis owing to the scarcity and heterogeneity of currently available studies, which prevents a systematic analysis. High-quality benchmarking studies were searched for, to cover the different sections of the review, and the studies included in the review were selected based on the reviewers' expertise in their respective fields. The review is organized such that auditory hallucinations as a phenomenon is first reviewed including the special populations of subjects at HR of psychosis and people in the healthy population with PLEs. Current and future drugs and potential drug targets in psychosis and auditory hallucinations are then reviewed, followed by three sections presenting fMRI in pharmacological studies in general, in antipsychotic drug studies specifically, and finally in antipsychotic drugs and auditory hallucinations, respectively.