Biomarkers in depression and bipolar disorder The main uses of biomarkers in drug development are11

• discovery and selection of lead NCEs;

• generation of pharmacokinetic (PK) and pharmacodynamic (PD) models;

• aid in clinical trial design and expedite drug development;

Table 4 Examples for biomarkers in psychotropic drug development

Biomarker procedures

Brain imaging technique

Cell-based imaging

Electophysiological marker

Laboratory-based marker

Psycho-

immunological marker

Neuroendocrine marker

Provocative anxiety tests

Genetic markers

Proteomic identification

Computed tomography (CT), regional cerebral blood flow (rCBF), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetoencephalography (MEG)

Fluorescent resonant energy tranfer

Confocal imaging in brain slices

Electroencephalogram (EEG), pupilometry, saccadic eye movements

Concentrations of catecholamines, hormones, enzymes, proteins, drugs, and drug metabolites

Immunoglobulin, lymphocyte responses, lymphokine, cytokine, interleukin, interferon, viral serology, Alz-50, anticardiolipin antibodies (ACA)

Dexamethasone suppression test (DST), thyrotropin releasing hormone stimulation teat (TRHST), growth hormone (GH) challenge test

Lactate infusion, carbon dioxide (CO2) challenge, cholecystokinin (CCK) challenge

DNA banking, genotyping, restriction fragment length polymophesis (RFLPs)

Nuclear magnetic resonance (NMR), lipoprotein fractions and subfractions, matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS)

Matrices mostly from plasma, urine, CSF, tissue, saliva, and hair.

Reprinted with permission from Bieck, P. R.; Potter, W. Z. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 227-246, © 2005 by Annual Reviews www.annualreviews.org.

• serving as surrogates for clinical or mortality endpoints;

• optimizing drug therapy based on genotypic or phenotypic factors; and

• definition of patient enrollment in studies and help with stratification.

Biomarkers are currently being investigated in psychiatry and neurology through a wide variety of procedures (Table 4) and the knowledge gain in the use of biomarkers is slowly being integrated into databases for use by the scientific community, e.g., NIMH drug companies.

The advantages, disadvantages, and limitations of selected biotechnologies for assessing the access of an NCE to the brain are listed in Table 5. Brain imaging technology is a facile methodology for studying the interaction of an NCE with its target, making this a preferred technique. However, there is a limited number of targets for which validated positron emission tomography (PET) or single photon emission computed tomography (SPECT) ligands are available. Furthermore, recent PET studies with a neurokinin 1 (NK1) receptor antagonist showed that the NCE had greater than 90% occupancy of central NK1 receptors and was active in an early Phase II efficacy study of depression but not subsequent larger Phase II studies, making this a striking example of a novel target with an excellent PET ligand that fails to be supported by clinical data and thereby questions the entire clinical hypothesis and the NCE.11

According to Bieck and Potter, a single approach may not provide the answer to addressing the question of brain penetration and drug efficacy.11 Instead, a multimodal approach to biomarkers in CNS disorders may well be the answer, using a combination of imaging technology (where PET ligands are feasible) and CSF studies.11

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