Molecular Psychiatry (2000) 5, 510–513  2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Increased cerebrospinal fluid levels of neurotrophin 3 (NT-3) in elderly patients with major depression C Hock 1 , K Heese 2,3 , F Mu ¨ ller-Spahn 4 , P Huber 5 , W Riesen 6 , RM Nitsch 1 and U Otten 2 1 Department of Psychiatry Research, University of Zu ¨ rich; Departments of 2 Physiology; 4 Psychiatry; 5 Clinical Chemistry, University of Basel, Switzerland; 3 BF Research Institute, National Cardiovascular Center, Osaka, Japan; 6 Institute for Clinical Chemistry and Hematology, State Hospital St Gallen, St Gallen, Switzerland Neurotrophin 3 (NT-3) is a member of the neurotrophin gene family which supports the sur- vival of specific neurons. NT-3 was shown to prevent the death of adult central noradrenergic neurons in vivo, a neuronal population which is associated with the pathophysiology of major depression. We quantitated CSF levels of NT-3 in elderly patients with major depression (DE) and compared them to patients with Alzheimer’s disease (AD), and mentally healthy control subjects (CTR). CSF levels of NT-3 were markedly and significantly elevated in the DE group, as compared to either the AD or the CTR group (P  0.01, and P  0.001, respectively). In terms of diagnostic accuracy, measurement of NT-3 levels in DE resulted in 73.9% sensitivity, and 89.7% specificity. Increased CSF levels of NT-3 may indicate a disturbance of the central noradrenergic system in patients with DE. NT-3 may constitute a biochemical candidate marker for clinical diagnosis and for the evaluation of therapeutic strategies in DE. Molecular Psychiatry (2000) 5, 510–513. Keywords: noradrenaline; basal forebrain; neurotrophins; ELISA; aging Introduction Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotro- phin 4/5 (NT-4/5) are members of the neurotrophin gene family which supports the survival, differen- tiation, maintenance, and repair of vertebrate neurons. 1 NGF supports the cholinergic neurons of the basal fore- brain system that are affected by neuronal loss in Alzh- eimer’s disease (AD). 2 BDNF supports cholinergic, dopaminergic and 5-hydroxytryptamine (5-HT) con- taining neurons. 3–5 NT-3 was shown to prevent the death of adult central noradrenergic neurons in vivo, 6 a neuronal population which is associated with the pathophysiology of major depression (DE). 7 In addition, NT-3 reportedly promotes survival of ventral mesencephalic dopaminergic neurons, 8 cerebellar granule neurons and Purkinje cells, 9 and acts on sen- sory or sympathetic neurons of the dorsal root, nodose and sympathetic ganglia. 10 Dysfunction of neuro- trophic systems in the adult mammalian brain may be reflected by alterations of neurotrophin levels in the cerebrospinal fluid (CSF), and may thus be of diagnos- tic value. Therefore, we quantitated CSF levels of NT- 3 in elderly patients with DE and compared them to mentally healthy control subjects (CTR), and to patients with Alzheimer’s disease (AD). We show here Correspondence: Dr C Hock, Department of Psychiatry Research, University of Zu ¨ rich, Lenggstrasse 31, CH-8029 Zu ¨ rich, Switzer- land. E-mail: chockbli.unizh.ch Received 25 October 1999; revised and accepted 4 February 2000 that CSF levels of NT-3 are increased in patients with DE as compared to the AD and CTR groups. Subjects and methods Patients with major depression (DE) were diagnosed according to the ICD-10 (F32.0x/1x, F33.0x/1x) and DSM-III-R (296.20–22, 296.30–32) criteria. Diagnosis of probable AD was made according to criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s disease and Related Disorders Association (NINCDS–ADRDA). 11 All patients were referred to the research ward from gen- eral practitioners, neurologists and psychiatrists for diagnostic purposes and screening for clinical trials. None of the patients was institutionalized. The group of healthy control subjects (CTR) consisted of patients who underwent lumbar puncture for orthopedic or neurologic diagnostic purposes and were shown to have normal CSF cell counts, total protein levels, and absence of signs of blood–brain barrier dysfunctions or cerebral IgG synthesis, as well as absence of psychiatric or central neurological disorders. DE, AD and CTR patients were carefully examined and received a thorough clinical examination. Psycho- metric testing included the Mini Mental State (MMS), 12 as a global screening instrument for dementia, and the Nurses’ Observation Scale for Geriatric Patients (NOSGER) 13 as a functional measure of dementia sever- ity. The patients with DE showed no cognitive disturb- ances in the clinical examinations and the Mini Mental State scores were within the normal range. Severity of