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Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it?

Alphs L, Benedetti F, Fleischhacker WW, Kane JM - Int. J. Neuropsychopharmacol. (2012)

Bottom Line: This paper seeks to clarify key issues related to this problem and identify potential solutions to them.Differences between placebo effect and response are characterized.Recent insights into the central nervous system mechanisms of placebo effect are described.

View Article: PubMed Central - PubMed

Affiliation: Janssen Scientific Affairs, LLC, Titusville, NJ, USA. lalphs@its.jnj.com

ABSTRACT
The effect of placebo observed in schizophrenia clinical trials represents a growing problem that interferes with signal detection for treatments, increases costs of development, discourages investment in schizophrenia research and delays the introduction of new treatments. This paper seeks to clarify key issues related to this problem and identify potential solutions to them. Differences between placebo effect and response are characterized. Recent insights into the central nervous system mechanisms of placebo effect are described. This is followed by a description of protocol/study design and study conduct issues that are contributing to a growing placebo effect in clinical trials. Potential solutions to these problems are provided.

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Related in: MedlinePlus

Differences in neural activity in placebo responders and placebo non-responders. These panels depict the relationship between clinical placebo response, as assessed through muscle rigidity at the wrist (a) and electrophysiological placebo responses, as measured by means of a single neuron recording (b), in Parkinson's disease. Note that in placebo responders (left), both muscle rigidity decreases and electrophysiological changes occur, whereas in placebo non-responders neither clinical nor electrophysiological changes take place (Benedetti et al.2004, 2009).
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fig001: Differences in neural activity in placebo responders and placebo non-responders. These panels depict the relationship between clinical placebo response, as assessed through muscle rigidity at the wrist (a) and electrophysiological placebo responses, as measured by means of a single neuron recording (b), in Parkinson's disease. Note that in placebo responders (left), both muscle rigidity decreases and electrophysiological changes occur, whereas in placebo non-responders neither clinical nor electrophysiological changes take place (Benedetti et al.2004, 2009).

Mentions: The advent of neuroimaging techniques and their use for experimental purposes has added anatomical and temporal details to the neurochemical information regarding placebo effect/response. A study using positron emission tomography (PET) suggests that placebo effect/response in Parkinson's disease is mediated by dopamine (de la Fuente-Fernández et al.2001). Placebo-induced changes in patients with Parkinson's disease were subsequently found to be associated with the reduction of bursting activity in subthalamic nucleus neurons (Fig. 1) (Benedetti et al.2004, 2009). Subsequently, Petrovic et al. (2002)showed overlap in the brain activation pattern generated by opioid-induced analgesia and by placebo-induced analgesia. Both approaches activated areas in the rostral anterior cingulate cortex and the orbitofrontal cortex. Subsequently, in spite of some discrepancies likely explained by methodological and procedural differences, PET, functional magnetic resonance imaging and magnetoelectroencephalography studies have suggested that placebo effect/response is mediated through activation of the descending pain control system, with modulation of activity in areas such as periaqueductal grey, the ventromedial medulla, the parabrachial nuclei, the anterior cingulate cortex, the orbitofrontal cortex, the hypothalamus and the central nucleus of the amygdala (Zubieta & Stohler, 2009).


Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it?

Alphs L, Benedetti F, Fleischhacker WW, Kane JM - Int. J. Neuropsychopharmacol. (2012)

Differences in neural activity in placebo responders and placebo non-responders. These panels depict the relationship between clinical placebo response, as assessed through muscle rigidity at the wrist (a) and electrophysiological placebo responses, as measured by means of a single neuron recording (b), in Parkinson's disease. Note that in placebo responders (left), both muscle rigidity decreases and electrophysiological changes occur, whereas in placebo non-responders neither clinical nor electrophysiological changes take place (Benedetti et al.2004, 2009).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3405769&req=5

fig001: Differences in neural activity in placebo responders and placebo non-responders. These panels depict the relationship between clinical placebo response, as assessed through muscle rigidity at the wrist (a) and electrophysiological placebo responses, as measured by means of a single neuron recording (b), in Parkinson's disease. Note that in placebo responders (left), both muscle rigidity decreases and electrophysiological changes occur, whereas in placebo non-responders neither clinical nor electrophysiological changes take place (Benedetti et al.2004, 2009).
Mentions: The advent of neuroimaging techniques and their use for experimental purposes has added anatomical and temporal details to the neurochemical information regarding placebo effect/response. A study using positron emission tomography (PET) suggests that placebo effect/response in Parkinson's disease is mediated by dopamine (de la Fuente-Fernández et al.2001). Placebo-induced changes in patients with Parkinson's disease were subsequently found to be associated with the reduction of bursting activity in subthalamic nucleus neurons (Fig. 1) (Benedetti et al.2004, 2009). Subsequently, Petrovic et al. (2002)showed overlap in the brain activation pattern generated by opioid-induced analgesia and by placebo-induced analgesia. Both approaches activated areas in the rostral anterior cingulate cortex and the orbitofrontal cortex. Subsequently, in spite of some discrepancies likely explained by methodological and procedural differences, PET, functional magnetic resonance imaging and magnetoelectroencephalography studies have suggested that placebo effect/response is mediated through activation of the descending pain control system, with modulation of activity in areas such as periaqueductal grey, the ventromedial medulla, the parabrachial nuclei, the anterior cingulate cortex, the orbitofrontal cortex, the hypothalamus and the central nucleus of the amygdala (Zubieta & Stohler, 2009).

Bottom Line: This paper seeks to clarify key issues related to this problem and identify potential solutions to them.Differences between placebo effect and response are characterized.Recent insights into the central nervous system mechanisms of placebo effect are described.

View Article: PubMed Central - PubMed

Affiliation: Janssen Scientific Affairs, LLC, Titusville, NJ, USA. lalphs@its.jnj.com

ABSTRACT
The effect of placebo observed in schizophrenia clinical trials represents a growing problem that interferes with signal detection for treatments, increases costs of development, discourages investment in schizophrenia research and delays the introduction of new treatments. This paper seeks to clarify key issues related to this problem and identify potential solutions to them. Differences between placebo effect and response are characterized. Recent insights into the central nervous system mechanisms of placebo effect are described. This is followed by a description of protocol/study design and study conduct issues that are contributing to a growing placebo effect in clinical trials. Potential solutions to these problems are provided.

Show MeSH
Related in: MedlinePlus