Negative symptoms are a fundamental dimension of schizophrenia despite of their limited role in the international diagnostic classifications. Eighteen instruments are identified of which 11 assess specifically the negative symptoms. The assessment of subjective experience is neglected in most of these negative symptom rating scales. Consequently, we present a new scale, the Self-report of Negative Symptoms (SNS), assessing the 5 consensual negative dimensions (emotional blunting, alogia, social withdrawal, anhedonia and avolition). This scale is an auto-evaluation constituted of 20 questions with a score ranging from 0 to 40.

Forty nine patients with schizophrenia and schizoaffective disorders (DSMIV) were evaluated in order to demonstrate three components of the scale’s validity: face and content validities and reliability.

No item was judged inappropriate or poorly formulated (face validity). According to experts, the universe of items clearly covers all the negative symptoms (content validity). The Cronbach’s coefficient (α=0.784) showed a good internal consistency (reliability). Factor analysis extracted 1 factor which accounted for 56.75% of the variance. Moreover, the SNS scores were significantly correlated with the SANS scores (r=0.526, p<0.001) and the negative CGI scores (r=0.599, p<0.001) supporting a good convergent validity. In contrast, there was no correlation between the SNS scores and the self-report insight scores demonstrating that patients with negative symptoms can evaluate themselves their negative symptoms independently of their level of insight of illness.

In conclusion, self-report of negative symptoms should be more used in clinical practice since it might allow the patients with schizophrenia to develop appropriate coping strategies.

Repetitive Transcranial Magnetic Stimulation (rTMS) of the frontal cortex has been shown to improve negative symptoms in schizophrenia in a number of small studies, although inconsistent results have also been reported. Neuroimaging has shown bilateral hypofrontality in schizophrenia, and rTMS may improve brain activation. We therefore aimed to investigate whether 10 Hz stimulation of the bilateral dorsolateral prefrontal cortex during 3 weeks would yield substantial treatment effects and would improvement of frontal activation.

ADHD as a developmental disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) is regarded as a developmental disorder based on its early onset in life, the genetic background, the gene-environment interaction, the neuropsychological deficits, as well as the different development of the brain as compared to controls. Yet a diagnostic test on the individual level is lacking, as is true for other psychiatric disorders. The implications of the lifespan duration of ADHD on behaviour, lifestyle and health make the disorder complex. In addition, comorbidity is high and adding to this complexity. In this presentation, latest findings on ADHD as developmental disorder will be presented, leading to a research agenda for the coming years.

Patients with cardiovascular diseases necessitate a specific role of pharmacotherapy with regard to efficiency as well as side-effect profile. Whereas most of the antidepressants can be viewed as effective, the older ones, specifically the tricyclic or tetracyclic antidepressants have cardiovascular side-effects and therefore do not pose an option for this group of patients. With the introduction of the selective serotonin-reuptake-inhibitors (SSRIs) or serotonin-noradrenalin-reuptake-inhibitors (SNRIs) a new era for the treatment of depression with cardiovascular diseases emerged. In large epidemiological surveys it is documented that for cardiovascular problems like heart attack, the administration of antidepressants is of crucial role and decreases mortality. On the other hand, it emerged recently that some of the antidepressants might cause problems with regard to a possible QTC-prolongation. In a large European drug surveillance project we evaluated the cardiological changes during antidepressant treatment with SSRIs compared to other classes of antidepressants. The results of this analysis indicate that the group of SSRIs do not show any increased incidence of QTC interval prolongation compared to other antidepressants. Furthermore, these clinical data confirm that severe cardiological side-effects such as QTC interval prolongation arise more likely during the treatment with tricyclic antidepressants. From our study we conclude that the restrictions and prescriptions of SSRIs stated by the FDA and EMA should be reconsidered.

Psychiatric disorders can be caused or strongly associated by endocrine and metabolic diseases. Especially depressive and anxiety disorders can occur with hypoglycemia, diabetes mellitus, hypothyroidism, hyperthyroidism, hypoparathyroidism. Endocrinological alterations and disturbances in the HPA-/HPT-axis are consistent findings in depressive disorders. Type 2 diabetes is also associated with cognitive dysfunction. Database on pharmacotherapy is sparse and partly inconclusive due to low-quality trials and the heterogenity of examined populations. In diabetes pts treatment with antidepressants showed clinically significant effects on depression outcomes, RCTs regarding maintenance therapy with SSRIs preventive effects for depression recurrence. On the other hand endocrine and metabolic side effects of psychotropics must be kept in mind. Second generation antipsychotics like risperidone, olanzapine or quetiapine are associated with hyperprolactinemia, hyperglycemia, impaired glucose metabolism, clinically with increased risk of metabolic syndromes, diabetes, amenorrhea, galactorrhea and sexual dysfunction. SSRIs have been associated with the syndrome of inappropriate antidiuretic hormone secretion. Lithium long-term treatment can lead to (subclinical) hypothyroidism. From a clinical point of view in some cases treatment with psychostimulants (i.e. methylphenidate) can help patients with medical diseases. Recommendations for the use of different psychotropics in endocrine and metabolic diseases are presented.

The relation between psychopharmacological drugs and liver can be expressed mainly in three ways: 1) interactions with other pharmacological agents that are metabolized in the liver; 2) impact of psychopharmacological drugs in liver disease patients; 3)Direct liver toxicity induced by psychopharmacological drugs.

Almost all psychopharmacological drugs are metabolized in liver and CYP liver isoenzymes are responsible for metabolizing at least in part, more than 80% of all prescribed drugs. Some drugs induce these izoenzymes and others inhibit them.

Liver metabolization of psychopharmacological drugs might be impaired in liver disease patients. By the other hand blood proteins are reduced in liver disease, increasing the concentration of drugs that bind to proteins. Moreover liver disease patients sometimes have encephalopathy which can be aggravated by some drugs.

Monitoring liver function might be prudent following prescription of psychopharmacological drugs, especially if direct liver toxicity has been proven.

From research to practice we emphasize some important issues in managing everyday cases in the context consultation liaison psychiatry and general psychiatry practice.

Recent genomic studies of schizophrenia have begun to reveal the genetic architecture of the disorder and have important implications for future research. We can draw two broad sets of conclusions from these findings. The first is that schizophrenia is highly polygenic, with hundreds and possibly thousands of distinct loci involved at the population level, and alleles with a spectrum of population frequencies contributing to risk. This complexity will prove challenging as we move towards trying to gain biological and mechanistic insights from genetic findings. However, despite this and the fact that much of the genetic risk for schizophrenia remains unaccounted for at the DNA level, there are some encouraging signs of convergence on to a set of plausible biological processes. The second is that genetic risk appears to be highly pleiotropic and does not map onto current definitions of disease. This, along with the lack of clear boundaries between disorders in clinical studies, suggests that there are likely to be overlapping mechanisms at work and that current diagnostic categories may not be optimal for stratifying cases for research into aetiology and pathogenesis.

Off label use of psychopharmacy is in widespread use. Some psychiatric disorders are more treated off label – this was for long time the case for bipolar disorder and probably still is – than in label.

What is off label medication? All medications without a proper licence by the respective drug authority? That means also medications which have a licence in another country/region off label, if not licenced in the respective country? That includes also medications which demonstrated evidence based efficacy and which are suggested in guidelines, but (so far) no licenced? The term regulates in a very strict way the use of certain compounds, while refusing others which are believed to belong to the state of art or even to be innovative.

The pros and cons of off label medication are described using the off label use of antidepressants as example. The antidepressants – in the beginning the tricyclics and later on novel antidepressants with anti-histminergic profile – started to be widely used off label, after the ban of the benzodiazepines, for the treatment of nervousness, anxiety, sleep problems (for long-time especially amitryptiline, doxepine, mianserine, mirtazapine, trimipamine). With the upcoming interest in bipolar depression the discussion started, whether the use of antidepressants is off label in this indication or supported by the general indication major depression. The use of antidepressant in personality disorders is off label, but has a long clinical tradition, although the cost – benefit – relation is unclear (induction of outbursts, induction of suicidality). The use of some special antidepressant (tricyclics especially amitryptiline, novel dual antidepressants) as adjunctive to pain therapy is partially in label, partially off label.

Whether a drug is available in a particular country is based on a political decision motivated by scientific and other arguments. Some authorities may decide that available evidence regarding clinical efficacy, safety and tolerance of a certain drug is insufficient, and manufacturers may consider that the market in a particular country is too small for the introduction of a drug. On the other hand, on an international level, guidelines for the treatment of psychiatric disorders are established by authors, authorities in the field of pharmacotherapy. The recommendations are based on the evaluation of studies but also on the opinions of experts. According to the categories of evidence (A – F), recommendation grades (1 – 5) are defined, and therefore, this has also to be considered at least partly as a subjective approach. Moreover, the off-label use of drugs comprises the 4 ‘D”: diagnosis, drugs, doses, duration (of treatment) (cf Baldwin, Kosky, Adv. Psychiat. Treatment 13 (2007) 414). In particular, psychostimulants, anticonvulsants, lithium and thyroid hormones are widely prescribed in off-label conditions, e.g., psychostimulants are used as add-on medications in treatment resistant depression, lithium in psychiatric disorders presenting a chronobiological component (e.g. some forms of alcoholism), some anticonvulsants such as topiramate are considered to be helpful for the treatment of alcoholism or weight problems. Moreover, almost all neuropsychiatric agents are prescribed for personality disorders, but almost none of them is officially introduced for this indication. Finally, the baclofen – alcoholism story illustrates the conflicts existing in the field of off label prescriptions.

In this talk I will discuss how we can establish functional correspondence in neuroimaging data across individuals. We will briefly review the challenges in inferring multivariate fine-grained functional structure shared across individuals from neuroimaging data despite anatomical variability. Specifically, we will discuss the relevance of discrepancies between anatomical and functional correspondence in light of evolution, brain development and disease. I will outline how to use manifold learning techniques to capture the functional connectivity architecture in individuals. These methods capture a multitude of relationships, such as functional connectivity and map them into a space that represents the entire relationship structure. This enables learning of a joint functional atlas in an embedding space representing the structure shared in a population. The resulting functional correspondence has several uses. First, it allows to remove possible anatomical confounds when comparing cohorts, secondly it allows to study the relationship between function and the location of its anatomical anchors. The talk will conclude with a discussion of results in pre-surgery language mapping, resting state networks, and treatment effect prediction.

Major depressive disorder is one of the most common and disabling disorders worldwide. Although a number of various treatment options (pharmacological, psychotherapeutic, neurostimulation etc.) is available, no single treatments isuniversally effective. Therefore, the identification of factors predicting apriori or early in treatment response or potential resistance is one of themost pressing needs in depression treatment. Most evidence coming from researchrelies on statistical significance that implies scientific but not necessarilyclinical usefulness. ‘Clinical” predictor should be reproducible, reliable, inexpensive, non-invasive and easily accessible in order to use in daily clinical practice. There are also manymethodological issues coupled with predictor or biomarkers research as a definition of clinical significance, discrimination ability of predictors, need for cross-validation of results and prospective testing as well [2]. Clinical and preclinical studies have identified a number of biological (biomarkers), clinical and psychological factors potentially associated with treatment outcome and several of them were replicated (depression severity, early improvement of depressive symptoms, theta cordance and other EEG predictors, BDNF serum level, anterior cingulate metabolism, 5-HTT polymorphism etc.) [1]. Despite the intensive research there is no sufficient evidence for any biological or other factor to be established as predictor of treatment outcome in routine clinical practice or to be an integral part of guidelines for treatment. For the future, a multivariable approach combining markers of response from various research domain may be beneficial to achieve clinically significant prediction.

This work was supported by a grant from Internal Grant Agency of Ministry of Health of Czech Republic No. NT 14287 and RVO-PCP/2013.

It has been proposed that depressive episodes could be “neurotoxic”, decreasing memory skills and/or regularly increasing neurocognitive retardation with the repetition of episodes. We describe two protocols which could reinforce the likelihood of this neurotoxic hypothesis, and a study showing that it is indeed possible to reduce the time before getting treatment response.

On the first protocol a large sample of depressed outpatients was tested for narrative delayed memory (Weschleer paragraph), before and after antidepressant treatment (Gorwood et al., 2008). Delayed memory skills after treatment response was strongly correlated to the length and the number of past depressive episodes. The second protocol assessed neurocognitive retardation during a depressive episode and after clinical remission is obtained. Once again we observed that neurocognitive retardation (TMT-A and -B) in remitted patients was highly correlated to the number of past depressive episodes (Gorwood et al., 2014). We then tested if treatment resistance could be detected a bit earlier than the 4 to 6 weeks observation usually considered as required. Indeed, we found that a two weeks observation is enough to decide if we should continue or change the present treatment. We furthermore saw that assessing emotions rather than depressive symptoms might be even more predictive of the chances of treatment success.

These studies reinforce the concept of neurotoxicity of depressive disorder, wich means that an important part of treatment resistence is acquired during the process of the disorder, and therefore stress the importance of treating early and completely each depressive episode, not only for an acute relief, but also to improve the long term prognosis of mood disorders.

Clinicians have few evidence-based options for the management of bipolar depression and even fewer for treatment-resistant bipolar depression (TRBD). To date, relatively few studies have examined the next-step treatment strategies for TRBD and no clear guidelines or unequivocal algorithms exist in order to inform clinicians on what to do when the first approved therapies fail. Although research on optimal treatments for bipolar depression has been increasing, a lack of a sufficient database and disagreements about the classic treatment of bipolar depression have precluded a consensual treatment algorithm for treatment-resistant bipolar depression, and well-designed studies on TRBD still lack (Vieta & Colom, 2010). Until recently, the algorithms for TRBD were undistinguishable from TRD’s, despite the absence of good evidence supporting the use of antidepressants in patients with bipolar disorder. In 2009, Pacchiarotti et al proposed a new definition for TRBD (Pacchiarotti et al, 2009). As a general rule, the management of TRBD includes the same operational steps as in unipolar TRD, but with totally different treatment options. Strategies include optimization of the dosage of the current drug, combination or augmentation and switch strategies, that is, introducing a new drug to replace the old one. However, the definition of TRBD is not based on lack of response to antidepressant, but to drugs such as quetiapine, lithium, and lamotrigine. This lecture will provide a challenging overview of the current state-of-the art in the management of TRBD and future developments.

The Group for the Study of Resistant Depression (GSRD) (Souery et al., 2007, Journal of Clinical Psychiatry 68: 1062-1070), a collaborative project between eight centers in Belgium, France, Greece, Italy, Israel and Austria developed a staging model that distinguishes between ‘non-responders” (patients who fail to respond to one form of treatment, administered for six to eight weeks), a condition which is now termed ‘insufficient response” by the European Medicines Agency (EMA), ‘treatment resistant depression” (TRD, patients that fail to respond to two or more adequate antidepressant trials of different classes of antidepressants), and ‘chronic resistant depression” (CRD, patients being treated with several antidepressants for more than twelve months). The clinical findings of the GSRD provide a set of eleven variables associated with treatment response, among them comorbid anxiety disorders as well as melancholic features (Souery et al., 2007, Journal of Clinical Psychiatry 68: 1062-1070). Although there is a plethora of hints in textbooks that switching the mechanism of action should be obtained when a patient does not respond to one medication, the results of the GSRD challenge this notion by describing that staying on the same antidepressant mechanism of action for a longer time is more beneficial than switching (Souery et al., 2011; World Journal of Biological Psychiatry 12: 364375). The results of the GSRD European multicenter project has recently been summarized by Schosser et al. (European Neuropsychopharmacology; 2012; 22: 259-266). New data including machine learning techniques to handle the large amount of data obtained in this ongoing research protocol will be presented.

Over the last years, numerous studies have revealed the neurocognitive basis of suicidal behavior. It is now thought that particular cognitive deficits may represent vulnerability factors to suicidal acts. This notably includes disadvantageous decision-making, reduced cognitive inhibition and, to a lesser extent, deficient memory. The neural basis of these deficits are under investigation and are mostly related to the orbitofrontal and dorsolateral prefrontal cortices. Some of these deficits, notably impaired decision-making, have been found in remitted patients, but also in first-degree relatives of suicide completers, suggesting that they are heritable endophenotypes. Future directions include the search for valid measures to be integrated to the clinical practice and targeted interventions. Preliminary findings will be presented.

Is there a neuroanatomical basis for the vulnerability to suicide?

Kees van Heeringen MD PhD

Unit for Suicide Research Ghent University, Belgium