Addiction Research Centres and the Nurturing of Creativity
Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, Mannheim, University of Heidelberg
Karl Mann, Central Institute of Mental Health, University of Heidelberg, Heidelberg, Germany. E-mail: email@example.com
Addictive behaviour is as prevalent in Germany as in other western countries, but in contrast to some European countries and the United States, very little money was given to this research field. Change came in the early 1990s, when the German government started to launch specific grants for addiction research. The first chair in addiction research was created in 1999 (Karl Mann) at the Central Institute of Mental Health Mannheim (CIMH; University of Heidelberg). The recruitment of a pre-clinical alcohol researcher as head of the department of psychopharmacology followed (Rainer Spanagel). This ‘addiction research cluster’ collaborates with several research groups at the CIMH (such as genetics). We inaugurated a clinical trial network which now comprises up to 20 treatment centres throughout Germany. Like most authors, we found effect sizes of different treatment modalities more in the low to moderate range, perhaps because of the heterogeneity of large patient samples. Therefore, we concentrated upon the biological basis of addiction in order to define more homogeneous ‘subtypes’ of patients for a better match with existing treatments. Results concerning genetics and neuroimaging (both animal and human) are promising, and could move our field towards a more personalized treatment approach. Our funding has been extended over the years, including involvement in several large European grants. We are studying substance-related problems as well as so-called ‘behavioural addictions’. As a natural consequence of this development, we are deeply involved both in informing the general public on addiction issues as well as in counselling policy makers in Germany.
THE INGENUITY OF THE MOMENT
It took an American to profoundly change addiction research in Germany. In 1995 Fritz Henn, an internationally known researcher in the field of depression, left the United States for the University of Heidelberg to become the director of the Central Institute of Mental Health (CIMH). While he found strong research traditions in schizophrenia, major depression and bipolar disorders, other areas such as addiction were only poorly researched. Most of the 30 academic chairs within psychiatry and psychotherapy were held by researchers working on psychoses or depression. Very few were occupied by colleagues interested primarily in dementia. Based on this analysis, Fritz Henn created the first academic department and the first chair in addiction research in Germany. Following a competitive search the position was filled in 1999 (Karl Mann). Additionally a pre-clinical alcohol researcher was recruited as head of the department of psychopharmacology within the CIMH (Rainer Spanagel). Thus an academic ‘addiction research cluster’ consisting of pre-clinical and clinical addiction research and including treatment facilities took up its work in early 2000.
RESOURCES AND EXTERNAL FUNDING
The infrastructure of the newly established Department of Addictive Behaviour and Addiction Medicine has been small from the beginning. The annual budget for research and teaching of about €350 000 per year roughly equals three permanent academic positions and one medical technician. Nevertheless, this basis proved sufficient for research collaborations within the CIMH and beyond. With five departments and 12 divisions guided by leading experts in their field, the CIMH covers a wide range of research topics in mental health. The areas of psychopharmacology, neuroimaging, genetic epidemiology, adult psychiatry, child and youth psychiatry and neuropsychology has offered fruitful collaborations.
After a sharp rise in people dying from heroin overdose and related problems, the German government decided to establish a specific research programme in the addiction field as a whole. In this situation our infrastructure and the potential for collaborations proved to be an enormous asset. The call asked for grant proposals submitted by regional addiction research clusters, which were reviewed by a board of distinguished international experts. Of 16 proposals, four consortia were selected, including our Baden-Württemberg Consortium (speaker: K.M.). Together, all four consortia formed the German Addiction Research Network .
Between 2001 and 2008, about €25 million were granted to the whole network. We received €12 million, which represented exclusively research money, with no overheads included. Several lines of research have been pursued since then (http://www.bw-suchtweb.de). The main idea was to use neurobiologically defined characteristics (including genetics) of patients to form subgroups for specific treatment approaches. This step towards ‘personalized medicine’ was tested in randomized controlled trials with the alcohol-dependent participants PREDICT study (Mann et al., see below ) and with tobacco-dependent probands . Next we applied for the newly created national genome research programme [National Genome Research Network (NGFN)] (Spanagel, Heinz, later Schumann and Kiefer). In collaboration with other groups in Germany we were able to perform the first genome-wide association and follow-up study [Genome-Wide Association Studies (GWAS)] in alcoholism . Finally, our expertise in the imaging field and collaboration with a strong pre-clinical addiction research group was the key to being granted an animal magnetic resonance (MR) scanner (9.4 Tesla). It is used in addition to two human scanners (3.0 Tesla) and offers a unique potential for parallel studies in humans and animals. Within a large centre grant [‘Sonderforschungsbereich’ (Collaborative Research Centre)], one such project deals with the direct in vivo measurement of brain glutamate. The MR-spectroscopy signal detected in humans and in animals is validated through microdialysis in rats. In a second group of translational projects within the Sonderforschungsbereich, the effect of glutamate-facilitated extinction on functional magnetic resonance imaging (fMRI) cue–reactivity and addictive behaviour is studied, again linking pre-clinical and clinical research  with psycho- and pharmacotherapy of addictive behaviour . Focusing upon neuroendocrine pathways of addictive behaviour within the ‘National Priority Program on Nicotine Dependence’, our group coordinates neuroendocrine endophenotyping to clarify the role of nicotine on stress response and appetite regulation .
In addition to national programmes research funding, an increasing amount comes from the European Union. At present, we are involved in three projects: PHEPA (Primary Health Care European Project on Alcohol; Peter Anderson), AMPHORA (Alcohol Measures for Public Health Research Alliance; Antoni Gual) and IMAGEN (reinforcement-related behaviours in adolescents; Gunter Schumann).
Altogether, grants and third party-research money amounts to approximately €800 000 a year. They are available in addition to the above-mentioned basic funding provided by the institute; again, this is research money only, no overheads included. This equals wages for two senior and two junior faculty members, as well as some six and eight postdoctorates.
RESEARCH ASSUMPTIONS, GOALS AND METHODS
The ‘addicted brain’ represents a model to understand the development and maintenance of addictive behaviour and the efficacy of treatment interventions. It also adds to our understanding of brain structure and functioning in the normal individual. While research into addiction and dementia both study changes developing over time, it is only in the addicted brain where neurodegenerative processes are partially reversable under abstinent conditions. Structural imaging , MR-spectroscopy , f-MRI  and positron emission tomography (PET)  are being used by our group in alcoholism, smoking , cannabis  and heroin dependence (unpublished) studies.
Funded by the federal state of Baden-Württemberg, we established a ‘DNA-bank, addiction’ (Schumann & Mann, later Kiefer). As a consequence of the above-mentioned GWAS in humans , we also tested polymorphisms distinguishing alcohol-preferring from non-preferring rats in patient samples. Indeed, one functionally relevant single nucleotide polymorphism (SNP) associated with the neuroendocrine system (GATA4) seems to be of relevance for treatment response in humans (Kiefer et al. under review). Thus, the effects of pharmacotherapy on the neuroendocrine system suggest targets and pathways of drug action and help to define endophenotypes for individualized treatment [14,15].
Computer-assisted self-infusion of ethanol (CASE) allows the retention of more reliable blood alcohol levels in experiments with intravenous (i.v.) injection of alcohol than after oral administration. Sean O'Connor, from the University of Indiana, refined his method in collaboration with our department . It fills the gap between pre-clinical studies in medication development and large clinical trials. Apart from early-stage pharmacotherapy studies, the method may also prove valuable for functional brain imaging studies under the influence of clearly defined and reproducible blood alcohol levels.
With a large spectrum of research methodologies, it was natural to extend our interest and our research topics to other additive behaviours. A year ago we began a large project in pathological gambling and began coordinating related efforts in Germany, Austria and Switzerland.
TREATMENT SYSTEMS RESEARCH
One of the early tasks of the newly created department, with its 24 beds and 20-day clinic places, was to shape the system for treating dependent patients. In Germany, the reimbursement of treatment is divided sharply into two areas: (i) acute short-term detoxification in somatic or psychiatric hospitals of up to 5 days, paid by the health insurance companies and (ii) rehabilitation treatment (still predominantly in residential settings for 2–3 months), paid by the pension funds. Early on our work focused upon creating the ‘missing link’ between the two. We initiated and evaluated a 3-week extended motivational treatment programme for in-patients . In addition to medical detoxification it offers motivational elements, and has proved to be effective . A very recent study confirmed that patients undergoing this form of treatment were more likely to benefit than the control group, where patients were treated in the classic manner of only 4–5 days in acute withdrawal . This model is now covered by the health insurance companies as part of acute medical treatment. It has been implemented successfully throughout most parts of Germany.
We have offered in-patient psychotherapy followed by out-patient aftercare for some time. Long-term outcome over 5, 10 and 16 years showed surprising rates of success, which were relatively stable in the abstinent group and in the group of unimproved but not in the so-called group of ‘improved’ drinkers . Based on pre-clinical research, the focus of our psychotherapy research has shifted recently to the development and evaluation of cue exposure training  and to the implementation of cognitive–behavioural interventions . At present, we study the effectiveness of combined psychopharmacological treatment with D-Cycloserine and cue exposure training. In collaboration with the Laboratory of Experimental Psychology at the University of Sussex (Theodora Duka), we study experimental conditioning, extinction and the acute effects of alcohol in social drinkers to enhance our understanding of learning processes and thus to provide a basis for further improvement of behavioural therapy [19,23].
LEAD CENTRE OF THE GERMAN CLINICAL TRIALS NETWORK
Since the early 1990s, pharmacotherapy for relapse prevention in alcoholism has become a major research topic. Based upon earlier work with acamprosate , the department started further clinical trials involving different academic centres within Germany. Naltrexone , tiapride  and rimonabant  were tested initially. Later our department took the lead in studying galantamine [28,29] and neramexane (unpublished). When the US Food and Drug Administration (FDA) decided to approve injectable naltrexone in the United States  they requested another study, where abstinence of participants at study inclusion could be guaranteed. Based upon the German treatment system described above, the sponsor decided to conduct this study using the German Clinical Trials Network (including several sites in Austria). The study was completed in 2009. Several new compounds are currently being tested; reviews [31–34] and meta analyses  have been published.
OPPORTUNITIES AND THE NURTURING OF CREATIVITY
We were lucky in being offered a great opportunity for conducting addiction research—but are we really using our potential and serving the neglected field of addiction medicine well? If so, how did it happen, what were the contributing factors? Finding answers could be facilitated by considering the following specific characteristics of our work.
Working less than 100 feet from several outstanding researchers in other fields was a key criterion to establishing a successful academic centre in addiction research in Germany.
Access to patients
Combining leadership for research as well as for the treatment of patients with responsibility for an in-patient facility, a day clinic plus an extensive out-patient clinic proved to be an indispensable resource.
Bright and enthusiastic people
During the last 10 years some outstanding faculty members have worked in the department: Andreas Heinz, now chair in psychiatry and psychotherapy at the Humboldt University in Berlin; Gunter Schumann, now head of the section for addiction biology at the Institute of Psychiatry in London; and Michael Smolka, now professor for systems biology in Dresden. Ulrich Zimmermann, Bernhard Croissant and Alexander Diehl are now all in leading positions throughout Germany, underlining the opportunities for career development in the addictions, which has been pointed out recently . At present, Falk Kiefer as deputy director of the department, Derik Hermann, Tillman Weber, Sabine Vollstaedt-Klein, Sabine Loeber, Tagrid Leménager and Mira Buehler are carrying the work forward.
In these people and many others the CIMH spirit of creativity and collaboration prevails even in the presence of competition for success. It was seeded by Fritz Henn and has received new momentum by the incoming director, Andreas Meyer-Lindenberg (since 2007).
GENERAL CONSEQUENCES AND FUTURE DEVELOPMENT
The accumulation of knowledge and experience, as well as our unique position within Germany, has created much interest from the national and international media. They contact us continuously for addiction issues of public concern. We are also holding key positions as policy makers and advisers of regional and national governments.
While the success of the department was achieved by a number of factors as outlined above, pure chance was also an important contributor. This is true in part for a number of national research programmes to which we were able to shape our research agenda, and is even more true with regard to the initial creation of the department. Without the single-handed decision of a charismatic individual nothing would have developed, at least not in this place and under these circumstances.
This needs to be kept in mind when we try to look into the future. The current chair of the department will retire in 2014. Flexibility in the choice of research directions is a fundamental basis for the overall success of institutes and universities, and an outgoing chair offers a superb chance for this. Fortunately, as it now seems, there are hopes that the department for addictive behaviour and addiction medicine in Mannheim will continue to exist, and a new chair will be recruited in 2014 or 2015.
Declarations of interest