The vast majority of schizophrenic patients demonstrates poor performance in different aspects of cognitive processing. Some of these cognitive deficits clearly have been identified as rate-limiting factors in social functioning. Over the past years, a series of meta-analyses has summarized the evidence for the benefits of cognitive remediation approaches. However, there are marked discrepancies between their findings.

The present contribution aims to provide a conclusive survey of the available evidence for the efficacy of cognitive remediation as derived from these meta-analyses and the findings of an own recent meta-analysis of all randomized controlled trials published in peer-reviewed journals.

Relevant meta-analyses and randomized controlled trials were identified by searching several electronic data bases and by hand-searching of reference lists. In order to compare the findings of the existing meta-analyses the reported effect sizes were transformed into a standardized effect size measure. For the own meta-analysis weighted mean effect size differences between comparison groups regarding various types of outcome were estimated. Their significance was tested by confidence intervals and heterogeneity tests were applied to examine the consistency of the effects.

The findings of systematic reviews covering cognitive remediation approaches differ considerably depending on the methodological rigor of included studies and the cognitive function targeted. The present meta-analysis provides support for small to medium improvements in attention, executive functioning and social cognition tasks, indicates small reductions in negative symptoms and a moderate transfer effect on social functioning. However, the durability of the effects remains unclear since follow-up data are missing.

Perturbation of epigenetic mechanisms, which is likely associated with an overexpression of DNA-methyltransferase 1 (DNMT1)in telencephalic GABAergic neurons of schizophrenia (SZ) patients, participates in the pathophysiology of cognitive disorders.

We hypothesize that tobacco abuse, which is very frequent in SZ patients, may be an attempt to self-medicate cognitive dysfunction by reducing DNMT1 overexpression.

In mice treated with nicotine (4.5mg/kg/sc twice a day for 5 days) and decapitated 2,4,8,12 or 24 hrs after the last dose of nicotine, we counted the number of DNMT1 mRNA- and protein-positive neurons in various brain areas using a two-dimensional counting method.

Mice receiving nicotine exhibited a 30-40% decrease in the number of DNMT1 mRNA- and protein- positive neurons in layers I and II of cingulate, piriform, somatosensory cortices and caudate-putamen. A single dose of nicotine causes only marginal changes in DNMT1 mRNA expression.

The high affinity nicotinic receptor antagonist mecamylamine (2mg/kg/sc twice a day for 5 days)given along with nicotine attenuates the nicotine-induced decrease of DNMT1 mRNA-positive neurons in various brain areas.

We also found that cortical layer I and hippocampal GABAergic neurons include high levels of α4 and α7 nicotinic acetylcholine receptor (nAChR)subunits which can then mediate the action of nicotine on GABAergic interneurons. The observation that repeated injections of nicotine decrease the DNMT1 mRNA and protein expression in telencephalic layer I and II cortical GABAergic neurons suggests that in these neurons, nAChR may have an impact on the epigenetic modulation of chromatin remodeling.

Agitation is a frequent symptom associated with schizophrenia, mainly in the acute or impending relapse phases, and can be defined as any inappropriate, excessive motor or verbal activity. Manifestations of agitation may include excitement, hostility, aggressive and destructive behaviours, verbal abuse and extreme personal distress. Agitation has an adverse effect on many aspects of psychiatric disorders, negatively impacting patient care, caregiver experience and society as a whole. In terms of patient care, the symptoms of agitation can hinder diagnosis and treatment of the psychiatric disorder. Delayed diagnosis and treatment and its associated effects can increase the duration of hospitalization for a patient. Agitation symptoms can heighten caregiver distress, as agitated individuals are generally perceived to be acting inappropriately. Among inpatients, agitation is a common warning signal that frequently precedes an act of violence and, therefore, is among the most fear-provoking aspects for caregivers. Potentially, this can lead to increased need for institutionalization, leading to societal implications due to the increased need for emergency care and the associated costs. Also, increased hospitalization further influences the patient experience - adversely affecting patient quality of life. Thus, addressing agitation as a symptom of schizophrenia is an important therapeutic target. Given the seriousness of these symptoms and their effects, together with the fact that patients with agitation associated with psychiatric disorders frequently present in the emergency department experiencing an acute psychiatric episode, rapid, effective intervention is key. The initial treatment period is critical for optimal patient outcomes, and an ideal treatment for a patient presenting with acute agitation would: calm the patient quickly, without excessive sedation; decrease the likelihood of harm to self or others; attenuate psychosis and associated symptoms; allow initiation of a therapeutic relationship between patient and physician; be easily and effectively administered; decrease the use of seclusion and restraint; and consider both short- and long-term treatment goals and patient health.

The induction of sleep was originally considered to be a desirable therapeutic endpoint for the rapid control of agitation associated with psychotic disorders. However, it has become clear that sleep is not essential for a decrease in agitation or for the rapid improvement in core psychotic symptoms. Indeed, although the initial calming effects of treatment may be considered useful, excessive sedation or ‘oversedation’ is not a desirable effect, as it can interfere with both the physician's ability to interview/evaluate the patient and establish an effective therapeutic alliance with them, and with the patient's ability to participate in their treatment (e.g., answer questions, hydrate themselves). Furthermore, oversedation has the potential to mask illnesses that show central nervous system depression as a symptom, which could lead to further morbidity or mortality. Thus, although sleep may be advantageous in certain circumstances, achieving control of agitation via rapid calming rather than sedation is becoming an important therapeutic goal. Management of acute agitation has traditionally involved the use of benzodiazepines, such as lorazepam; however, problems with oversedation have led to the increased use of intramuscular antipsychotics in place of, or in combination with, benzodiazepines. Although combination treatment, for example, with intramuscular haloperidol plus intramuscular lorazepam, may provide superior efficacy to treatment with either agent alone, the sedative effects are at least as great as with the use of benzodiazepines as monotherapy. Specific calming without excessive sedation is emerging as a significant clinical advantage of intramuscular formulations of atypical antipsychotics versus conventional treatments.

The first challenge in the treatment of acute agitation associated with schizophrenia is to control agitation without excessively sedating the patient, while also treating the symptoms of schizophrenia. Although oral formulations of antipsychotics have shown efficacy in the treatment of agitation, some agitated patients may not be able to take oral drugs and it may be necessary to use an intramuscular form of medication. Intramuscular formulations of benziodiazepines, typical antipsychotics and, more recently, atypical antipsychotics, have all proved effective first-line therapies for the rapid control of agitation associated with psychotic disorders. Although widely used, intramuscular benzodiazepines have been associated with excessive sedation, and typical antipsychotics, such as intramuscular haloperidol, have a high propensity for causing acute extrapyramidal symptoms. Distressing side effects may adversely impact on patient acceptance of, and adherence to, future antipsychotic therapy. Intramuscular atypical antipsychotics may provide superior alternative treatments owing to improved safety and tolerability versus typical agents. Clinical studies have demonstrated the safety and efficacy of intramuscular formulations of aripiprazole, olanzapine and ziprasidone for the treatment of agitation associated with schizophrenia, and these agents have been approved for use in the USA and some European countries. Although rapid control of agitation is the primary goal, the longer-term effects of antipsychotic therapy also require consideration. Patients initially treated with an intramuscular antipsychotic will typically transition to oral therapy for the long-term management of their disorder. Therefore, the long-term safety and tolerability of oral therapy is important. For example, treatment-associated sedation can adversely affect patient quality of life and social integration during longer-term treatment, whereas treatment with antipsychotics that are associated with significant risk of weight gain, glucose dysregulation and dyslipidaemia may have serious implications for long-term patient health. Transferring from an intramuscular to an oral antipsychotic may impose a risk of the emergence of adverse effects, breakthrough symptoms and loss of therapeutic advantage, particularly if transitioning between intramuscular and oral formulations of different antipsychotics; ideally, continuation with the same agent would minimise this risk.

Selection of appropriate treatment for anxiety disorders is influenced by several considerations, including psychiatric comorbidity. Emerging data suggest that anxiety disorders have a chronic course and a high comorbidity with depression. Successful treatment can be facilitated by first establishing treatment goals, which include managing acute anxiety and following through to remission. Prevention of recurrence of anxiety disorders should be the ultimate objective.

Various treatment options exist for the treatment of anxiety disorders, including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants, pregabalin, benzodiazepines, buspirone, and reversible and irreversible MAO inhibitors. Some SSRIs have been demonstrated efficacy in both acute and long-term trials. Regarding their risk-benefit ratio, they are established as first-line therapies. The combination of drug treatment with cognitive behaviour therapy (CBT) is also recommended.

The chronic nature of anxiety disorders, different treatment response among different anxiety disorders and the recognition of their frequent comorbidity with depression requires an informed and evidence based choice of the best pharmacological approach to the individual patient. The presentation will present the most recent data from randomised clinical trials of newer generation agents and put them into perspective, to help the physicians to appropriately diagnose anxiety disorders and achieve the goal of bringing patients to full remission.

Depression is a disabling disorder associated with considerable comorbidity, risk of suicide and social consequences. Although antidepressants are among the most prescribed therapeutic agents, recent reviews highlight the significant percentage of depressed patients who fail to achieve a response or remission.

Although epidemiological and clinical data do not support severe depression as a separate illness category, and there is no consensus on the definition of "severe depression" regarding diagnostic scales, evidence suggest that the severity of depressive symptomatology may be associated with a worse prognosis and an increased mortality. Furthermore is there a perception that specific subpopulations of depressed patients e.g. melancholic patients or treatment resistant patients suffer of more severe forms of depression. The treatment of severely depressed patients is thus of major concern in view of the debilitating course of the disease.

Some early studies suggested that tricyclic antidepressants (TCAs) like clomipramine were more effective that selective serotonin reuptake inhibitors (SSRIs) paroxetine or citalopram in "endogenously" depressed patients. Other reviews report comparable efficacy of TCAs and SSRIs in patients with severe or melancholic depression, with SSRIs being better tolerated.

Recent data suggesting a surprisingly better differentiation of escitalopram, the active enantiomer of racemic citalopram, regarding effeicacy in more severely depressed patients (MADRS > 30 or > 35) versus SSRIs such as paroxetine and citalopram as well as versus the SNRI venlafaxine argue for a differentiated treatment approach, based on severity of symptoms.

The perception of Obsessive Compulsive Disorder (OCD), once seen as a rare refractory condition, has changed significantly over the past two decades. Neuroimaging and genetic findings have advanced the understanding of the neurobiology of OCD and new treatment options have improved the outlook for patients.

A consensus group at the International Anxiety Disorders Conference in Cape Town, South Africa in February 2006, felt it was timely and appropriate to revisit OCD, to identify key developments in the field of OCD and to examine how they might be translated into clinical practice.

The group reviewed the currently available data on symptomatology, diagnosis, assessment, psychobiology and treatment of OCD in order to provide an up-to-data summary of the literature and recommendations for the treating physician. Special attention was paid to the current controversies about the relationship of OCD to OCD spectrum disorders, and the subtyping of OCD. An important issue was also of whether OCD should be considered as a distinct disorder, separate from the anxiety disorders. Based on the available evidence, it was proposed to remove OCD from the anxiety disorders and place it within a separate category of OCDs. To do justice to the complex and heterogeneous presentation of OCDs it was also proposed to utilize a combination of categorical and dimensional approaches in the diagnostic process. The consensus was that this would enable not only the tailoring of treatment, but would also be helpful to studies on the neurobiology and endophenotyping of OCD.

Key issues in the neurobiology OCD, including the role of serotonin and dopamine, the cortico-striatal circuits and genetic factors, were addressed with respect to their relationship to special populations, such as treatment resistant patients, tic disorders and "schizo-obsessive' patients, and the response to various treatments.

Substantial evidence from controlled studies demonstrate efficacy for clomipramine and SSRIs in the acute treatment of OCD across the lifespan. There have been fewer studies of long-term treatment and it remains less conclusively understood as to how well treatments that have been shown to be effective in short-term studies maintain their efficacy over the longer term, though placebo-referenced trials suggest efficacy for clomipramine, fluoxetine and sertraline up to twelve months. Most relapse prevention studies in acute responders revealed a significant advantage for remaining on active treatment (paroxetine, sertraline and fluoxetine at higher doses). For some of these studies methodological problems impaired their ability to discriminate active from placebo treatment on the chosen relapse criterion.

In a double-blind dose-finding study, 458 OCD patients were randomized to escitalopram (fixed at 10mg or 20mg), or 40mg paroxetine or placebo. At week 12 - the primary efficacy endpoint - 20 mg escitalopram showed a significant improvement in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) compared to placebo (p<0.005). At week 24, escitalopram 10mg (p<0.05) and 20mg (p<0.005) showed significantly greater improvements in Y-BOCS total scores than placebo - as did paroxetine 40 mg (p<0.005). In a relapse prevention study, 320 patients (ITT) who had responded following 16 weeks of open treatment with escitalopram, were randomized to placebo or escitalopram for a further 24 weeks of double-blind treatment. The primary analysis (time to relapse) showed a significant advantage for escitalopram (Log-rank test p<0.001), and the risk of relapsing was 2.7 times higher for placebo compared to escitalopram. These results suggest that escitalopram is effective for acute and long-term treatment and relapse-prevention in OCD.

Agomelatine is a new antidepressant with an unique pharmacological profile. It is a potent agonist of melatonin receptors (MT1 and MT2) and also an antagonist at 5-HT2C receptors Agomelatine's acute efficacy in treating MDD was seen in three placebo-controlled studies, including a dose-ranging study with paroxetine as active comparator.

The meta-analysis of these trials showed a significant difference between agomelatine and placebo in the main efficacy analysis, the HAMD score (= 2.86 0.56; P<0.001) and in the CGI scale (=0.47 0.10; P<0.001).

Furthermore, evidence of agomelatine's efficacy in severe depression was illustrated by the meta-analysis of the patient subgroup with a baseline HAMD 25. Analysis of pooled data demonstrated an increase in the magnitude of the agomelatine-placebo difference with increasing severity at baseline.

The antidepressant efficacy of agomelatine was also evaluated in direct comparison to venlafaxine in 2 trials. Agomelatine showed at least comparable efficacy to venlafaxine in depressed patients after 6 and 12 weeks of treatment.

Agomelatine did not show the typical side effects found with selective serotonin reuptake inhibitors (SSRIs) (ie, gastrointestinal disorders, weight gain, serotonergic syndrome, and insomnia).

Moreover, agomelatine was shown to lack discontinuation symptoms compared with placebo in a study showing significant discontinuation symptoms with paroxetine.

In conclusion, the experience with agomelatine across a wide range of clinical trials suggests that agomelatine offers an important alternative for the treatment of depression, combining efficacy, even in the most severely depressed patients, with a favourable side-effect profile.

A breakthrough has recently been made in antidepressant research with the development of agomelatine. Agomelatine has a distinct pharmacological profile compared with all other classes of clinically available antidepressants.

Agomelatine is a high-affinity agonist at both the melatonergic MT1 and MT2 receptor types, and, in addition, blocks 5-HT2C receptors. Agomelatine did not significantly bind to any other site studied. In accordance with this profile, agomelatine resynchronized circadian rhythms and elicited a dose-dependent elevation in extracellular levels of noradrenaline and dopamine in the frontal cortex of freely moving rats while exerting no effect upon serotonin levels. The antidepressant actions of agomelatine have been described in several validated animal models: learned helplessness, forced swim, chronic mild stress, mice with impaired glucocorticoid receptors, isolated aggressive mice, and the marble burying test, with antidepressant-like effects being shown in all behavioral paradigms examined. Based on these results, the nocturnal sleep pattern of psychosocially stressed male tree shrews (a valid animal model for depression) was investigated: agomelatine resynchronized disrupted circadian rhythms and antagonized the effect of stress on the total amount of rapid eye movement (REM) sleep and on the fragmented sleep pattern. In conclusion, the antidepressant efficacy of agomelatine may be due to its receptor profile, and it is hypothesized that melatonergic and 5-HT2C receptors may be acting in synergy, thus representing a novel approach to treating depression.

In all life forms, circadian rhythms are defined by a period of approximately 24 hours. The daily light/dark cycle governs rhythmic changes in behavior and physiological and mental functions, ie, in activity, core body temperature, hormones, sleep-wake cycle. All circadian rhythms are driven and controlled by the biological clock, which in mammals is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus.

Disruption of circadian organization is a characteristic of a variety of affective disorders, especially major depression, and, circadian abnormalities may constitute a core component of the pathophysiology of depression and may also determine the treatment response.

Depressed patients have documented abnormalities in mood, body-temperature, neuroendocrine secretion, and, most importantly and disabling, in sleep (approximately 90% of patients complain about their sleep). The sleep alterations are mainly related to poor sleep quality and maintenance and to difficulties in maintaining alertness during the day. Polysomnographic recordings show disruption of sleep continuity with prolonged sleep latency, increased wake time during the night, increased early morning wake time, decreased slow-wave sleep, and disinhibition of REM sleep. Most antidepressants can influence the architecture of sleep: SSRIs, SNRIs, and some TCAs (clomipramine) have "alerting" effects whereas others, among them, mirtazapine or trazodone, are sleep promoting often also causing sedation and daytime sleepiness. An important clinical goal in the treatment of major depression would therefore include antidepressants that improve both mood and quality of sleep without impairing daytime alertness.