BDNF plasma levels variations in major depressed patients receiving duloxetine.

It has been frequently reported that brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate BDNF levels variations in MDD patients during antidepressant treatment with duloxetine. 30 MDD patients and 32 healthy controls were assessed using Hamilton Depression Scale (HAM-D) and monitored for BDNF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. According to early clinical response to duloxetine (defined at week 6 by reduction >50 % of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who reached clinical response at week 12. Laboratory analysis showed significant lower baseline BDNF levels among patients compared to controls. During duloxetine treatment, in ENR BDNF levels increased, reaching values not significantly different compared to controls, while in ER BDNF levels remained nearly unchanged. Lower baseline BDNF levels observed in patients possibly confirm an impairment of the NEI stress-adaptation system and neuroplasticity in depression, while BDNF increase and normalization observed only in ENR might suggest differential neurobiological backgrounds in ER vs. ENR within the depressive syndrome.

Electroretinographic modifications induced by agomelatine: a novel avenue to the understanding of the claimed antidepressant effect of the drug?

BACKGROUND: Agomelatine, the first melatonergic antidepressant, has been postulated to enhance the dopaminergic activity at the central nervous system by 5-hydroxytryptamine receptor type 2C (5-HT2C) antagonism, yet the impact of melatonergic agonism on this pathway is unclear. Previous studies employing simplified, yet reliable, proxy (retinal) measures of the central nervous system dopaminergic activity, namely the standard electroretinogram (ERG) technique, suggested a reduction of the dopaminergic activity of the main ERG parameter, the b-wave, by pure melatonin, notably a hormone devoid of any antidepressant activity. Therefore, the antidepressant effects of the melatonergic antidepressant drug agomelatine should be reflected by a differential b-wave trend at ERG versus the effect exerted by pure melatonin, which was eventually found to be due to a contrasting effect on central dopaminergic transmission between the two drugs. OBJECTIVE AND METHODS: The aim of the present preliminary ERG study carried out on healthy volunteers (n=23) receiving agomelatine was to explore the impact of this antidepressant drug on b-wave amplitude and latency of cones in daylight conditions using standard ERG. RESULTS: As postulated, agomelatine induced an enhancement of retinal dopaminergic activity, in contrast to what has been previously documented for melatonin. CONCLUSION: Given the limits of this explorative study, especially the lack of a control group and that of a luminance response function to measure retinal sensitivity, further studies in clinical samples are recommended to allow more tenable conclusions about the potential role of ERG in discriminating between 5-HT antagonism and melatonergic (MT) agonism in relationship to the claimed antidepressant effect of agomelatine.

Duloxetine-bupropion combination for treatment-resistant atypical depression: a double-blind, randomized, placebo-controlled trial.

The efficacy, safety, and tolerability of combined bupropion versus placebo using duloxetine as active reference drug, in patients with a DSM-IV diagnosis of major depression with atypical features and a history of treatment resistance, were evaluated in this preliminary six-week study. Patients (n=46) had a baseline Hamilton Depression Scale (HAM-D) ≥14 and were randomly assigned to 150/300 mg/day bupropion vs. placebo, which was added to 60 to 120 mg/day duloxetine depending on baseline depression severity. Atypical features of depression were assessed using the additional eight-item module of the Structured Interview Guide for the HAM-D with the Atypical Depression Supplement. By week 6, only five (21.7%) patients receiving duloxetine+placebo vs. six (26.1%) patients on the bupropion combination achieved response. No significant difference in final HAM-D scores between the two groups was observed between those patients achieving response. The presence of a higher number of atypical features significantly predicted non-response, with the relevant binary logistic regression model correctly classifying 17 out 22 (77.3%) of non-responders [Exp(B)=0.294; p=0.016] vs. 17 out 23 (73.9%) [Exp(B)=0.353; p=0.028] non-responder cases in the "+placebo" and "+bupropion" groups, respectively. In those patients receiving bupropion, treatment-emergent adverse events leading to withdrawal were more common among those receiving lower doses of the combination drug, and no life-threating dangers were noted. Additional studies, including an adequate course of duloxetine trial, are nonetheless aimed to allow a firm conclusion about the usefulness of the combination of duloxetine and bupropion for treatment-resistant cases of major depression with atypical features.

VEGF plasma level variations in duloxetine-treated patients with major depression.

BACKGROUND: The vascular endothelial growth factor (VEGF) signaling, which modulates angiogenesis and neurogenesis within the neurovascular unit, might play an important role in the neuro-endocrine-immune (NEI) stress-adaptation system. Recent evidence suggests that VEGF is involved in the pathophysiology of a number of diseases including major depressive disorder (MDD) and is affected by some treatments, including antidepressants. The objective of the study was to investigate the VEGF level variations in MDD patients during antidepressant treatment with duloxetine, a relatively new SNRI. METHODS: A total of 30 MDD patients and 32 healthy controls were assessed using the Hamilton Depression Scale (HAM-D) and monitored for VEGF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. RESULTS: According to early clinical response to duloxetine (defined at week 6 by reduction>50% of baseline HAM-D score), the MDD patients were divided into early responders (ER) and early non-responders (ENR). During duloxetine treatment, we found an opposite trend in the VEGF levels between ER and ENR: in ER the VEGF levels significantly increased in association with clinical response at W6, while in ENR the VEGF levels significantly decreased in association with an overall clinical response at W12. LIMITATIONS: Small sample size. CONCLUSIONS: The opposite trends in VEGF levels, increasing in ER and decreasing in ENR, might reflect differential Norepinephrine/Serotonin effects of duloxetine on differential neurobiological backgrounds of depressive syndromes. Overall, the modulation of VEGF signaling within the neurovascular unit during antidepressant treatment could hypothetically favor the remodeling of neural circuitry, contributing to adaptive adjustment of the NEI stress-adaptation system.

Beyond the cliff of creativity: a novel key to Bipolar Disorder and creativity.

How brain processes translate into creativity is still an unsolved puzzle in science. Although a number of conceptual models of creativity has been proposed to date, the exact nature of the process is still unknown. Recent findings support the idea that creativity may reside upon a continuum with psychopathology. If creativity is meant as "the capability of generating novel and appropriate ideas to solve problems", the missing pieces of the puzzle might be nested in the link between creativity and Bipolar Disorder. The existence of such a link is widely accepted by the Scientific Community. What still remains unknown is the nature of this link. An unconventional perspective is adopted during the investigation. Starting from the observation that depression in Bipolar Disorder might possibly trace back to ancient survival strategies in extreme climatic conditions - i.e. hibernation - the paper analyses old and recent findings in different disciplines: paleo-anthropology, information technology, neurobiology. Hints from the related research fields are linked together. The unified framework that emerges, still as a set of hypotheses, is reported in the conclusions. A novel key of interpretation of both creativity and Bipolar Disorder is thus provided. The core result is that normal people, creative individuals and patients affected by Bipolar Disorder share the same mind mechanism for problem-solving. The mechanism consists of two specific components, which are described in detail in the paper. Dysfunctions in brain myelination, making signal interference possible, hold a big role. The conclusions of the paper are in agreement with reports by patients affected by Bipolar Disorder concerning their subjective experience during mania, which is traditionally described as prone to creativity. To make readers aware of such an experience, a synthesis was elaborated by the first author, in the unusual shape of a short story. The short story is the narrative version of a real diary of a real patient, tutored by the second author. The short story is available to readers on request.

NGF serum levels variations in major depressed patients receiving duloxetine.

BACKGROUNDS: Nerve growth factor (NGF) is involved in the modulation of the neuro-endocrine-immune (NEI) system, whereas alterations in neuroplasticity and NEI homeostasis seem to play a role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate NGF levels variations in MDD patients during antidepressant treatment with duloxetine, a relatively newer SNRI. METHODS: 30 MDD patients and 32 healthy controls were assessed using Hamilton depression scale (HAM-D) and monitored for NGF serum levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. RESULTS: According to early clinical response to duloxetine (defined at week 6 by reduction >50% of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who overall reached clinical response at week 12. Laboratory analysis showed overall significant lower baseline NGF levels among depressed patients compared to healthy controls, not significantly in ER and significantly in ENR. During duloxetine treatment NGF levels further decreased in association with clinical response, reaching significantly lower values in ER at W6 compared to controls, and in ENR at W12 compared to baseline. CONCLUSIONS: A decrease in NGF levels during duloxetine treatment in association to clinical response could be indicative of a relative restoring of NEI stress-adaptation system, since stressors, inducing neuronal instability due to neurotrophins activity changes, permits circuitry remodeling as background in the selection of alternative adaptive behaviors. However, the lower baseline NGF levels found in MDD patients that further decrease during the treatment could represent a lower neurotrophin set point, possibly reflecting a functional impairment in stress-adaptive neuroplasticity in depressive disorders.

Adjunctive agomelatine therapy in the treatment of acute bipolar II depression: a preliminary open label study.

PURPOSE: The circadian rhythm hypothesis of bipolar disorder (BD) suggests a role for melatonin in regulating mood, thus extending the interest toward the melatonergic antidepressant agomelatine as well as type I (acute) or II cases of bipolar depression. PATIENTS AND METHODS: Twenty-eight depressed BD-II patients received open label agomelatine (25 mg/bedtime) for 6 consecutive weeks as an adjunct to treatment with lithium or valproate, followed by an optional treatment extension of 30 weeks. Measures included the Hamilton depression scale, Pittsburgh Sleep Quality Index, the Clinical Global Impression Scale-Bipolar Version, Young Mania Rating Scale, and body mass index. RESULTS: Intent to treat analysis results demonstrated that 18 of the 28 subjects (64%) showed medication response after 6 weeks (primary study endpoint), while 24 of the 28 subjects (86%) responded by 36 weeks. When examining primary mood stabilizer treatment, 12 of the 17 (70.6%) valproate and six of the 11 (54.5%) lithium patients responded by the first endpoint. At 36 weeks, 14 valproate treated (82.4%) and 10 lithium treated (90.9%) subjects responded. At 36 weeks, there was a slight yet statistically significant (P = 0.001) reduction in body mass index and Pittsburgh Sleep Quality Index scores compared to respective baseline values, regardless of mood stabilizer/outcome. Treatment related drop-out cases included four patients (14.28%) at week 6 two valproate-treated subjects with pseudo-vertigo and drug-induced hypomania, respectively, and two lithium-treated subjects with insomnia and mania, respectively. Week 36 drop outs were two hypomanic cases, one per group. CONCLUSION: Agomelatine 25 mg/day was an effective and well-tolerated adjunct to valproate/lithium for acute depression in BD-II, suggesting the need for confirmation by future double blind, controlled clinical trials.

Medicine and psychiatry in Western culture: Ancient Greek myths and modern prejudices.

The origins of Western culture extensively relate to Ancient Greek culture. While many ancient cultures have contributed to our current knowledge about medicine and the origins of psychiatry, the Ancient Greeks were among the best observers of feelings and moods patients expressed towards medicine and toward what today is referred to as 'psychopathology'. Myths and religious references were used to explain what was otherwise impossible to understand or be easily communicated. Most ancient myths focus on ambiguous feelings patients may have had towards drugs, especially psychotropic ones. Interestingly, such prejudices are common even today. Recalling ancient findings and descriptions made using myths could represent a valuable knowledge base for modern physicians, especially for psychiatrists and their patients, with the aim of better understanding each other and therefore achieving a better clinical outcome. This paper explores many human aspects and feelings towards doctors and their cures, referring to ancient myths and focusing on the perception of mental illness.

Obsessive-compulsive disorder and related disorders: a comprehensive survey.

Our aim was to present a comprehensive, updated survey on obsessive-compulsive disorder (OCD) and obsessive-compulsive related disorders (OCRDs) and their clinical management via literature review, critical analysis and synthesis. Information on OCD and OCRD current nosography, clinical phenomenology and etiology, may lead to a better comprehension of their management. Clinicians should become familiar with the broad spectrum of OCD disorders, since it is a pivotal issue in current clinical psychiatry.

Medicine and psychiatry in Western culture: among Ancient Greek myths and modern prejudices.

While many ancient cultures contributed to our current knowledge about medicine and psychiatry origins, Ancient Greeks were among the best observers of feelings and moods patients could express toward medicine and toward what today referred as "psychopathology". Myths and religious references were used to explain what elsewhere impossible to understand or easily communicated. Most of ancient myths focus on ambiguous feelings patients could have towards drugs, especially psychotropic ones. Interestingly, such prejudices are common yet today. Recalling ancient findings and descriptions made using myths, should represent a valuable knowledge for modern physicians, especially for psychiatrists, and their patients, with the aim of better understanding each other and therefore achieving a better clinical outcome. The paper explores many human aspects and feelings toward doctors and their cures, referring to ancient myths, focusing on the perception of mental illness.

Aripiprazole augmentation in poor insight obsessive-compulsive disorder: a case report.

BACKGROUND: Obsessive-compulsive disorder is associated with a relevant impairment in social and interpersonal functioning and severe disability. This seems to be particularly true for the poor insight subtype, characterised by a lack of consciousness of illness and, consequently, compliance with treatment. Poor responsiveness to serotonergic drugs in poor insight obsessive-compulsive patients may also require an augmentation therapy with atypical antipsychotics. METHODS: We reviewed a case in which a patient with a long history of poor insight obsessive-compulsive disorder was treated with a high dosage of serotonin reuptake inhibitors. RESULTS: The treatment resulted in a poor outcome. This patient was therefore augmentated with aripiprazole. CONCLUSION: Doctors should consider aripiprazole as a possible augmentation strategy for serotonergic poor responder obsessive-compulsive patients, but further research on these subjects is needed.

Epileptic seizures but not pseudoseizures are associated with decreased density of the serotonin transporter in blood platelet membranes.

The density of the serotonin transporter in the plasma membranes of blood platelets was evaluated by labelled paroxetine binding in three different groups. These groups were: normal controls, epileptic patients having undergone a recent seizure (less than 4 days before) and patients who equally recently presented psychogenic non-epileptic seizures (pseudoseizures). Real seizures resulted in a significant decrease of membrane serotonin transporter density. In the instances of pseudoseizures, its membrane density was undistinguishable from that of normal controls. These data lend further support to the idea that down regulation of serotonin transporter may play a homeostatic role in the cessation of epileptic seizures.

Modifications of sleep EEG induced by chronic vagus nerve stimulation in patients affected by refractory epilepsy.

OBJECTIVE: The aim of this study was to evaluate the impact of chronic vagus nerve stimulation (VNS) on sleep/wake background EEG and interictal epileptiform activity (IEA) of patients with medically refractory epilepsy. METHODS: From a broader sample of 10 patients subjected to baseline and treatment polysomnographies, spectral analysis and IEA count have been performed on 6 subjects' recordings, comparing the results by means of statistical analysis. RESULTS: An overall increase in EEG total power after VNS has been observed, more marked in NREM sleep; collapsing EEG power spectra into 5 frequency bands, we have found a statistically significant increase in delta and theta in NREM sleep, and of alpha in wakefulness and REM sleep. The incidence of IEA is diminished, although not significantly; only the duration of discharges is significantly diminished. CONCLUSIONS AND SIGNIFICANCE: Long-term VNS produces an enhancement in sleep EEG power of medically refractory epileptic patients. These results may be related to a better structured composition of EEG, and it is possible that chronic VNS may have a major role in enhancing the brain's ability to generate an electrical activity.

Soluble amyloid beta-protein is increased in frontotemporal dementia with tau gene mutations.

The relationship between senile plaques and neurofibrillary tangles, the main pathologic lesions of Alzheimer's disease, is not completely understood. We addressed this issue examining the type and amount of amyloid beta-protein (Abeta) associated with the soluble and insoluble tissue fractions in the frontal cortex of 8 cases with frontotemporal dementia with parkinsonism caused by mutations of the Tau gene (FTDP-17), in which the intracellular accumulation of polymerised tau is definitely the primary cause of neurodegeneration. As control, we examined 7 cases with frontotemporal dementia lacking distinctive histopathology (DLDH) as well as 8 pathologically normal subjects. In all cases the presence of Abeta deposits was ruled out using immunocytochemistry on sections adjacent to those used for biochemical analysis. ELISA analysis showed a 2.7 and 2.1 fold (p < 0.01) increase of soluble Abeta42 and Abeta40 in FTDP-17, compared to normal and DLDH brains, both of which had comparable levels of Abeta species. Furthermore, the immunoreactivity of the intracellular Abeta42 was significantly increased in cortical neurons of subjects affected with FTDP-17. The results demonstrate that the aggregation of tau protein produces an accumulation of Abeta, which, however, does not reach the critical concentration needed for Abetaplaques formation.

Pathogenesis of degenerative retinopathies induced by thioridazine and other antipsychotics: a dopamine hypothesis.

Thioridazine and other antipsychotics (neuroleptics, dopaminergic antagonists) can cause degenerative retinopathies with histological, electrophysiological and symptomatological features similar to those of primary retinitis pigmentosa. It was formerly suggested that these retinopathies are due to drug absorption by melanin of the eye which damages the choriocapillaris first and subsequently the photoreceptors and the retinal pigment epithelium. An alternative explanation of the still unclear mechanisms involved in the pathogenesis of thioridazine and other phenothiazines retinopathies has underlined the role of the drug effects on the activity of some retinal enzymatic systems which can lead to retinal dystrophy. More recent data on the complex role of dopamine (DA) and of its receptor subtypes in the retina has provided evidence that the D2 family of DA receptors, in particular the D4 receptor, is involved in the control of the synthesis of melatonin, a factor that has been shown to regulate several aspects of retinal physiology and to increase photoreceptor susceptibility to be damaged by light. Based on this knowledge, as well as on clinical data and on pharmacological considerations concerning the differences recently shown to exist among the various antipsychotics as regards their affinity for the DA receptor subtypes, we hypothesize that neuroleptic induced blockade of retinal D2/D4 receptors is among the initial events of these drug-induced degenerative retinopathies. Clinicians should be aware of the retinotoxic effects not only of thioridazine and some others phenothiazines, but also of those possibly caused by other typical and atypical antipsychotics. By evaluating the retinal status and function before and during the treatment of psychiatric patients, it should be possible to choose more accurately the safest drugs, particularly when treating predisposed subjects.