A. Iannitelli

Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival, neurite outgrowth and synapse formation. Recent observations suggest that treatment with typical and atypical antipsychotic drugs affect NGF and BDNF levels in the rat brain. The atypical antipsychotic olanzapine has a low incidence of side effects, such as extrapyramidal and anticholinergic symptoms. Since NGF and BDNF are involved in the regulation of cholinergic, dopaminergic and serotonergic neurons in the central nervous system (CNS) we hypothesized that chronic olanzapine treatment will influence the distribution of NGF and BDNF in the rat brain. To test this hypothesis we administered olanzapine for 29 days in the drinking water at the doses of 3 and 15 mg/kg body weight and measured the levels of NGF and BDNF in the brain of Wistar rats. Olanzapine increased NGF in the hippocampus, occipital cortex and hypothalamus. In contrast, olanzapine decreased BDNF in the hippocampus and frontal cortex. Although the significance of these findings is not clear, a heuristic hypothesis is that olanzapines clinical effects and a favorable side effect profile are in part mediated by neurotrophins.

Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders.

Neurotrophic factors, such as nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety‐like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic‐like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients.

Haloperidol Administration in Humans Lowers Plasma Nerve Growth Factor Level: Evidence that Sedation Induces Opposite Effects to Arousal

Studies reported in recent years have indicated that the level of nerve growth factor (NGF), in both the brain and in the bloodstream, increases following stressful events and anxiety-associated behaviour. These observations prompted us to investigate whether an anti-arousal drug would induce an opposite effect. We have reported that the administration of haloperidol (HA), a neuroleptic drug clinically used for psychiatric disorders, decreases NGF levels in the hypothalamus of adult male mice. In the present study, we showed that HA reduced the basal NGF plasma levels in 8 neuroleptic-free schizophrenic patients. These observations strengthen the hypothesis that NGF may play a functional role in stress-coping responses.

Neurological soft signs and cerebral measurements investigated by means of MRI in schizophrenic patients

Neurophysiologic research has shown a Neurological Soft Sign (NSS) characteristic prevalence in schizophrenic patients, and correlations between NSS and the most frequently cerebral alterations. The aim of this study was to investigate, by means of MRI, the quantitative alterations of cortical and subcortical structures and their correlation with NSS in a sample of schizophrenic patients. Linear measures of lateral ventricular (Evans ratio), third ventricular (Third Ventricular Width), hippocampal (Interuncal Index) and cerebellar (Verm Cerebellar Atrophy) atrophy were made on magnified MR images of 33 patients with a DSM IV diagnoses of chronic schizophrenia. NSS were evaluated with the Buchanan and Heinrichss Neurological Evaluation Scale (NES). Lateral ventricular enlargement showed to be correlated with right stereoagnosia item (p=0.001). Hippocampal atrophy, with right stereoagnosia item (p=0.023), with forefinger-right thumb opposition (p=0.004), forefinger-left thumb opposition (p=0.029 and face-hand extinction (0.26). Third ventricle enlargement showed to be correlated with forefinger-right thumb opposition (p=0.001), forefinger-left thumb opposition(p=0.021) and total sensorial integration (p=0.012). Cerebellar atrophy showed to be correlated with rhythmic drumming item (p=0.042), forefinger-right thumb opposition (p=0.007), forefinger-left thumb opposition (p=0.026), left specular movements (p=0.049), face-hand extinction (p=0.001), right-left confusion (p=0.005) and with left forefinger-nose index (p=0.032). Results obtained confirm the correlation between NSS and neuroanatomical alterations in schizophrenia.

Corpus callosum abnormalities and potential age effect in men with schizophrenia: An MRI comparative study

The goal of this investigation was to evaluate corpus callosum (CC) morphometry in schizophrenia. In consideration of possible confounders such as age, gender and handedness, our study sample was restricted to right-handed male subjects, aged 18-55 years. In addition, we controlled for age at onset, illness duration and exposure to antipsychotic medication. Midsagittal CC linear and area Magnetic Resonance Imaging (MRI) measurements were performed on 50 subjects with schizophrenia and 50 healthy controls. After controlling for midsagittal cortical brain area and age, Analysis of Covariance (ANCOVA) revealed an overall effect of diagnosis on CC splenium width and CC anterior midbody area and a diagnosis by age interaction. Independent Student t tests revealed a smaller CC splenium width in the 36- to 45-year-old age group among the patients with schizophrenia and a smaller CC anterior midbody area in the 18- to 25-year-old age group among the patients with schizophrenia compared with controls. Age, age at onset, illness duration and psychopathology ratings did not show any significant correlations with the whole CC MRI measurements. A negative correlation was found between CC rostrum area and the estimated lifetime neuroleptic consumption. The results are discussed in terms of the possibility that CC structural changes may underlie the functional impairments, frequently reported in schizophrenia, of the associated cortical regions.

Neurological Soft Signs and Corpus Callosum morphology in schizophrenia.

OBJECTIVEnNeurological Soft Signs (NSS) have been found to be more prevalent in schizophrenic patients. A breakdown in intracortical functional connectivity, including interhemispheric communication, has been suggested in the pathogenesis of schizophrenia. Indeed, problems with interhemispheric information transfer via the Corpus Callosum (CC) have been documented in schizophrenics. Our study goal was to relate NSS to CC morphology.nnnMETHODSnCC Magnetic Resonance Imaging (MRI) measurements were collected from 29 right-handed male schizophrenia inpatients. NSS were evaluated employing the Neurological Evaluation Scale (NES). We examined the scores obtained from the NES total and the three NES subscales: Integrative Sensory Function, Motor Coordination, and Sequencing Of Complex Motor Acts. We compared CC morphology of patients with high NSS with that of patients with low NSS. Correlation analyses were performed to further clarify the relationship between CC size, NSS, and total lifetime antipsychotic consumption.nnnRESULTSnPatients with high scores at the Sequencing Of Complex Motor Acts subscale showed a smaller CC rostral body, whereas patients with high scores at the Integrative Sensory Function subscale showed a smaller CC splenium. For both the NES total and the Sequencing Of Complex Motor Acts subscale, high scores were accompanied by an increase of the CC genu. Correlation analyses revealed a significant inverse correlation between the CC rostral body size and the Sequencing Of Complex Motor Acts subscale score. In addition, a significant positive correlation was shown between the CC genu size and both the NES total and the Sequencing Of Complex Motor Acts subscale scores. The presence of NSS and the accompanying CC structural abnormalities were independent on antipsychotic treatment.nnnCONCLUSIONSnOur data provide evidence for an association between NSS and CC morphology and further support the hypothesis of a disturbed interhemispheric functional connectivity in schizophrenia.

Influence of obstetric complication severity on brain morphology in schizophrenia: an MR study

IntroductionThe purpose of this study was to determine if a causal relationship exists between obstetric complications (OCs) severity and linear magnetic resonance (MR) measurements of brain atrophy in patients with schizophrenia.Materials and methodsLinear measurements of ventricular enlargement (bifrontal span, Evans ratio, and bicaudate ratio) and hippocampal atrophy (interuncal distance) were completed on MR images obtained in 47 patients with schizophrenia. Regression analysis was used to look at association with OCs severity, assessed by the “Midwife protocol” of Parnas and colleagues. The relationship between MR measurements and phenomenologic variables such as age at onset, illness duration, and exposure to antipsychotic medications was explored. The relationship between MR measurements, OCs severity, and symptom presentation was also investigated.ResultsOCs severity was significantly associated with MR measurements of ventricular enlargement (bifrontal span, Evans ratio). As the severity of OCs increased, bifrontal span and Evans ratio increased. This effect was independent of age at onset, illness duration, or even antipsychotic treatment. Interestingly, bifrontal span, Evans ratio, and OCs severity score all showed a significant positive correlation with hallucinatory symptomatology.ConclusionAlthough confirmatory studies are needed, our findings would support the idea that environmental factors, in this case severe OCs, might partly contribute to ventricular abnormalities in schizophrenia.

Reduced pineal volume in male patients with schizophrenia: no relationship to clinical features of the illness

Several investigations have suggested pineal gland abnormalities in the pathogenesis of schizophrenia. The pineal volume on brain magnetic resonance imaging scans was calculated in 15 male schizophrenic inpatients and in 16 matched control subjects. The statistical comparison found a significant difference of pineal gland volume between schizophrenics and controls (P = 0.022), with a smaller pineal volume in the schizophrenics. These results do not confirm the previous data of Schizophrenia Res. 14 (1995) 253, showing no significant pineal volumetric differences between schizophrenics and normal controls. Since the present study is based on a smaller but more homogeneous sample of patients, this could reduce the heterogeneity features of the schizophrenic disease. No correlation was found between pineal volume and clinical and psychopathological features of the schizophrenic subjects. Volume reduction in schizophrenia could be at least partially included in the wider brain developmental abnormalities of the illness or in the late effects of previous neuroleptic treatments.

Potential neuroprotective effect of lithium in bipolar patients evaluated by neuropsychological assessment: preliminary results.

Accumulating evidence is delineating a neuroprotective/neurotrophic role for lithium. However, its primary effects on cognition remain ambiguous. We sought to investigate the profile of cognitive impairment in patients with bipolar disorder and to determine whether continued treatment with lithium preserves cognitive functioning.

Ocular Nerve Growth Factor Administration Modulates Brain-derived Neurotrophic Factor Signaling in Prefrontal Cortex of Healthy and Diabetic Rats.

Nerve growth factor (NGF) eyedrops (ed‐NGF) activate brain neurons, stimulate growth factors, including brain‐derived neurotrophic factor (BDNF), and exert neuroprotection in the forebrain of streptozotocin‐induced diabetic rats (STZ rats). In this study, the effects of ed‐NGF on BDNF signaling in the prefrontal cortex (PFC) were explored in healthy and STZ‐diabetic rats, in which cortical neuronal and axonal loss, and altered circulating BDNF associated with depressive phenotype are also described.