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.

7 Reads
  • Source
    • "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? "
    [Show abstract] [Hide abstract]
    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.
    Journal of Psychopharmacology 05/2014; 28(6). DOI:10.1177/0269881114532857 · 3.59 Impact Factor
    • "For example, high-functioning youth with ASD with anxiety disorders have shown a positive response to CBT in several pilot trials (Reaven et al. 2012; Storch et al. 2013; White et al. 2013; Wood et al. 2009a). A drug development program built on the notion that anxiety disorders are independent from ASD and not different from anxiety disorders in typically developing children would likely encounter the regulatory issue referred to as pseudospecificity (Laughren and Levin 2006). This term reflects the FDA's concern about a drug approval built on a narrow indication. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the high rate of anxiety in individuals with autism spectrum disorder (ASD), measuring anxiety in ASD is fraught with uncertainty. This is due, in part, to incomplete consensus on the manifestations of anxiety in this population. Autism Speaks assembled a panel of experts to conduct a systematic review of available measures for anxiety in youth with ASD. To complete the review, the panel held monthly conference calls and two face-to-face meetings over a fourteen-month period. Thirty eight published studies were reviewed and ten assessment measures were examined: four were deemed appropriate for use in clinical trials, although with conditions; three were judged to be potentially appropriate, while three were considered not useful for clinical trials assessing anxiety. Despite recent advances, additional relevant, reliable and valid outcome measures are needed to evaluate treatments for anxiety in ASD.
    Journal of Autism and Developmental Disorders 10/2013; 44(5). DOI:10.1007/s10803-013-1974-9 · 3.06 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Current Topics in Behavioral Neurosciences 11/2011; 11:365-88. DOI:10.1007/7854_2011_177
Show more