Over the last two decades, much progress in the prevention and early detection of first-episode psychosis has been achieved. And currently, the inclusion of a psychosis risk syndrome in DSM-V is discussed. But while differences between early-onset and adult-onset psychoses have frequently been pointed out, in the early detection of psychoses, developmental aspects are rarely considered, and results that have been derived from predominately adult samples, i.e., at-risk criteria are generally just transferred to children and adolescents. Emerging evidence from child and adolescent general population, birth cohort and clinical samples, however, question this unrestricted transferability of these results to younger age groups. This presentation will therefore outline the special aspects in the early detection of psychosis that should be considered in children and adolescents. The presentation will cover (i) evidence for the need of a validation of at-risk criteria in children and adolescents and (ii) evidence for a longer DUP in adolescent onset compared to adult onset psychosis and its clinical implications.

As cosmopoets we create our world - but we do not create our world independently from our surroundings. What we are doing is not a poetry work in the sense of arbitrary inventions, but an attempt to transfer extensively and intensively psychical processes into communicable events. Patients suffering from delusions are also cosmopoets, they also create their world. It is a more or less understandable world, it is a world which is more or less similar to the world of the non-deluded, and it is a world which on the one hand terrorizes the patient but on the other hand attracts the patient by its sublime beauty. In this context W.Janzarik spoke from an ‘enemy/partnership’ of patients with delusions of persecution. The deluded world is a non-contingent terrifying but also in any case at least to some extent a beautiful and attractive world. Thrown in the risky and ugly world of mental disorders characterized by ambiguity and precariousness, patients are looking for islands of safety and sublime beauty; such islands may represent delusional convictions. As meanings of the disorder and the resulting ambivalence between attractiveness and suffering represent important disorder maintaining factors, knowledge about them provide the indispensable basis for effective treatment strategies (in particular psychotherapy) of delusional syndromes.

The disposition and maintenance of alcohol addiction has been associated with dysfunctional learning, particularly with increased salience attribution to alcohol-associated stimuli and Pavlovian-to-instrumental transfer, which establishes an effect of alcohol-associated cues on operant alcohol seeking and consumption. Previous imaging studies showed that dopamine dysfunction in the ventral striatum is associated with increased brain activation elicited by alcohol-associated cues in brain areas associated with attention. Furthermore, brain activation elicited by non-alcohol (e.g. monetary) reward was decreased in detoxified alcohol-dependent patients. Neuroadaptation following addiction therefore seems to augment neuronal responses to well-established, drug-associated stimuli while interfering with the learning of new, reward-seeking behaviour patterns. Using functional magnetic resonance imaging (fMRI) we showed that in detoxified alcoholics, reward-dependent reversal learning is impaired compared to healthy controls, and that this impairment correlates with reduced functional connectivity between the ventral striatum and the dorsolateral prefrontal cortex. Furthermore, we will present first data from a multimodal imaging study combining fMRI and positron-emission-tomography (PET) to measure the association between dopamine synthesis reduction and impaired functional brain activation during reversal learning in detoxified alcohol-dependent patients compared with healthy controls.

The objective and aim of this case-control study was to replicate an earlier finding of a significant relationship between prenatal exposure to famine and substance use disorders later in life and to examine the sex ratio at birth in the study populations. We compared the number of addicted individuals in a population prenatally exposed to a severe hunger period with matched individuals in a non-exposed population. The gender distribution of patients with substance use disorders and healthy controls were calculated and all data were quantified as odds ratios. The findings confirm that prenatal exposure to famine is a risk factor to develop substance use disorder later in life. Men are at risk in particular by exposure to famine during the first trimester, women by exposure during the third trimester. The sex ratio men to women at birth was 3 : 1 in the patient groups compared to 1:1 in the healthy controls. The results were discussed in the light of the possible disastrious future consequences for the hunger regions in our world.

Treatment of alcoholism is successful but effect sizes are in the low to moderate range. Heterogeneity of patients entering treatment trials could be one potential explanation. Several attempts have been made to subgroup patient for specific treatment approaches (“matching”). A new approach includes biological data such as pharmacogenetics and neuroimaging for treatment-patient matching.

In the PREDICT study (Mann et al., 2009) 426 alcohol-dependent patients were randomized either to placebo, naltrexone or acamprosate. Design and questionnaires were similar to the US COMBINE Study (Anton et al., 2006). Extending Project MATCH and the COMBINE Study we used biological and psychopathological characteristics of patients in order to test their response to naltrexone or acamprosate. In pharmacogenetics 14 SNPs from an own genome-wide association and follow-up study (Treutlein et al., 2009) were tested for differential treatment outcome. Indeed, one SNP showed a significant gene dose effect under acamprosate. Using neuroimaging we confirmed that an increase in brain activity in the ventral striatum is related to time to relapse. We also found support for our hypothesis concerning the rewarding characteristics of alcohol in a certain subgroup of patients. Here f-MRI BOLD response in the ventral striatum predicted a positive naltrexone response. Furthermore, new opioid receptors in alcoholics and normal controls were assessed using carfentanil PET.

Analyses are still underway.

In conclusion the treatment of alcoholism is moving towards a personalised approach. This holds the potential for a significant increase in effect sizes of our treatment trials and thus for better treatment options for our patients.

Major problems in treating patients suffering from addictions derive from the fact that the diagnostic category dependence syndrome covers a highly inhomogeneous patient group. Therefore uniform therapeutic approaches inflexibly following treatment guidelines have not fulfilled prognostic expectations. This was the starting point for developing a new modular resource-oriented treatment program in the Anton Proksch Institute Vienna.

Changing paradigms in the treatment of addiction, the Orpheus Programme offers a host of different modules designed to help patients to discover their own aims, objectives, values, and resources. The main task of the Orpheus modules is an increasing autonomous and joyful life. Abstinence represents no longer the only final goal of therapy, but is an important step to offer space and possibilities for the patients’ new life. When life becomes once again beautiful and filled with joy and meaning, addictive substances lose their seductive power: The more beautiful and attractive the patient's life, the less the drugs attractiveness. As illustrated by Orpheus, who defeated the sirens (as a symbol for addictive agents) by making the better, louder, and more attractive music, it becomes the patients’ main task to make a better “music of life”; the Orpheus modules are not training programs telling the patients how the better life looks like (as in former moral therapy); they intend to provide places, spaces and atmospheres encouraging and promoting the patients to make possible the possible.

Suicide is one of the leading causes of death worldwide, mortality from suicide being approximately 2%. Attempted suicide appears to be a major risk factor for suicide completion. Anger, aggression and impulsivity are personality traits associated with suicide attempt. We analysed anger, impulsivity and temperament/character scales as predictors of aggression and self-aggression in suicide attempters and compared this to anger- and aggression-related traits between impulsive and premeditated suicide attempts as well as between violent and non-violent suicide methods.

The State-Trait Anger Expression Inventory (STAXI), the Questionnaire for Measuring Factors of Aggression (FAF), and the Temperament and Character Inventory (TCI) were assessed.

Higher aggression scores, as measured by FAF, were predicted by being male, meeting criteria for borderline personality disorder and having higher angry temperament scores as assessed by STAXI. TCI dimensions associated with self-aggression were high harm avoidance, high impulsivity and low selfdirectedness.

State anger, inwardly directed anger and inhibition of aggression were also predictors of self-aggression.

In conclusion, impulsivity and harm avoidance have emerged as temperament dimensions independently associated with self-aggressive tendencies in personality. Such interactions could explain the correlation between temperament and suicidality but further research is needed. Anger and selfdirectedness appear to have some effects on suicide attempt.

In the majority of countries, suicide rates increase progressively with age, the highest suicide rates occurring in men above 75 years. Given the progressive aging of population in industrialized countries, old age suicide is one of the greatest public health problems. Although suicide attempt, and particularly completed suicide are relatively rare events in the community, they are very common among older psychiatric patients who contact different levels of health care system, particularly some weeks or months before the suicide event. More than one-third of suicide victims have at least one prior suicide attempt, which significantly increases the risk of future attempts and completed suicide. However, the rate of attempted to completed suicide decreases with increasing age indicating that the lethality of suicidal behaviour is much higher in older persons. Suicide is a very complex, multifactorial human behaviour with several biological and psychosocial components, associated with a number of

• 1/ Psychiatric (e.g., major mental disorders),

• 2/ Psycho-social (e.g., adverse life situations), and

• 3/ Demographic (e.g., male gender) suicide risk factors.

Although depressive disorders and substance-use disorders are the two most common diagnoses among suicide victims, depression is more common and substance abuse is less prevalent in later-life suicide victims. Beside depression and prior suicide attempt, social isolation, loss of relatives/friends and physical illnesses are the most important risk factors for suicide in this age-range. Available studies suggest that appropriate acute and long-term treatment of depression in combination with psychosocial interventions reduces suicide mortality even in this very high-risk population.

Suicide is a typical phenomenon of the elderly and mainly among men. Besides the importance of suicide in terms of public health there is fewer interest to prevent suicide in old age. This can be explained by stigma, poor evaluation of the dimension of the problem and lack of politic will.

Suicide prevention and the care of survivors of suicide depend on the mental health network of care. Interventions to reduce suicide can be made at individual level and at level of the development of policies and strategies. The detection of the persons at risk of suicide and the management of the suicide attempt are two main strategies to prevent suicide. Both received recently an important support from WHO with its publication mhGAP Intervention Guide which was conceived to be used in non-specialized health-care settings by health-care providers working at first- and second-level facilities. It includes guidance on evidence-based interventions to make the diagnosis and manage a number of priority conditions, including suicide.

Our review of the literature pointed to the necessity to develop additional research to determine:

• • the role of somatic disorders as precipitant factor;

• • the role on suicide of the pre-morbid personality, cognitive functioning, social support and recent and chronic stressing events;

• • the participation of normal and pathological ageing on the expression of the suicide behavior;

• • the biological markers of suicide in old age;

• • the potential impact on suicide rates of educational interventions for the general public and for caregivers.

Due to the advancement of antidepressant medication, more patients receive treatment in everyday practice, and response/remission is not achieved in the majority of the patients. Several attempts to validate the definition of treatment resistance have been undertaken and the criteria usually encompased to treatment sequences are that two different classes of antidepressants given in a sufficient dosage for a sufficient time have to be administered. Clinically, it is evident that this defintion does not include the treatment refractory patients which could be defined as not responding to numerus trials including electroconvulsive therapy. The goal to improve treatment through the use of predicitve biomarkers has not as yet been obtained and will be the challenge for the future. The clinical variables predicting treatment resistance include comorbid anxiety disorders as well as melancholic features. 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 few controlled trials which have been undertaken to challenge this notion revealed that staying on the same antidepressant mechanism of action for a longer time is more beneficial. In previous times, the conjunctive use of agents such as lithium or thyroid augmentation have been proposed, however the new data achieved with atypical antipsychotics demonstrate a more rapid improvement. Techniques such as brain stimulation or vagus nerve stimulation have also shown promising early results. Treatment resistance continues to be a major barrier achieving remission in patients with major depressive disorder and a thorough re-evaluation of the condition and its treatment is needed.

Borderline Personality Disorder (BPD) is the most common personality disorder which afflicts an estimated 2% of the general population, 10% of individuals seen in outpatient mental health clinics and 15–20% of psychiatric inpatients. Patients with BPD present a large variety of symptoms, high rates of comorbid conditions, substantial use of healthcare resources and constitute a significant social and economic burden. This disorder often is resistant to psychotherapeutic and pharmacological interventions. These therapeutic difficulties lead to common psychotropic drug prescription for BPD patients in clinical practice and, according to our results, in Spain virtually all patients with BPD are prescribed drug treatment and polypharmacy is common. It is possible that polypharmacy may also be a reflection of the severe difficulties encountered during the management of these patients. Another explanation could be the psychiatrist's ‘desperation’ due to the patients’ deterioration or lack of improvement, so that polypharmacy may be used to compensate the lack of funded and sustained psychotherapy programmes which would be required to successfully treat these patients in the long term.

Antidepressant-resistant major depression (AD-RD) is a great challenge for the treating clinician. The most widely accepted definition of AD-RD refers that the depressed patient does not show a clinically significant response after at least two adequate trials of different classes of antidepressants. In spite of the fact that there are several causes of AD-RD in general, there is increasing evidence that one of the most common sources of it is the unrecognized bipolar nature of the “unipolar” major depressive episode, when the patients receive antidepressant monotherapy - unprotected by mood stabilizers/atypical antipsychotics. While it is well documented that the optimal clinical response to antidepressants is much rare in bipolar I and II than in unipolar major depression, only the most recent clinical studies have focused on the boundaries between treatment-resistant unipolar major depressive disorder and bipolar disorder. The most widely noted conclusion of the prior studies on AD-RD is that if noncompliance, hypothyreosis, use of “depressiogenic” drugs and pharmacokinetic causes etc, can be excluded, antidepressant-resistance reflects the heterogeneity of depressive disorders and different subgroups of depressed patients respond (or do not respond) to different drugs. However, current psychopathological research on the complex relationship between unipolar depression and bipolar disorders show that the most common source of antidepressant-resistance in DSM-IV diagnosed unipolar major depression is the result of the subthreshold or unrecognized bipolar nature of the depressive episode and antidepressant-induced (hypo)manic switches, antidepressant-resistance and “suicide-inducing” potential of antidepressants seem to be related to the underlying bipolarity of the major depressive episode.

The treatment of bipolar disorder is complex and the overall results of monotherapy are not satisfactory. Combination and add-on studies suggest that in acutely manic patients who are partial responders to lithium, valproate or carbamazepine, a good strategy would be to add haloperidol, risperidone, olanzapine, quetiapine or aripiprazole. Adding oxcarbazepine to lithium is also a choice. For patients with refractory bipolar depression the only positive data concern adding lamotrigine to lithium. During the maintenance phase the combination of quetiapine plus mood stabilizer is superior to monotherapy in the prevention of manic and depressive recurrences in either manic, depressive, or mixed index episode over a period of 2-years. These combination studies appear to be the first to report prevention on both depression and mania regardless of the type of index episode.

Discontinuation studies suggest that patients stabilized on combination therapy (olanzapine plus lithium/valproate or mood stabilizer plus ziprasidone) do worse when the antipsychotic is discontinued. The recently published BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy. Add on studies suggest that at least some strategies could be useful in patients with inadequate response to monotherapy. Overall, although there is no compelling data that combination treatment does better than monotherapy, the data suggest that those patients stabilized on combination treatment might do worse if shifted from combination, and patients refractory to monotherapy could benefit with add on treatment with olanzapine, valproate, an antidepressant or lamotrigine, depending on the index acute phase.

In the last decade new psychotropic agents have been licensed for the treatment of bipolar depression and mania. We wanted to evaluate if this led to changes in psychotropic prescriptions for bipolar-inpatients over the time-period from 2000 to 2007.

On two reference-days per hospital and per year, the following data are recorded for all patients on the wards under AMSP surveillance: all drugs applied on that day with the daily dosage for psychotropic drugs, ICD-diagnosis, age, and sex. In our analysis we evaluated data from 2000 (N = 210) and 2007 (N = 383).

We found a decrease of psychotropic monotherapy from 13.8% in 2000 to 4.7% in 2007. The percentage of inpatients receiving 5 or more psychotropics increased significantly from 10.95% in 2000 to 22.19% in 2007 (chi2: 11.199, df:1, p < 0.001). Furthermore we found a significant decrease of prescriptions for one or two psychotropics (38.89% to 16.38%) in bipolar-depressed-inpatients, but not in bipolar-hypo/manic-inpatients (chi2: 17.929, df:1, p < 0.001). The most frequently prescribed psychotropic in bipolar depression in 2000 was lithium-carbonate (median-dosage: 675 mg/day) and in 2007 valproic-acid (median-dosage: 1000 mg/day). In bipolar hypo-/mania the most commonly prescribed psychotropic in 2000 was again lithium-carbonate (median-dosage: 675 mg/day) and in 2007 valproic-acid (median-dosage: 1500 mg/day). The most frequently prescribed combinations were those of cbamazepine with lithium-carbonate (4.76%) in 2000 and of valproic-acid with quetiapine (8.88%) in 2007.

In our bipolar sample polypharmacy increased over the years. Further studies evaluating the safety of this polypharmacy, as well as putative effects of psychotropic combination-treatment in bipolar disorder are needed.

Bipolar disorders are characterized by many different forms and episodes, which require specific pharmacological treatments. For the treatment or prevention of manic episodes, lithium salts, some atypical antipsychotic drugs and some anticonvulsants were introduced. Antidepressant drugs but also a very limited number of anticonvulsants (lamotrigine) and antipsychotic drugs (quetiapine) are recommended for the treatment of depressive episodes. In addition, benzodiazepines or related compounds may be useful as comedications for sleep problems or for their sedative properties. Polypharmacy is therefore rather common, also in case of insufficient response to a single drug, when the administration of a combination of active agents appears to be promising.

Most of these drugs are substrates of cytochrome P-450, and many of them are also either inducers or inhibitors of some of its isozymes. Interactions may also occur at the level of conjugating enzymes. Increasingly, knowledge about the underlying mechanisms of drug transport from intestine to the blood, and from the blood to the brain helps to predict interactions at this level. Indeed, many drugs are transported by P-glycoprotein, and inhibitors and inducers, respectively, may modify the transport of psychotropic drugs. Therefore, it is recommended to consider the interaction profile of each drug before initiating a combined treatment and adapt medication. Sometimes, despite it is known that interactions may occur with pharmacodynamic consequences, some risky combined treatments may nevertheless be useful. In such situations, careful titration of the drug doses and therapeutic drug monitoring are recommended.

Chronotherapeutics (light, darkness, sleep manipulations, melatonin) offer a new synthesis of non-pharmacologic interventions designed to accelerate remission in patients with depression and bipolar disorder. Combinations of light and wake therapy achieve fast results and, by reducing residual symptoms, also minimise relapse over many months. In addition, chronotherapeutics seem to be a major facilitator of drug response, and, in combination with antidepressants, a promising method to stabilise patients over the long term. The above treatments fulfil the unmet needs for a new antidepressant drug - short latency of action, fewer residual symptoms, lack of side effects, shorter hospital stays, and less relapse, as well as WHO criteria for interventions that are effective, affordable and sustainable. Yet, despite the growing evidence for their efficacy, and more than thirty years of implementation, it is surprising how limited their use still remains. Is it an image problem (alternative medicine, too simple) or a marketing problem (not patentable, therefore not profitable)? One important factor is lack of insurance reimbursement, because of not being a listed treatment (because they do not go through official clinical trial registration at federal regulatory agencies). Perhaps it is the patients who will spearhead the transition, together with a younger generation of psychiatrists curious to find biologically active alternatives to medication.

See: the nonprofit, multilingual patients’ website www.cet.org and clinicians’ website www.chronotherapeutics.org