This contribution provides a systematic review on recent developments in psychological interventions for bipolar disorder. The main focus of research to date has investigated the role of different psychotherapeutic approaches (cognitive behavioural therapy, family focused therapy, interpersonal and social rhythm therapy, psychoeducation) as an adjunct to pharmacotherapy for remission and relapse prevention. The review will assess efficacy and effectiveness of these interventions, their common ingredients, limitations and predictors of outcome. It will further explore the potential role of psychological interventions for primary prevention of bipolar disorders in high risk children and adolescents. Suggestions will be made for future work in these areas.

Suicide is well represented in the WHO mortality databases, providing the opportunity to study and discuss how ethno-genetic, cultural, religious, economical and political issues may influence suicide rates in different regions and countries. The problem is that all these factors act together and often with contrasting effect. Suicide rates in Europe vary widely - from about 30 per 100000 of population in Lithuania, Russian Federation, Belarus and Kazakhstan to about 1-2 per 100000 in Cyprus, Azerbaijan, Georgia, Armenia and Greece. It is possible to see from the map, that suicide rates diminish when moving from North to South and from East to West. This may be discussed within the so called “Finno-Ugrian hypothesis”. Gender is one of the issues most widely discussed in suicidal behavior. Across Europe males commit suicides 3-5 times more often than females. Dramatic changes in suicide rates on the post-soviet space are associated with male suicides, while female suicides remained almost unchanged. One explaination is a higher susceptibility of males to socio-economic stress while females seem to be more protected. There is a general rule that suicide rates go up with increasing age. In countries like Ukraine, suicide is significantly higher in rural than in urban areas. Other factors influencing suicides are seasonality, alcohol and substance abuse in the given population. Life-stress and its equivalents seem to be very important, as many other conditions (like cardiovascular and cerebrovascular diseases and accidents) have the same pattern as suicide when studying mortality rates across Europe.

Many European countries have a national suicide preventive programme. In June 2008, a new national programme for suicide prevention was approved by the Swedish Parliament in Sweden. One of the nine strategies in this programme is an assignment called ‘Lex Maria’ - to report all suicides that occur within or 28 days after contact with the healthcare system to The National Board of Health and Welfare (NBHW). Lex Maria guarantees that a systematic evaluation will always occur, providing opportunities to identify components which can be improved when treating suicidal patients. All Lex Maria reports are registered in a separate database at NBHW, allowing systematic analysis at a national level. The methodology used in this analysis will be presented, with examples of individual cases.

Analysis of all suicide cases, which occurred in Sweden in 2006 within the health care system, uncovered the following areas which should be improved when working with suicidal people:

• • Better routines for suicide risk assessment;

• • Better routines for documentation of suicide risk assessment and changes in patients mood;

• • Better routines for the transfer of information within the same unit;

• • Better communication between units to ensure correct transfer of information;

• • Better routines for collaboration between care givers to ensure a continuity of care.

Suicide, particularly in the case of current major depression, is quite common among patients who contact their GPs some weeks or months before their death. However, prior studies have shown that GP’s education, regarding the diagnosis and treatment of depressive disorders, can reduce suicide mortality in the given area served by trained GPs. The aim of our present study was to evaluate the effectiveness of a depression-management educational program for GPs in a region with a very high suicide rate (over 50 per 100.000) in Hungary. Twenty-eight GPs and their lead nurses, servicing 73,000 inhabitants in the region of Kiskunhalas, participated the 5-year educational program together with estabilishment of a Depression Outpatient Clinic and psychiatrist telephone consultation service. The annual suicide rate in the Kiskunhalas region decreased from 59.7/100.000 (5-year preintervention average) to 49.9/100.000. This decrease was significantly greater than both the county and whole Hungary (p=0.001 and p=0.001, respectively). However, the increase of antidepressant prescription was greater in the intervention region compared with both the county and whole Hungary and in women compared with men (p=0.02). There was no change in alcohol-related deaths or rate of unemployment in the intervention region during the whole study period (1996-2000 vs 2001 and 2005). The findings support earlier studies showing that continuous GP education on diagnosis and treatment of depression is an effective method of suicide prevention. The high importance of alcoholism in local suicides was unanticipated and not addressed, suggesting that optimal suicide prevention plans must also consider major local risk factors.

The European Alliance Against Depression (EAAD) is a 4-level, community-based intervention programme to improve the care of depressed patients and prevent suicidality in Europe (1). Effects of this intervention concept have been evaluated in the intervention regions concerning the number of suicidal acts as primary outcome (2) but also concerning several other aspects, such as changes in attitudes towards depression in the general population, prescription rates of antidepressants or media coverage. Results provide first evidence that this intervention concept is highly cost-efficient. The European Commission listed EAAD as a ‘best practice’ model in its Green Paper (European Commission 2005).

This presentation will give a brief overview of comparison of DSMIV and ICD10 classification systems for mental and behavioural disorders. It will summarise what work was carried out in developing these systems in terms of their cross-cultural validity and reliability. It will also review the subsequent research into the validity and reliability of these systems. Finally some of the relevant approaches and methods would be discussed in relation to the issue of cross-cultural validity and reliability of diagnostic classification

Psychiatric and psychological testing are used extensively in both clinical and research contexts, with the goal of providing an objective indication of the construct being measured. At the same time, it has long been recognized that there is no such thing as a culture free or even fair test, to the extent that cultural bias-the constant and systematic statistical error due not to chance but to ethnic group membership-can seriously undermine the validity of a psychological or psychiatric test. The very construct being measured may not have a culturally compatible equivalent, or, relatedly, the behavior sampled in a given item or combination of items may not be associated with the construct in question in the same way across all cultures. In addition the means by which the behavior is sampled-the instrument construction, the sorts of questions or their structure, for example-can vary in familiarity across cultures. Finally, the individual items themselves may be poorly or ambiguously translated, may be predicated on specific cutlural norms, or, indeed, the meaning of the item can vary cross-culturally. Finally, sampling bias pertains to the representativeness of the sample, however, this is all the more complex given that constructs such as “race”, “ethnic group” and so forth are often poorly defined and ambiguous, and thus who is and who is not included in a given group may further undermine the validity of the test. Despite these difficulties, concrete steps can be taken to increase the cultural validity of the test used.

For a long time it was assumed that depressive disorders were a classic western problem specific to industrial states. However, the World Bank discovered in a study as early as 1993 that depression in Third World countries was already fifth on the list of illnesses which comprise the largest contribution to the Global Burden of Disease. Affective and behavioural disorders as well as somatic complaints represent the three central categories of symptoms in depression. In western cultures an affective disorder is seen as the main characteristic of a depression, whereas in other cultures different symptoms can be in the foreground. The increase in supraregional communication and cooperation as well as the worldwide increase in immigrant populations demand that cultural aspects are considered in the diagnosis and treatment of depression. Physicians need to consider the cultural background of their patients in order to achieve an optimal therapy. If the sociocultural aspects, which cannot always be fully appreciated, of a culturally sensitive diagnosis are not taken into consideration, this can lead to an artificial prevalence of the disorder by making false diagnoses. In order to minimize these mistakes, the guideline for judging cultural influencing factors should be used to complete the diagnosis.

Not only the development of culturally adequate therapy concepts and institutions, but also the expansion of knowledge about the psychopathology and epidemiolgy of psychic disorders, e. g. of depression in immigrant groups and the examination of their use of treatment facilities, are the goals of cross-cultural psychiatry and psychotherapy.

In an ongoing attempt to improve efficacy of electroconvulsive therapy (ECT) while minimizing side-effects, both different electrode placements and stimulus parameters have been studied. It has been shown that the traditional bitemporal electrode placement and modern techniques such as bifrontal and unilateral ECT are efficacious, depending on the stimulus used. Modern ECT-devices deliver a square wave brief pulse stimulus. An unresolved issue in the use of brief pulse stimulation concerns the optimal pulse width. It has been suggested that the use of a stimulus with an ultra brief (UB) pulse width, i.e. 0.3 ms, is substantially more efficient in seizure induction, thus needing less energy, and producing less cognitive side-effects than standard pulse width (i.e. 0.5-2 ms) stimulation. There has been a concern, however, of lower antidepressant efficacy of UB ECT, with patients needing additional treatment sessions. Moreover, it has been suggested that the diminished antidepressive efficacy is encountered solely with the combination of an ultra-brief pulse width and bilateral electrode placement, as compared to unilateral UB ECT or standard pulse ECT. In a randomized trial, the antidepressive efficacy and cognitive side-effects of bifrontal and right unilateral UB ECT were compared. It was shown that, using an ultra-brief pulse width, BF ECT is as efficacious as UL ECT, although patients receiving UL ECT achieved response/remission-criteria after a smaller number of treatments. In both treatment conditions there was an improvement of cognitive function, both during and after the treatment course.

The efficacy of electroconvulsive therapy (ECT) is widely recognized and indications are well defined for acute treatments. Surprisingly, the use of continuation and maintenance ECT (M-ECT) is uncommon after acute remission. This is partly because of the scarcity of scientific evidence. Indications are poorly defined and the practice is based on case reports and small open studies. Recent data suggest that M-ECT is a viable treatment option in severe affective and psychotic illnesses, especially in recurring, drug-resistant or medically compromised patients who suffer toxic effects with psychotropics.

Studies regarding the duration and frequency of treatment sessions are laking. The time interval between sessions and duration of treatment vary according to clinical requirements, and should be individualized. The length of treatment and deciding when to stop it are still uncertain. Controversial data about the relation between the frequency of sessions and diagnostic is found. An inverse relation between good prognostic factors for each patient and the frequency of M-ECT was described. During continuation and maintenance ECT, seizure threshold increases until a plateau not being clear when the plateau is reached and if it depends on other treatment variables.

The risk of cognitive dysfunction following M-ECT is one major concern. A transient memory and attention dysfunction are described after acute ECT. Recent studies seem to suggest that M-ECT is cognitively safe.

Electroconvulsive therapy (ECT) is a very effective treatment in severe psychiatric disorders. One of the main drawbacks of ECT is the high and early relapse rate in the absence of post- ECT treatment. After a successful ECT- course, pre- ECT pharmacotherapy is often continued. There is, however, no evidence that proves this strategy effective. The research on post- ECT treatments is limited, but promising. The available studies show that relapse rates can be decreased from more than 80% to 40% or less using either imipramine (1), the combination of lithium and nortriptyline (2) or continuation- ECT (3). The question whether or not starting antidepressants during the course of ECT ca further decrease relapse rates remains unanswered. Preliminary data show that starting antidepressants medication during the ECT course has no impact on post- ECT relapse. There is an urgent need for further research on treatment strategies to decrease the unacceptable high relapse rates after recovery from ECT.

During recent years magnetic (MRI) studies have pointed to a reduction in hippocampal volume in patients with severe depression. Volumetric changes reflect the actual number of days that individuals have been depressed (1). These findings have heightened interest in studying hippocampal structure and function in experimental animals, especially during and after electroconvulsive seizures -the most powerful of antidepressant therapies (2). Both before and after 2000, with the earliest report on hippocampal neurogenesis following seizures, findings of gliogenesis and synaptogenesis have been reported (3). During the last decade further studies of neurotropic factors have supported ideas of the role of neuroplasticity related to ECT in humans (4). All antidepressant medications, but not antipsychotics, have a similar, but weaker effect on hippocampal neurogenesis. We hypothesize that an induction of neurotropic factors leading to hippocampal neurogenesis may play a major role for the action of ECT (5).

Cognitive deficits are increasingly recognized as key features of schizophrenia, important determinants of poor psychosocial outcome and targets for treatment strategies. The huge literature on the topic made it clear that cognitive impairment is present in the majority of subjects with schizophrenia, is not an epiphenomenon of symptoms, is a risk factor for psychotic disorders and seems to contribute to poor functional outcome more than symptoms. However, relationships of cognitive impairment with symptoms, drug treatment and duration of untreated psychosis remain controversial and studies involving large cohorts of first episode schizophrenia patients are highly needed to address these topics adequately. The European First Episode Schizophrenia Trial collected demographic, clinical, psychosocial and cognitive baseline data in 498 first episode patients with schizophrenia, schizophreniform or schizoaffective disorder, with minimal or no prior exposure to antipsychotics, and in 220 healthy subjects, comparable with patients for age, sex, race and education level of parents. Z scores of the examined cognitive abilities (number of standard deviations below the comparison group means) ranged from -0.88 to -1.73. No association was found between the duration of untreated psychosis and cognitive impairment. Psychopathological dimensions were weakly correlated with cognitive impairment both at baseline evaluation and after six months of treatment.

According to EUFEST findings, cognitive impairment in patients with first-episode schizophrenia is moderate/severe, has no association with the duration of untreated psychosis, involves several domains of cognition, and is largely independent from psychopathology.

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.