The treatment of patients suffering from borderline personality disorder (BPD) in combination with substance addiction requires an integrative therapeutic approach. Dialectical behavioural therapy (DBT) is well evaluated and effective for the psychotherapeutic treatment of patients with BPD. We have extended classic DBT and integrated modern elements for the treatment of substance dependency into a standardized inpatient concept. This talk will give a short overview of the efficiency of psychotherapeutical methods for the treatment of the combination of both disorders. Finally we will present a psychotherapeutic concept for patients suffering from BPS and substance addiction following DBT in line with Marsha Linehans approach.

Alcohol dependence is one of the most fatal mental diseases amongst men in western industrialized nations and is the major risk factor for the development of more than 60 chronic illnesses. With no further intervention, relapse rates in detoxified alcoholics are high and usually exceed 85% of all detoxified patients. It has been suggested that stress and exposure to priming doses of alcohol and to alcohol-associated stimuli (cues) contribute to the relapse risk after detoxification.

In the last decades there has been substantial progress in scientific research of the neurobiological principles of alcohol-related disorders. Recent studies using multi modal imaging techniques like functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) observed dysfunctions of the mesolimbic dopaminergic brain reward system (ventral striatum including the nucleus accumbens): Functional brain activation is increased during the processing of alcohol-associated cues and decreased during the confrontation with other non-alcoholic reward-indicating stimuli. This alcohol-associated “hijacking” of the reward system is associated with craving and the prospective relapse risk.

Moreover, the reward-associated learning seems to be disturbed in alcohol-dependent patients, so that addicted persons have problems to integrate informations about positive and negative consequences of their actions and to adapt their behavior accordingly. Personality traits like impulsiveness seem to be relevant in this context as well.

These findings about the different neurobiological mechanisms of addiction and relapse raise hope for new psychotherapeutic and pharmacological treatment approaches of alcohol dependence that is adapted to individual relapse mechanisms and needs.

In the last few years aripiprazole and pregabalin showed to be promising medication in alcohol use disorders, due to their action on the mesolimbic dopaminergic reward pathway (aripiprazole) and as a presynaptic modulator of the excessive release, in hyperexcited neurons, of excitatory neurotransmitters (pregabalin).

In a recent trial run by our group (Martinotti et al., 2009a) aripiprazole at low dosage (5-10 mg) was compared with naltrexone, one of the approved drugs used in alcohol relapse prevention. The study showed that the number of subjects remained alcohol free for the entire study period and the number of subjects relapsed was not significantly different in the two groups, whereas the survival function showed that patients treated with aripiprazole remained abstinent from any alcohol amount for a longer time with respect to those treated with naltrexone. In another randomized, double blind, placebo controlled study (Anton, 2008), there was no difference between aripiprazole (at high dosage, up to 30 mg) and placebo on the primary end point possibly because of dose-related attrition. In a recent trial the combination of aripiprazole and topiramate has proposed with positve results (Kenna, 2009).

As to pregabalin, a recent clinical trial of comparison versus naltrexone (Martinotti et al., 2009b) showed, in fevour of pegabalin, an improvement of specific symptoms in the areas of anxiety, hostility and psychoticism. Pregabalin also resulted in better outcome in patients reporting a comorbid psychiatric disorder. In another study (Martinotti 2009c) pregabalin was also efficacious in the treatment of withdrawal symptoms.

Attention Deficit and Hyperactivity Disorder (ADHD) is a common disorder, estimated as afflicting 4-6% of the adult population. Latent Inhibition (LI) is a robust phenomenon that is demonstrated when a previously inconsequential stimulus is less effective in a new learning situation than a novel stimulus. Attentional theories of LI state that unattended stimulus preexposures reduce stimulus salience and subsequent associability. A relationship between LI and the dopaminergic system is suggested since dopamine-agonists weaken the LI effect, and dopamine antagonists strengthen it. The effects of medication for ADHD on LI are of interest, since dopamine agonists should weaken LI, but the improvement in attention should potentiate it. To date, only two studies, both with children, have examined the relationship between ADHD and LI.

In the present study, we will compare the LI effect in 100 adults with ADHD, with and without medication, as well as compare them to a matched healthy control group. In addition, all the participants will be administered the Schizotypal Personality Questionnaire, State & Trait Anxiety Inventory, Beck Depression Inventory, the Baron-Cohen Autistic Questionnaire, and the Similarities sub-test from WAIS-R. The LI procedure will be administered to both groups twice with two equivalent versions of the procedure (order counterbalanced). The ADHD patients will take part in the first version of the procedure without medication and in the second version 1.5 hours after taking the medication; the controls will have the same time interval between versions, but without the medication administration. Results will be presented at the meeting.

ADHD in adults is frequently associated with unstable or irritable moods reflecting difficulties with emotion regulation. Effect sizes of drug treatments on symptoms that reflect difficulties with emotion regulation, are similar to those on core ADHD symptoms, with co-variation of around 0.8 between the two types of symptoms during the treatment response. We therefore set out to investigate whether variability in mood results from the same aetiological processes that lead to variability in behaviour and cognitive performance in ADHD. Using real-time self-monitoring of emotional states and ADHD symptoms every two hours for 3-5 days, we characterised the mood changes in ADHD. Variability in both mood and ADHD symptoms (measured as the standard deviation) were significantly correlated with self-rated ADHD symptoms of inattention and hyperactivity. Subsequent analyses will link the observed symptom changes to cognitive-electrophysiological measures which are reliable indicators of core processes that underlie cognitive deficits associated with ADHD. We previously showed that a familial reaction time (mean and variability) factor explains 70% and commission and omission errors 20%, of the familial effects on ADHD. This finding concurs with the developmental model of Halperin which postulates that ADHD is linked to an early-appearing and enduring subcortical dysfunction, reflected in reaction time variability, while persistence/desistence of ADHD is dependent on maturational changes in executive control during adolescence reflected in commission and omission errors. We propose that at a behavioural level the subcortical deficit leads to dysregulation of a number of processes, including attentional, impulsive and emotional control.

Although a good selection of antidepressants is available nowadays, the pharmacotherapy of depression still represents a challenge for psychiatrists worldwide. International guidelines and textbooks advise monotherapy with a selective serotonin reuptake inhibitor as treatment of first choice in depression. However, still one third of the depressive patients do not respond to the first antidepressant treatment implicated. Furthermore, approximately 20%-30% of them prove to be treatment resistant for two different antidepressants with different mechanisms of action. For these treatment resistant patients (TRD) augmentation and combination strategies are advised.

According to AMSP surveillance data (European international pharmacovigilance program, named AMSP: Arzneimittelsicherheit für Psychiatrie) from 2007 (obtained in 54 psychiatric institutions), 1829 depressive inpatients were recorded on the two reference days. 1674 inpatients received an antidepressant medication and among them 875 were concomitantly treated with an antipsychotic medication. Although the majority of inpatients were treated with one antidepressant (72%); 28% received two or more antidepressants. The most common combination of antidepressants was Venlafaxine with Mirtazapine (5,6%) being followed from Citalopram with Mirtazapine (2,7%). Interestingly similar findings have been recently reported from an US database.

Polypharmacy, although needed in treatment resistant cases, has a greater risk for adverse drug reactions and most augmentation strategies have not been tested regarding their long term safety. A combination of antidepressants seems only to be useful if they engage different mechanisms of action. Further clinical studies addressing combination strategies are needed in order to evaluate their benefit against monotherapy.

Numerous studies in different countries throughout the world have shown that 30-60% of schizophrenia patients, when treated with antipsychotic drugs, receive two or more antipsychotics simultaneously.

Reasons for antipsychotic polypharmacy are not often well described, they might be insufficient efficacy (was the maximal tolerable dosage given?), tolerability problems (severe or transient, treatable by other drugs?) or an “unfinished switching procedure”: Cross-tapering from antipsychotic A to antipsychotic B is stopped halfway at a reduced dosage of A and a sub-therapeutic dosage of B, because this combination seems to work. However, it is not known whether B alone would be better.

Most often, antipsychotics with different receptor binding and side effect profiles are combined, although scientific evidence supporting the common practice is rather limited. Most controlled studies did not reveal an advantage of the combination versus monotherapy. Particularly for clozapine, where anecdotal reports and open trials indicated the usefulness of a combination with amisulpride, aripiprazole or risperidone, double-blind trials were mostly negative. However, in individual patients, hard or impossible to define, well-reflected combinations might be justified.

The few controlled studies and the resulting suggestions for everyday practice are presented to answer the following questions: When (after how many weeks of monotherapy) is a combination justified? Are there any criteria to decide switching the antipsychotic versus combining antipsychotics? Which combination(s) of antipsychotics might be useful?

Alcohol stimulates dopamine release and chronic intake is associated with neuroadaptation in the brain reward system. Previous studies described

1. 1) increased brain activation following the presentation of alcohol-associated stimuli, which was directly correlated with dopamine D2 receptor reductions in the ventral striatum, and

2. 2) a decreased response to stimuli that predict non-alcohol (e.g. monetary) rewards.

This alteration of brain responses to alcohol-associated versus non-alcohol cues may result from altered reward-associated learning in alcoholism. Indeed, alcohol-dependent patients displayed a decreased learning rate and performeance in a probabilistic reversal task. A brain imaging study revealed that the decreased learning rate was associated with impaired prefrontal-striatal connectivity during reward-dependent reversal learning. These results point to deficits in reward-associated learning, which contribute to alcohol craving. Since such reward-associated learning deficits can interfere with learning of new, non-alcohol associated behavior, cognitive behavior therapy may profit from taking such learning speed impairments into account.

Stress can be defined as the subject's response - both emotionally and physically - to stimuli (stressors) from the environment. Stressors are not necessarily negative. They are, when they exceed the subject's ability to cope with them in a physiological way. This level of stress is indicated as pathological stress.

Addiction and pathological stress are strongly interrelated on several levels. Animal studies have shown that the pathological stress during the development may be the most important factor that brings the vulnerability for addiction to expression. Stress during pregnancy may have a decisive influence on brain development and the subject's ability to cope with stress during later life. Patients with post traumatic stress disorder have an increase risk for the development of substance use disorders.

The brain reward system is a major target for the central and peripheral stress system. The catecholamines that mediate the stress response play an important role in the development of addiction. Addictive drugs such as stimulantia act as stressors by activating stress hormons. The process of craving is strongly associated with activated stress systems. Therefore, the adequate treatment of substance use disorders requires interventions that reduce pathological stress for the patient, either by diminishing environmental stress or by increasing the ability to cope with stress.

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.

Recent theories of addictive behaviors suggest that neurocognitive mechanisms, such as attentional processing, cognitive control, and reward processing play a role in the maintenance or development of addiction. Several studies will be discussed demonstrating the role of these neurocognitive mechanisms in addiction. Moreover, clinical issues such as the feasibility to use neurocognitive measures as predictor of treatment success and relapse will be discussed.

Findings from family, adoption and twin studies suggest that vulnerability to bipolar disorder follows a polygenic mode of inheritance with multiple genes, each of small effect, combining and contributing to the risk and the clinical expression of the disorder. The endophenotype approach has been proposed as a way to identify susceptibility genes in disorders with complex underpinnings. Endophenotypes are supposed to bridge the genotype to the clinical syndrome and to have a simpler genetic architecture than clinical diagnoses.

Our first aim is to confirm if cognitive measures are good potential endophenotypes. Therefore, we will examine the reliability and frequency of cognitive impairments in individuals with bipolar disorder and their biological relatives. The study of healthy relatives avoids confounding factors and should help identify potential endophenotypes.

We will also look for evidence linking particular cognitive impairments to specific genes on one hand and to the risk for bipolar disorder, on the other.

A literature review of articles published in 2008-2009 suggests that the genetic architecture of cognitive endophenotypes is more complex than initially predicted. In many published studies, no genetic association was found between cognitive deficits in bipolar disorder. We will try to understand the reasons and consequences of those disappointing results by analysing some methodological limitations, in particular regarding the statistical treatment of confounding factors.

We will also discuss theoretical considerations pointing out the fact that we may have been expecting too much and oversimplifying when supporting the idea that cognition is a less complex entity than bipolar disorder.