Food and Drug Administration Perspective on Negative Symptoms in Schizophrenia as a Target for a Drug Treatment Claim

Food and Drug Administration, DNDP, HFD-120, 5600 Fishers Lane, Rockville, MD 20853, USA.
Schizophrenia Bulletin (Impact Factor: 8.45). 05/2006; 32(2):220-2. DOI: 10.1093/schbul/sbi039
Source: PubMed


Negative symptoms of schizophrenia are not adequately addressed by available treatments for schizophrenia. Thus, it is reasonable
to consider them as a target for a drug claim. This article describes the thought process that the Food and Drug Administration
(FDA) will undertake in considering negative symptoms of schizophrenia as a novel and distinct drug target. Beyond this basic
question, this article identifies a number of design issues that the FDA needs to consider regarding how best to conduct studies
to support claims for this target. These design issues include (1) what population to study, (2) what phase of illness to
target, (3) whether to focus on the negative symptom domain overall or on some specific aspect of negative symptoms, (4) the
role of functional measures in negative symptom trials, and (5) optimal designs for targeting drugs for add-on therapy or
broad-spectrum agents.

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    • "In order to evaluate whether restoration of positive mood symptoms in MDD could be a " legitimate " target for a drug development program, developers might ask a series of questions (Laughren and Levin, 2005): • Are decreased positive mood states phenomenologically distinct from other symptoms of MDD, and do they have a course that is distinct from other symptoms? • Do experts in the scientific community consider decreased positive mood states a distinct aspect of MDD, and is this distinctness reflected in the diagnostic nomenclature? "
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    ABSTRACT: Restoration of positive mood, in addition to reducing negative mood, is an important treatment goal in the management of depression. The need to restore positive mood states in depressed patients is not adequately addressed by available treatments for major depressive disorder (MDD), suggesting that this mood dimension could be a useful target for drug development. However, for positive mood restoration to become a valid target for antidepressant drug development certain questions should be answered: are symptoms of decreased positive mood phenomenologically distinct from other symptoms of MDD? Should they be considered a distinct aspect of MDD in the diagnostic nomenclature? Is there evidence for differential responsiveness to treatment? Is the underlying pathophysiology understood and different from that of other MDD symptoms? Is low positive mood specific to depression or does it contribute to psychopathology in other disorders? Beyond these basic questions, this review identifies a number of design issues that need to be considered when conducting studies that target improving positive mood. These design issues include (1) what population to study, (2) what line of treatment to target, (3) the appropriateness and validation of methods and measures to evaluate positive mood and its restoration, (4) the role of functional outcome measures in determining success of the treatment, and (5) optimal designs for add-on therapy versus monotherapy agents.
    Full-text · Article · May 2014 · Journal of Psychopharmacology
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    • "The single-minded emphasis on monotherapy for disorders that are heterogeneous (at least as currently defined) may be one factor that tends to preclude attention to neglected clinical targets (Hyman and Fenton 2003). On the other hand, inappropriately narrow clinical indications are likely to be disapproved by the FDA as ''pseudospecific'' (Laughren and Levin 2006), leading to the need to ''walk the tightrope'' in adequately addressing these targets. More generally, there is little evidence that the morbidity or mortality associated with psychiatric illness has changed in the era of modern psychopharmacology (Insel and Scolnick 2006). "
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    ABSTRACT: Functional neuroimaging is a novel technique for the study of drug action in the brain. The emerging role of this method is intimately tied to the unique challenges to advancing drug development for neuropsychiatric disorders. This chapter first presents a brief overview of the important treatment needs that remain to be met, which serve as clinical targets for drug development. Important factors that hinder progress in drug development, which arise from clinical, scientific and economic issues, are acknowledged. This sets the stage for the unique advantages of functional neuroimaging modalities such as functional MRI (fMRI) as a biomarker and drug development tool, in both clinical and preclinical phases. The physiological basis of the fMRI signal is briefly outlined, and aspects of neural signaling related to this signal change, with emphasis on implications for pharmacology studies. The utility of fMRI for evaluating the full anatomic extent of central neurotransmitter systems in a dynamic manner is then described. This is a critical advantage, and particularly important for studies of how systems such as the monoamines modulate distributed neural networks during cognitive processes in both health and illness, and how these actions are modified with pharmacological intervention. Central catecholamine systems are seen as paradigmatic targets amenable to pharmacologic fMRI. fMRI is observed to occupy a unique position in the armamentarium of methods available to the pharmacologist and the drug development process, and poised to play an expanding role in basic and clinical neuroscience.
    Full-text · Article · Nov 2011 · Current Topics in Behavioral Neurosciences
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    • "We report here a comprehensive psychometric evaluation of the revised CAINS in a large, diverse sample of outpatients with schizophrenia or schizoaffective disorder based on recommendations that clinically stable patients are preferred for negative symptom treatment development studies (Kirkpatrick et al., 2006, Laughren and Levin, 2006). The first goal was to examine the scale's latent structure through a series of complementary structural analyses. "
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    ABSTRACT: Progress in the development of new pharmacological and psychosocial treatments for the negative symptoms of schizophrenia is impeded by limitations of available assessment instruments. The multi-site Collaboration to Advance Negative Symptom Assessment in Schizophrenia (CANSAS) was established to develop and validate a new clinical rating scale using a transparent, iterative, and data-driven process. The Clinical Assessment Interview for Negative Symptoms (CAINS) was designed to address limitations of existing measures and assess consensus-based sub-domains, including asociality, avolition, anhedonia, affective blunting, and alogia. The structure and psychometric properties of the CAINS were evaluated in a sample of 281 schizophrenia and schizoaffective outpatients at four sites. Converging structural analyses indicated that the scale was comprised of two moderately correlated factors - one reflecting experiential impairments (diminished motivation and enjoyment of social, vocational, and recreational activities) and one reflecting expressive impairments (diminished non-verbal and verbal communication). Item-level analyses revealed generally good distributional properties, inter-rater agreement, discriminating anchor points, and preliminary convergent and discriminant validity. Results indicate that the CAINS is a promising new measure for quantifying negative symptoms in clinical neuroscience and treatment studies. Results guided item modification or deletion, and the reliability and validity of the revised, shorter version of the CAINS is in the final phase of development within the CANSAS project.
    Full-text · Article · Jul 2011 · Schizophrenia Research
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