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BACKGROUND/AIMS: In major depression cognitive impairment is common and may persist despite improvement in psychopathology. So far it is unclear how closely related improvement in cognitive functioning is to the clinical course of depression. Further, it is unclear whether recovery from cognitive impairment is linked to changes in serum brain-derived neurotrophic factor (sBDNF). The objectives of this study were (1) to explore the predictive value of cognitive impairment for therapeutic outcome, and (2) to assess the association between cognitive performance and sBDNF levels over a 6-week course of antidepressant treatment. METHODS: Twenty-five adult patients suffering from major depression underwent standardized treatment with duloxetine. Both severity of depression as assessed by the Hamilton Depression Rating Scale and sBDNF levels were measured at baseline, and after 1, 2 and 6 weeks of treatment. Cognitive performance, i.e. alertness, working memory, and divided attention, was assessed at baseline, after 1 week, and at the end of treatment after 6 weeks. RESULTS: Higher performance in alertness and divided attention at baseline correlated with less severe depression at week 6. During the first week of treatment, a greater increase in sBDNF was associated with a greater improvement in alertness at week 6. CONCLUSION: Greater alertness at baseline was a predictor of favorable antidepressive treatment outcome. Moreover, the early increase in sBDNF correlated with improvement in attention functioning. Thus, recovery from cognitive impairment and an early increase in sBDNF seem to be associated.

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RATIONALE: Major depressive disorder has been associated with low serum levels of brain-derived neurotrophic factor (sBDNF), which is functionally involved in neuroplasticity. Although sBDNF levels tend to normalize following psychopathological improvement with antidepressant treatment, it is unclear how closely sBDNF changes are associated with treatment outcome. OBJECTIVES: To examine whether baseline sBDNF or early changes in sBDNF are predictive of response to therapy. METHODS: Twenty-five patients with major depressive disorder underwent standardized treatment with duloxetine. Severity of depression, measured by the Hamilton Depression Rating Scale, and sBDNF were assessed at baseline, and after 1, 2, and 6 weeks of treatment. Therapy outcome after 6 weeks was defined as response (≥50 % reduction in baseline Hamilton Depression Rating score) and remission (Hamilton Depression Rating score <8). The predictive values for treatment outcome of baseline sBDNF, and early (i.e., ≤2 weeks) changes in sBDNF and Hamilton Depression Rating score were also assessed. RESULTS: At baseline, sBDNF correlated with Hamilton Depression Rating scores. Treatment response was associated with a higher baseline sBDNF concentration, and a greater Hamilton Depression Rating score reduction after 1 and 2 weeks. A greater early rise in sBDNF correlated with a decreased early Hamilton Depression Rating score reduction. CONCLUSIONS: Even though higher baseline sBDNF levels are associated with more severe depression, they may reflect an increased capacity to respond to treatment. In contrast, changes in sBDNF over the full course of treatment are not associated with psychopathological improvement.

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Among a variety of drugs used in the treatment of anxiety disorders, benzodiazepines and antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are at present the most established and prescribed. In fact, recent guidelines recommend the antidepressants SSRI and SNRI as well as pregabaline, a newly developed drug, as the 1st choice treatment in generalized anxiety disorder (GAD). However, antidepressants have several disadvantages (latency of onset of action, adverse effects and drug interactions) that should not be neglected. Pregabaline is a drug with a new mechanism of action. Clinical studies up to now indicate a rather rapid and efficient anxiolytic effect comparable to that of benzodiazepines, with no risk of abuse. Pregabaline has been recently introduced in Switzerland for the treatment of GAD.

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Anxiety disorders are persistent impairing diseases, with often chronic course and suffering from symptoms throughout a life-span. The medication with the most evidence of efficacy is the benzodiazepines having a low incidence of side effects but may cause physical dependence, withdrawal and sedation. The use of these drugs should be limited to the acute treatments during the first several weeks in combination with an SSRI or and SNRI for the treatment of the acute phase. After three to four weeks, when antidepressants become effective, benzodiazepine dose should be tapered over a one week period. Among the antidepressants, the SSRI and the SNRI are considered a first-line therapy because of their favourable side effect spectrum compared to tricyclic antidepressants. However, the association with side effects such as nausea, sweating, sexual dysfunction and gastrointestinal problems and insomnia may be intolerable for a number of patients. Combining antidepressants and benzodiazepine therapy or medication treatment and psychotherapy may lead to an increase in improvement in patients not responding to one treatment approach alone. The most effective treatment for managing the recurrent symptoms of this chronic disorder are still unknown and other studies and approaches are in need as remission rates are still only about 40%.

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Objective. To assess clinical advantages of fast dissolving tablet (FDT) formulation of mirtazapine by comparison to conventional (CT) mirtazapine tablets in the treatment of depressed patients. Methods. A posteriori analyses of pooled data of a total of 30 studies (of at least 6 weeks duration, total N=3510) with CT and FDT in depressed patients was performed. Weight changes were recorded at baseline and regular intervals until the end of the study. Patient preferences for the one or the other formulation, as well as the appraisal of the FDT qualities, were assessed by means of a global internet-based survey including 5,428 patients. Results. Compared with mirtazapine CT, the FDT was associated with an average 0.3 kg less weight increase (P=0.0015) during the 6 weeks of treatment. The qualities and preference for FDT (global survey) were positively evaluated by the majority of patients. Particular advantages of FDT over CT were: better compliance (47.3% of raters), taste, ease and overall convenience of use (>75% of raters). Conclusions. The FDT mirtazapine differed from conventional tablets (CT) not only regarding somewhat less weight increase and overall use preference, but more importantly, regarding better compliance with treatment.

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Objective. The purpose of the present study was to document the experience with the use of a new, fast-dissolving oral tablet (FDT, RemeronSolTab®) of mirtazapine, a NaSSA antidepressant, in the treatment of depressed patients in daily practice in Switzerland. Methods. It was an open, prospective collection of observations in a total of 1121 depressive patients (>18 years old, both sexes). The treatment duration was 8 weeks with assessments after the second and eighth week. Efficacy measures were CGI (seven points) and specific check-lists for the ratings of severity of anxiety and sleep disturbances. At the end of the trial the acceptance (eight-item questionnaire) of the new formulation was recorded too. Results. The results showed that there was highly significant (P<0.001) and rapid improvement of severity of depression, anxiety and sleep disturbances in the whole population. Subgroup analyses showed that the antidepressant efficacy was independent of gender, initial severity of depression or of the type of depression (first episode, recurrent, chronic depression). The majority of patients (80%) liked at least one of the properties of FDT and, out of 75% of patients having experience with conventional tablet, 50% stated to be better compliant with this new formulation. Conclusion. This report documents the antidepressant efficacy of mirtazapine FDT. The new formulation found good acceptance by the patients. The results also suggest a likelihood of improved compliance with the mirtazapine FDT.

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Ten years after the introduction of the first drug for the treatment of Alzheimer's disease, tacrine, it seems appropriate to reappraise the pharmacological processes of innovation in the field of research in dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, in terms of experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets deserving of initial consideration. * The article first considers the use of animal models of Alzheimer's disease, which are classified according to two categories: animals with lesions of some neuronal pathways specifically implicated in clinical symptoms (i.e. lesions of the nucleus basalis of Meynert, the origin of cholinergic projections to the cortex underlying memory processes); and transgenic models, which are intended to reproduce some of the neuropathological hallmarks of Alzheimer's disease. Drugs can be tested in animals with such alterations for their effect on neuropathology, neurochemistry and behavioural disturbances. More recently, in silico models have been developed, which offer the possibility of simulating the pharmacodynamic effects of drugs in specific areas of the brain. These experiments are helpful in distinguishing purely symptomatic effects from disease-modifying effects, the latter being the ultimate goal of the modern pharmacology of dementia. * The second breakthrough considered in this article is the codification and standardisation of clinical methods for obtaining a more accurate and earlier diagnosis (the recent introduction of the concept of "Mild Cognitive Impairment", which includes patients who will later develop a true clinical dementia syndrome). In that respect, the determination of the biological markers of Alzheimer's disease (apolipoprotein E, amyloid substance, protein-tau, isoprostane) as well as progress in neuroimaging (functional positron emission tomography [fPET]-scan, single photon emission-computed tomography [SPECT], functional nuclear magnetic resonance [fNMR]) are discussed in terms of their potential as new tools in the early stages of drug development (surrogate markers). The methods used during the comparative clinical trials (phase III) have been elaborated and internationally standardised during the assessment of the different acetylcholinesterase inhibitors (AChE-I), with the knowledge that, since 1994, four of these have been officially approved: tacrine, donepezil, rivastigmine and galantamine; the same methods have been used for developing memantine, a recently-launched modulator of glutamatergic neurotransmission. The validated scales now take into consideration not only the cognitive dimensions of Alzheimer's disease but also the behavioural symptoms, with the introduction of the concept of BPSD (behavioural psychological symptoms of dementia). Some proposals to improve this clinical assessment of anti-dementia drugs are presented here. * The section of this article dealing with prospective issues considers the main pathways of interest in drug innovation and the elucidation of new targets for the future compounds. As well as their symptomatic effects on the different components of cognition, drugs should be neuroprotective and limit the lesions documented in Alzheimer's disease, with the aim of progressing far beyond the amyloid hypothesis (immunisation, beta-sheet breakers, secretase inhibitors). The field of excitotoxicity (which is mainly glutamate dependent) appears fruitful, because of the possibility of pharmacological intervention at the different steps in the excitotoxic process. All the new directions presented in this article support the concept of true disease-modifying agents. In conclusion, this prospective review should be considered as a guide in fostering drug innovation in Alzheimer's disease and related disorders and should help to decrease the gap existing between neuroscience and therapeutics.

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Ten years after the introduction of the first drug, tacrine, in the treatment of Alzheimer's disease, it seems appropriate to re-appraise the pharmacological processes of innovation in the research field of dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, regarding experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets to consider in priority. This review deals with this objective in three parts: (1) assessment of current therapeutics, (2) discussion of the experimental models and clinical practices and (3) prospective drugs of the future. The implementation of considered strategies will require the involvement and close cooperation between political decisions, pharmaceutical companies and the scientific community.

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