Abstract
The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I–IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase III trials and provide insights into disease modification in phase IV trials.
Highlights
As noted in a historical review on drug development, the process has evolved from a chemistry-based process to integrating pharmacology and clinical sciences to the contributions of molecular biology and genomics.[1]
Negative findings with promising new agents have often led to premature shelving of such compounds and many large pharmaceutical companies have gradually abandoned their focus on central nervous system (CNS) drug development because of the perception that trials in this area are ‘risky,’ given the greater than 50% of failure in adequately powered trials.[2]
It should be pointed out that simple Pharmacological magnetic resonance imaging (phMRI) activation, while it may confer some information of drug-brain activation, the efficacy of the drug might depend more on functional connectivity of how the drug affects certain brain circuits.[22,23]
Summary
As noted in a historical review on drug development, the process has evolved from a chemistry-based process to integrating pharmacology and clinical sciences to the contributions of molecular biology and genomics.[1]. Pharmacological magnetic resonance imaging (phMRI) allows for the direct (effects of drug on brain systems) and indirect (effects of drug on responses) evaluation of drug action in humans in early phase studies.[29] Examples of phMRI use for evaluation of drugs in humans are numerous (examples of direct measures include buprenorphine;[22] fosaprepitant;[39] mirtazapine).[40] It should be pointed out that simple phMRI activation, while it may confer some information of drug-brain (receptor/s) activation, the efficacy of the drug might depend more on functional connectivity of how the drug affects certain brain circuits.[22,23] in a few patients important data on CNS penetration can be assessed. Rheumatoid arthritis General anxiety disorder Schizophrenia Schizophrenia Autistic disorder Autistic disorder Schizophrenia Methamphetamine abuse ADHD ADHD Major depression Cerebral palsy Depression Healthy Migraine Depression Autism spectrum disorders Bipolar depression Model of depression Addiction Irritable bowel syndrome Depression Stress/healthy Healthy Alzheimer’s disease Alzheimer’s disease Fragile-X Dysthymic order Depression Depression Depression Interoceptive awareness Sleep/pain Depression Alzheimer’s disease Depression Depression (children) Depression Depression Depression Multiple sclerosis Depression Social anxiety disorder Social anxiety disorder Food addiction ADHD Irritable bowel syndrome Attentiveness Depression Neuropathic pain Obesity Alzheimer’s Mild cognitive impairment Alzheimer’s disease Tourette’s syndrome Healthy Bipolar mania Bipolar disorder Bipolar disorder Multiple systems atrophy Spinocerebellar ataxia 2 Back pain Bipolar depression Alcohol craving ADHD TBI memory Addiction Fibromyalgia Cognition Healthy Schizophrenia Social anxiety disorder Osteoarthritis Autism Social cognition Healthy Pain/healthy
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