Although there is no doubt about its efficiency, pharmacotherapy of depression still faces several problems that have to be focused upon and hopefully solved. Besides the problem of drug-resistance and delayed response, the need to achieve remission has become increasingly important.

As for the near future, there is great hope that new mechanisms of action can overcome the limitations of the traditional and current antidepressant medications. Unfortunately, some of the recent developments that raised the most interest either turned out to be less effective than hoped, such as the substance P antagonists, or did not yet lead to a drug likely to be marketed in the near future, such as CRF antagonists, for example. On the other hand the first melatonergic antidepressant, agomelatine, is seen as a successful new development.

Drug development can currently be based on improved brain imaging techniques, better animal models, and an increased knowledge of genetic markers. Hopefully this will result in a change in the pharmacotherapy of depression and psychiatric diseases in general. From a clinical point of view, new antidepressants should target the following unmet needs: early onset of action; increased proportion of remission; broad spectrum of efficacy including physical symptoms, pain, sleep disorders, circadian rhythm disorders, etc; good efficacy in subtypes of depression, such as atypical depression; efficacy in bipolar depression without inducing switches to mania; lack of side effects of TCAs and modern antidepressants, especially lack of cardiac side effects, anticholinergic side effects, sedation, weight gain, sexual side effects, etc.

The clinical development program strategy of a new treatment of depression to be registered in Europe must be built in agreement with recommendations of the CHMP guidance.

Demonstration that an antidepressant is effective in treatment of major depressive disorders requires consideration of specific recommendations notably regarding the use of placebo and reference drugs, efficacy assessment, designs features and safety aspects.

In the field of depression, comparisons between test medicinal product and reference drugs are difficult to interpretate since the level of placebo response is high and variable. An adequate evaluation of antidepressant efficacy is firstly based on randomised double blind comparison versus placebo. For short term efficacy, studies with 6 week-treatment period are required and three arm trials including placebo and active control are recommended. Regarding the long term efficacy, relapse prevention study is the design recommended for demonstrating that the short term effect can be maintained over time.

Assessment of efficacy criteria includes both clinical relevance and statisitical significance, particularly:

Improvement expressed as difference between baseline and post-treatment score in symptomatology and as proportion of responders.

Remission, defined as a condition where no or only few signs remained, with a justified cut-off on a validated rating-scale.

In randomised withdrawal trials, efficacy is expressed as number of patients relapsing and/or time to relapse.

The acceptable scales for use as primary endpoint include the HAM-D17 scale, the MADRS scale. Cautions regarding designs features, safety assessment and the global methodological issues faced in conducting such program will be detailed in the presentation.

During the process of drug development, the sponsoring pharmaceutical manufacturers conduct numerous clinical trials to demonstrate the therapeutic efficacy and safety of new antidepressive agents. These trials are required to provide ‘substantial evidence of effectiveness’ in accordance to terms and conditions codified by law. Accordingly, the design and conduct of clinical studies of new antidepressants are strongly impacted by the need to comply with scientific standards as well as by regulatory requirements for approval. Regulatory requirements are typically published in standard ‘Guidance documents’, but in practice the ‘one size fits all’ approach has room for interpretation for specific indications and clinical trials. Detailed statistical criteria applied for the regulatory evaluation of individual drug trials are typically not available in the standard medical literature, but are accessable via the FDA's Summary Basis of Approval Documents (SBAs). This presentation will examine SBA materials and published scientific literature to gain insight into factors that were considered for the establishment of substantial evidence of effectiveness from a statistical perspective. Specifically, the presentation will investigate critical elements considered for the evaluation of results of controlled trials of new antidepressive agents. Such elements include the measurement of relevant clinical outcomes, definition of endpoints, effect sizes, multiple inferences, and principal trial design choices such as placebo- or active-controlled trials. In addition, the presentation will review the contribution of placebo response to the frequent negative results in antidepressant clinical trials, and discusses the implicatons of this knowledge of the placebo response for future trials and clinical practice.

In the clinical practice, physicians are routinely asked to make decisions whether to initiate or continue antidepressant treatment in a situation where no safety data are available. As an example can serve pregnancy and breast-feeding, where controlled clinical trials provide little guidance. Females of fertile age are rarely included in the early phases of clinical testing, the Phase IIb and III trials have a standard provision to use a reliable contraception. Pregnancy during drug trial is considered as a ‘serious adverse event’ with subsequent study discontinuation. The reasons are not just ethical and legal but also marketing, the drug manufacturers fear to have their products associated with potentially grave side effects, such as malformations. Drug treatment in pregnancy and lactation thus pose a highly relevant clinical problem that cannot be addressed in controlled trials. Excessive concerns of negative consequences could erroneously result in generalizing recommendation not to get pregnant or to abort existing pregnancy. However, fetus may be already exposed to drugs early in the first trimester during frequently unplanned pregnancies; in addition, recent epidemiological data indicate increasing consumption of psychotropics, including antidepressants, by pregnant women. Psychiatrists have to weigh the known risks of treatment discontinuation versus potential risks for the fetus and infant. They should also consider whether alternative non-pharmacological interventions (psychotherapy, ECT, rTMS) are accessible or effective. The only available safety data on antidepressants come from animal studies, epidemiological trials, drug registries, case series, anecdotal case vignettes and clinical observations.

Supported by the research project MZ0PCP2005.

An understanding of the epidemiology of alcohol and drug use in young women is important to appreciate the considerable morbidity and mortality associated with it and to understand the impact of such use on offspring. Although abstention rates are consistently higher among women than men in general substance misuse is increasing in young women. Differences in definitions, measurement techniques, availability, social acceptability and affordability partly explain the great variability in reported prevalence rates. Alcohol exposure among pregnant women varies from 0.2% to 14.8%. An Australian national survey revealed that nearly half of pregnant and or breast-feeding women up to 6 months postpartum were using alcohol. A Swedish study reported risky use of alcohol during the first 6 weeks of pregnancy, at 15%. Cannabis use among pregnant women varies from 1.8% to 15%. The reported prevalence of opiate use during pregnancy ranges from 1.65 to 8.5%. Cocaine use among pregnant women is reported to be between 0.3% and 9.5. Most pregnant women stop or reduce their substance use during pregnancy and this might be an opportune moment for detection and treatment. Substance use tends to increase sharply in the postpartum period with adverse consequences on mother and baby. Perinatal substance misuse interventions can reduce adverse neonatal outcomes. On the basis of relatively high rate of substance use disorders during pregnancy and postpartum period, effective screening and intervention strategies should be implemented.

Smoking, alcohol and illicit drug misuse during pregnancy lead to toxic harmful consequences for mother and especially for the fetus, neonate or child. In case of misuse of illicit substances pregnant women mostly suffer from polytoxicomania (3 substances and more) and the misuse of illicit substances is often accompanied by severe smoking and drinking of alcohol. Therefore it is often difficult to methodologically differentiate the single toxic effects. Basing on this knowledge in the presentation a view on the single toxic and /or chronic effects of addictive drugs will be given.

1. 1. To clarify single toxic effects of the addictive drugs diagnostic procedure about regulary and/ or ecstatical consume and the diagnose of abuse or dependence acc. to DSMIV or ICD 10 and the analysis of relapse behaviour for each substance should be done.

2. 2. The toxic effects of the different substances in pregnancy will be reported. Nearly al addictive substances (nicotine (+CO, +tar), alcohol, THC, psychostimulants, heroine) go into placenta and thereby have multiple toxic effects like f.e. decreased perfusion and infarct of the placenta leading f.e. to intrauterine retardation of growth, premature detaching of placenta, premature birth, to deformities, various later heavy postpartal effects (lung and breath diseases, sudden death, fetal alcohol syndrome, neurological dysdevelopment, cardial malformations, learning disturbances, ADHD etc). The toxic effects of the various substances will be differentiated so far it is possible.

3. 3. The different therapeutic approach of the various addictive drugs during pregnany (withdrawl treatment, opioid substitution) will be discussed.

Knowledge of the epidemiology of substance use and associated problems demonstrates that a sizeable minority of pregnant women are using substances, and following delivery the majority revert to higher levels of misuse which is to the detriment of themselves and their babies. There is a rapidly accumulating range of effective interventions for substance misuse. Pregnancy can be a turning point for the delivery of such treatments as women attend obstetric services. This is an opportune moment for detection and treatment, if generalists have the skills to manage less severe problems and referral to specialists is possible. It is important to be able to determine when a patient requires specialist referral for the health and safety of the patient, their baby and the family and for the integration of provision by professionals involved in their care. This symposium will outline the basis of expert assessment and judgement regarding appropriate psychological treatment interventions for this group of young women within the framework of comprehensive service models.

There are two major forms of long-term depression (LTD) of synaptic transmission in the central nervous system, which require activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). In synapses in the perirhinal cortex we have directly compared the Ca2+ signalling mechanisms involved in NMDAR-LTD and mGluR-LTD. Whilst both forms of LTD involve Ca2+ release from intracellular stores the Ca2+ sensors involved are different; NMDAR-LTD involves calmodulin, whilst mGluR-LTD involves the neuronal Ca2+ sensor (NCS) protein NCS-1. In addition, there is a specific requirement for IP3 and PKC as well as protein interacting with C-kinase (PICK-1) in mGluR-LTD. NCS-1 binds directly to PICK1, via its BAR domain, in a Ca2+-dependent manner. Furthermore, the NCS-1-PICK1 association is stimulated by activation of mGluRs, but not NMDARs, and introduction of a PICK1 BAR domain fusion protein specifically blocks mGluR-LTD. Thus, NCS-1 is a component of a novel mechanism involved in mGluR-LTD.

Investigation of molecular and cellular mechanisms of synaptic plasticity is the major focus of many neuroscientists. There are two major reasons for searching new genes and molecules contributing to central plasticity: first, it provides basic neural mechanism for learning and memory, a key function of the brain; second, it provides new targets for treating brain-related disease. Here, I propose that LTP in the anterior cingulate cortex (ACC) as a synaptic model for emotional fear and chronic pain in the brain. Integrative approaches including genetic, neurobiological and physiological methods are used to investigate the roles of cortical neurons and microglia in synaptic LTP, fear and chronic pain. We have identified several key calcium-stimulated signaling molecules including AC1, CaMKIV and FMRP for AMPA receptor mediated cingulate LTP, trace fear memory, and chronic pain. By contrast, microglia only contributes to changes in spinal dorsal horn, but not in the cortex. Our findings strongly suggest that ACC LTP may serve as a cellular model for studying central sensitization that related to fear and chronic pain, as well as pain-related cognitive emotional disorders.

An accumulating body of evidence shows that the retrieval process of long-term memory is not static and requires de novo protein synthesis. Thus long-term memories are dynamic and particularly become fragile during its retrieval. Importantly, memory retrieval is regarded as a step necessary for incorporating new information into preexisting memories. We have examined whether protein degradation is involved in the memory reorganization or not. In this presentation I will present the evidence that synaptic proteins are degraded by polyubiquitination and proteasome pathway in the hippocampus after the retrieval of contextual fear conditioning. In addition, we found that the infusion of a proteasome inhibitor into the hippocampus prevented the memory impairment induced by anisomycin, a protein synthesis inhibitor. This indicates that ubiquitin/proteasome-dependent protein degradation is involved in destabilization processes accompanying the memory retrieval. It also supports our hypothesis that preexisting memory is disrupted by synaptic protein degradation before updated memory is strengthened by protein synthesis. Our data also showed that synaptic protein degradation plays a critical role in fear memory extinction, a simple form of memory reorganization. Taken together, synaptic protein degradation is critically involved in the reorganization of the preexisting memories.

Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here I show that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were changed. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neuronsw as dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Statistical clustering of human post-mortem brains using 10 genes derived from the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an “immature DG” in adulthood might serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

Activity-dependent gene expression through activation of Ca2+-CREB signal transduction pathways has been thought to play a central role in fear memory formation. On the other hand, retrieval of fear memory triggers two time-dependent phases of reactivated memory; reconsolidation and extinction. To understand the mechanisms for determining the fate of the reactivated fear memory, we investigated roles of CREB in reconsolidation and extinction of contextual fear memory and then analyzed the brain-regions regulating reconsolidation and extinction by identifying regions where CREB-mediated gene expression is activated and then examining the role of protein synthesis in those regions on reconsolidation and extinction. We first showed that activation of CREB-mediated transcription is required for reconsolidation and long-term extinction of contextual fear memory. Using immunocytochemical analyses, we demonstrated that CREB is activated in the hippocampus/amygdala and amygdala/medial prefrontal cortex (mPFC) in the reconsolidation and extinction phases, respectively. Similar results were observed by analyzing the expression of a CREB-dependent gene, Arc. We finally showed that reconsolidation and long-term extinction of the contextual fear memory depended on new gene expression in the hippocampus/amygdala and amygdala/mPFC, respectively. Thus reactivated contextual fear memory is reconsolidated or extinguished through distinct CREB-mediated gene expression regulation in the hippocampus, amygdala and mPFC.

Many risk factors for alcohol dependence have been pointed out on the basis of large cohort analyses, including antisocial personality disorder, familial history of substance abuse and initial effect of the first consumption of alcohol, these factors having large overlaps. In addition, a low level of response to first alcohol drink has been reported to increase the risk of future alcohol-dependence. This response to first dinks is a genetically influenced characteristic, but the genes involved remain unknown.

The Susceptibility Addiction Gene Environment (SAGE) cohort was designed to assess addictions and psychiatric disorders in a cohort of young adults. All 3.895 college students of the French region “Champagne Ardennes” were eligible. Of them, 3.056 (1.834 males and 1.224 females; mean age 20.42 years, s.d 1.4) were enrolled on their campus during a single day and completed an intake assessment. The final sample was based on 2.730 subjects (70.08%) who fulfilled the inclusion criteria, namely having ever drink at least once in their lifetime. The level of response to alcohol during early consumption was assessed, as well as the DSM criteria for alcohol dependence at the time of interview. DNA was also collected.

Our results confirm the strong association between low level of response to alcohol and the risk of dependence. Furthermore, the genotyping of several candidate genes allowed disentangling the potential intermediate factors between the first consumption and the development of later dependence. These findings emphasize the utility of the endophenotype approach in the genetic study of addictive disorders

Several randomised clinical trials (RCT) have demonstrated the efficacy of cognitive behavioral therapy in the treatment of Posttraumatic Stress Disorder (PTSD). However, the external validity of these studies is limited with regard to PTSD related to childhood sexual abuse which often results in severe and complex sympomatology accompanied by a variety of concurrent disorders or symptoms, for example self-mutilation, suicidal ideation, or severe dissociation. Nearly 30% of patients with PTSD have a co-occuring borderline personality disorder (BPD). The prevalence rates of PTSD in patients with BPD vary between 40% and 60%.

Several RCTs have shown the efficacy of Dialectical Behavioral Therapy (DBT) in the treatment of borderline patients, who exaggerate severe behavioural dyscontrol. However specific treatment for co-occuring PTSD has been lucking.

Clinical lore suggests that exposure to trauma-relevant memories can potentially aggravate dysfunctional behaviour in patients with BPD. Empirical research however reports discrepant results with two studies documenting deleterious effects of comorbid BPD on treatment outcome, whereas one study did not find an impact.

DBT-P was specifically tailored to treat patients with PTSD after sexual abuse during childhood. DBT-P includes training in emotion regulation and mindfulness, cognitive interventions and exposure elements, usually in combination with the use of skills. To evaluate the efficacy of DBT-P as compared to a wait list control group a RCT is currently carried out. Preliminary data, which will be presented, revealed large between effect sizes for the primary outcome measures (PDS, CAPS).

The basis for decision making in pharmacopsychiatry is not as trivial as one might think. There was a tradition to believe that we have more or less specific drugs with a more or less specific mode of pharmacological mode of action for special indications, such as schizophrenia depression etc. However, the situation is apparently much more complex and the clinical decision making is far from being that trivial. The current development of new psychopharmaca is heading for different directions: either broadening the indication for one compound, or looking for subtypes of a more general indication. Some of these main aspects shall be discussed in the presentation.

The decision making in pharmacopsychiatry is rather complex, involving nosological and syndromatological aspects. We have to understand that the pharmacological mechanism of a psychopharmacon is not directly associated with only one psychiatric disorder but often with several. This is already true for psychopharmaca, which have only one mechanism, such as SSRIs, but even more so for drugs like the modern antipsychotics, which have a wide spectrum of receptor interactions and can therefore be effective in quite a variety of psychiatric disorders. Apart from broadening the indication of a psychopharmacon, a development in the direction of exceeding specification and, amongst others, of involving new mechanisms of action can be observed.

The preparations of DSM V/ICD-11 are in progress. The frustrations and limitations engendered by the categorical model in psychiatry led to the suggestion of alternative dimensional models of classification, e.g. to the suggestions for a dimensional view of psychosis. However there are strong arguments for keeping the categorical classification maybe with inclusion of new criteria, such as neurocognitive impairment for schizophrenia and even there are suggestions for new categories such as nonaffective remitting acute psychosis.

Therapeutic indications of drugs are developed by the industry and are approved by regulatory agencies (FDA, EMEA). Indications are linked to diagnostic categories as defined by DSM-IV/ICD-11, e.g. one antipsychotic is indicated for the treatment of both schizophrenia and bipolar disorder, while another is only indicated for the treatment of schizophrenia. These indications are used by the insurance industry to manage financing of drug treatment.

Changes in the criteria of a diagnostic category will result in a revision of approval which may include the obligation for new studies. Generic companies are now an important part of the major pharmaceutical markets, however many of them do not have the capacity to launch clinical studies, which may lead to the withdrawal of marketing authorization of important drugs. Clinical studies seem to be unavoidable for licensing recently available drugs for the new diagnostic categories of DSM V/ICD 11. The introduction of diagnostic categories by a dimensional approach may lead to “double book keeping”: a dimensional diagnosis used for the medical practice and a categorical one for the insurance.