Brain-Derived Neurotrophic Factor: The Neurotrophin Hypothesis of Psychopathology By Dan J. Stein, MD, PhD, Willie M.U. Daniels, PhD, Jonathan Savitz, PhD, and Brian H. Harvey, PhD Dr. Stein is professor in and chair of the Department of Psychiatry and Mental Health at the University of Cape Town in South Africa, and is also on faculty at the Mount Sinai School of Medicine in New York City. He is the author of Philosophy of Psychopharmacology: Happy Pills, Smart Pills, and Pep Pills published by Cambridge University Press. s Dr. Daniels is professor in the Department of Physiology at the University of Kwazulu-Natal in Durban, South Africa. Dr. Savitz is post-doctoral fellow at the National Institute of Mental Health in Bethesda, Maryland. Dr. Harvey is professor in the Department of Pharmacology at North-West University in Potchefstroom, South Africa. Faculty Disclosures: Dr. Stein has received grant support/honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck A/S, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, and Wyeth. Drs. Daniels, Savitz, and Harvey do not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Funding/Support: Dr. Stein receives support from the Medical Research Council of South Africa. Dr. Harvey is funded by the National Research Foundation of South Africa (grant no 2073038). Authors’ note: This case is based on an amalgam of the authors’ experience. 945 ABSTRACT While฀monoaminergic฀hypotheses฀of฀psy- chopathology฀remain฀popular,฀there฀has฀been growing฀interest฀in฀the฀role฀of฀neurotrophins in฀neuropsychiatric฀disorders.฀Basic฀labora- tory฀work฀has฀documented฀the฀importance฀of neurotrophins฀in฀neuronal฀survival฀and฀syn- aptic฀plasticity,฀and฀a฀range฀of฀clinical฀studies has฀provided฀analogous฀evidence฀of฀their฀role฀ in฀neuropathology.฀Work฀on฀gene฀variants฀in฀ brain-derived฀neurotrophic฀factor,฀and฀associ- ated฀changes฀in฀structural฀and฀function฀brain฀ imaging,฀have฀further฀contributed฀to฀our฀under- standing฀of฀this฀area.฀Much฀remains฀to฀be฀done฀ to฀delineate฀fully฀the฀relevant฀mechanisms฀by which฀brain-derived฀neurotrophic฀factor฀and other฀neurotrophins฀contribute฀to฀psychopa- thology,฀and฀to฀develop฀targeted฀therapeutic interventions.฀Nevertheless,฀the฀neurotrophin฀ hypothesis฀has฀already฀given฀impetus฀to฀a range฀of฀valuable฀research. CASE REPORT Steven฀is฀a฀62-year-old฀man฀who฀presented for฀treatment฀for฀depression.฀His฀symptoms included฀anhedonia,฀low฀energy,฀lack฀of฀con- centration,฀and฀poor฀memory.฀He฀had฀difficulty฀ recalling฀important฀conversations฀and฀meetings.฀ He฀was฀particularly฀concerned฀about฀the฀latter฀ symptoms฀because฀his฀work฀as฀an฀accountant required฀him฀to฀be฀mentally฀focused฀and฀well฀ organized.฀A฀thorough฀neuropsychiatric฀work- up฀revealed฀no฀evidence฀of฀any฀general฀medical disorders฀accounting฀for฀these฀symptoms.฀He฀ was฀treated฀with฀a฀selective฀serotonin฀reuptake฀ inhibitor฀for฀several฀months.฀Although฀his฀over- all฀mood฀improved,฀he฀was฀particularly฀grate- ful฀for฀the฀effects฀of฀pharmacotherapy฀on฀his concentration฀and฀memory,฀and฀the฀consequent improvement฀in฀his฀functioning฀at฀work. COGNITIVE-AFFECTIVE NEUROSCIENCE Neurotrophins฀are฀secreted฀peptides฀that฀are฀ essential฀for฀the฀differentiation฀and฀survival฀of฀ neurons,฀and฀play฀a฀key฀role฀in฀synaptic฀plastic- ity. 1 ฀After฀the฀early฀discovery฀of฀nerve฀growth฀ factor,฀a฀range฀of฀mammalian฀neurotrophic฀fac- tors฀were฀identified,฀including฀brain-derived฀neu- rotrophic฀factor฀(BDNF).฀They฀share฀a฀similar฀ structure,฀are฀synthesized฀as฀precursor฀proteins฀ Pearls in Clinical Neuroscience CNS Spectr 13:11 © MBL Communications, Inc. November 2008 945