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Escitalopram (ES-CIT) is a widely used, highly specific antidepressant. Until now there has been very little evidence on how this drug under pathological conditions affects an important feature within the pathophysiology of stress-related disorders such as depression: the endogenous neurotrophins. By using a well-characterized rat model in which chronic stress induces depressive-like behavior, the levels of neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were determined in representative brain regions and serum using a highly sensitive improved fluorometric two-site ELISA system. There was a significant increase of BDNF in the left and right cortices after stress treatment (twofold increase) that was reversed by application of ES-CIT. An ES-CIT-dependent NGF reduction in stressed rats was detectable in the right cortex only (P = 0.027). The left hippocampus revealed significantly higher amounts of BDNF (2.5-fold increase) protein than the right hippocampus. These interhemispheric differences were unrelated to stress or ES-CIT treatment in all animals. BDNF and NGF of the frontal cortex, cerebellum, and serum did not change between the study groups. There was a negative correlation between body weight and serum BDNF, independent of stress or ES-CIT treatment. In conclusion, BDNF and NGF show substantial changes in this rodent model of chronic social stress, which is susceptible to antidepressant treatment with ES-CIT and therefore may constitute a neurobiological correlate for the disease.

The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important mediators of brain and neuronal development, the maintenance of homeostatic conditions in the adult nervous system, and the complex interplay of central and peripheral physiological and pathophysiological factors. To date there are few studies examining blood concentrations of neurotrophic factors in large samples of healthy and diseased individuals and no published study specifically addresses peripheral BDNF and NGF levels in late life. Using improved highly sensitive and specific fluorometric two-site enzyme-linked immunosorbent assays we examined BDNF (n=465) and NGF (n=175) serum levels in a large cohort of elderly individuals (age range: 70-103 years). Neither BDNF nor NGF serum levels proved to be normally distributed, indicating that previously published studies with small sample sizes using parametric testing may be misleading. A significant correlation was found between BDNF and platelet count (r=0.344, p<0.01), age and BDNF protein (r=-0.101, p=0.029) and BDNF and NGF serum levels (r=0.152, p=0.04). No other major influencing factors were found including gender, depression, and dementia.

Long-term alcohol abuse has deleterious effects on the peripheral and central nervous system. Nerve growth factor (NGF) is a pleiotropic neurotrophic protein involved in development, maintenance of function and regeneration of nerve cells. We examined patients in different stages of alcohol disease and measured their NGF serum concentrations based on the hypothesis that these reflect the state of disease. We examined 57 patients suffering from alcohol-dependence for more than 2 years (DSM IV) on day 8 of a qualified withdrawal, 18 patients with Korsakoff's syndrome and 40 healthy controls. In addition to clinical examination, careful history taking and a standard neuropsychological test battery, serum NGF concentrations were measured by a highly sensitive enzyme-immunoassay. Of the 57 patients 9 had suffered from severe withdrawal delirium in the past, other clinical parameters were alike. Cognitive test performance did not differ from the control group. Mean NGF levels of controls amounted to 42.1pg/ml (S.D. 68.0); mean levels of patients with alcohol dependence were raised significantly to 401.5pg/ml (S.D. 932.6) without delirium in the past and even further to 3292.5pg/ml (S.D. 4879.6) with former withdrawal delirium. By contrast, patients with persistent amnestic disorder (Korsakoff's syndrome) showed values identical to the controls. NGF serum levels were significantly elevated in alcohol-dependent patients, more so in those with prior delirium. Their cognitive tests being normal, this possibly reflects the activity of NGF as an endogenous repair mechanism for damaged neurons. In accordance with this hypothesis, NGF values are "normal" in patients with persistent alcohol-related cognitive decline.

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values.

Psychologically stressful events have been reported to elevate nerve growth factor (NGF) serum concentrations. NGF and cortisol serum concentrations were measured in 20 healthy male volunteers before (3 p.m.) and after (5 p.m.) an academic oral presentation and on a control day. Cortisol showed a significant overall change (p=0.001), i.e. cortisol serum concentrations were increased on the lecture day at 3 p.m. (p=0.007; 155%) and at 5 p.m. (p=0.001; 175%) as compared with the control day. In contrast to cortisol no significant differences among the four serum NGF measurements was detected (Chi-quadrat 2.94, df=3, p=0.401), i.e. the NGF serum concentrations remained unchanged on the lecture day at 3 p.m. (p=0.279) and at 5 p.m. (p=0.627) as compared with the control day. We conclude that NGF serum levels do not change during acute stress, at least after this type of stressor., (Copyright 2004 Taylor and Francis Ltd.)

Long-term cannabis abuse may increase the risk of schizophrenia. Nerve growth factor (NGF) is a pleiotropic neurotrophic protein that is implicated in development, protection and regeneration of NFG-sensitive neurones. We tested the hypothesis that damage to neuronal cells in schizophrenia is precipitated by the consumption of cannabis and other neurotoxic substances, resulting in raised NGF serum concentrations and a younger age for disease onset. The NGF serum levels of 109 consecutive drug-naive schizophrenic patients were measured and compared with those of healthy controls. The results were correlated with the long-term intake of cannabis and other illegal drugs. Mean (+/- SD) NGF serum levels of 61 control persons (33.1 +/- 31.0 pg/ml) and 76 schizophrenics who did not consume illegal drugs (26.3 +/- 19.5 pg/ml) did not differ significantly. Schizophrenic patients with regular cannabis intake (> 0.5 g on average per day for at least 2 years) had significantly raised NGF serum levels of 412.9 +/- 288.4 pg/ml (n = 21) compared to controls and schizophrenic patients not consuming cannabis (p < 0.001). In schizophrenic patients who abused not only cannabis, but also additional substances, NGF concentrations were as high as 2336.2 +/- 1711.4 pg/ml (n = 12). On average, heavy cannabis consumers suffered their first episode of schizophrenia 3.5 years (n = 21) earlier than schizophrenic patients who abstained from cannabis. These results indicate that cannabis is a possible risk factor for the development of schizophrenia. This might be reflected in the raised NGF-serum concentrations when both schizophrenia and long-term cannabis abuse prevail.

Human nerve growth factor (NGF) serum concentrations were measured in a healthy sample of 126 participants by a modified highly sensitive and specific two-site enzyme immunoassay. The measured NGF concentrations differ considerably from a normal distribution. The median NGF concentration was 19.68 pg/ml with an interquartile range of 11.06-41.74 pg/ml, which means that 50% of the NGF levels are in this range. In our healthy sample, we found no gender differences but a slight age-related decrease of NGF (r=-0.1326, P=0.1560). Moreover intraindividual stability of NGF was examined in ten volunteers, where no significant changes of serum NGF concentrations were detected over 4 weeks. This stability of our repetitive measurements over 4 weeks suggests that this neurotrophin may be an intraindividually solid marker at least in human serum.

Abstract: Although genetically closely related AB-Halle (ABH) and AB-Gatersleben (ABG) mice inbred strains differ in activity and aggressive behaviour. These behavioural traits have been observed especially in response to social challenges, where ABH mice develop a highly aggressive and active behaviour, which cannot be observed in their ABG counterparts. In contrast to ABG mice, basal brain serotonin, dopamine and noradrenaline concentrations in ABH mice are low but highly stimulated by social challenges. Since brain-derived neurotrophic factor (BDNF) modulates central neurotransmitter systems and has been involved in aggressive and activity behaviour, we studied specific concentrations of BDNF and NGF protein in several brain regions of ABG and ABH mice. A significant higher concentration of BDNF protein was found in the hippocampus of 5 weeks and 5 months old ABH mice, when compared to ABG mice. BDNF was also higher in the cortex of 5 weeks and 5 months old ABH mice. Moreover BDNF concentrations were higher in the striatum of 5 months old ABH mice when compared to ABG mice. NGF concentrations in ABH mice were not changed in all measured brain regions but higher in older age in the hippocampus of ABG mice as compared to ABH mice. We hypothesize, that BDNF might be involved in the behavioural and neurochemical mechanisms of aggressive behaviour. [Copyright &y& Elsevier]

Abstract: Generalized anxiety disorder (GAD) is a chronic stress disease with permanent physical tension and cognitive strain. Raised nerve growth factor (NGF) serum levels were reported as an acute stress reaction in soldiers before their first parachute jump even before the rise in cortisol. Taking GAD as a clinical model of chronic stress, we measured NGF in the serum of 22 patients with GAD before and after cognitive–behavioural therapy (CBT) and compared them to those of healthy normal controls. Treatment response was tested by the values of the State and Trait of Anxiety Inventory (STAI) and the Hamilton Anxiety Scale (HAM-A) as treatment outcome variables. The NGF values of patients and controls were similar at baseline (p =0.8941); however, with successful treatment, corresponding to a mean reduction in the HAM-A by more than 50% and a reduction in the clinical global impression scale (CGI) median from 4 to 1, the patients'' NGF serum concentrations rose significantly (p =0.0006) which might correspond to an altered stress reaction, possibly contributing to good therapeutic response with CBT. There were 3 patients with a HAM-A decrease of less than 15%. In those patients NGF rose only marginally. Hence, the increase in serum NGF seems to indicate good treatment response. [Copyright &y& Elsevier]