Early-life exposure to adverse environmental cues during critical windows of time in the prenatal and/or early postnatal life period could predispose the individual for somatic andmental diseases. This especially holds for stress-related disorders such as depression in which HPA-axis dysregulation plays a pathophysiological role. This is in line with the ‘fetal (or developmental) programming-hypothesis’ which has been tested in numerous preclinical experimental. We tested this hypothesis in humans in a prospective longitudinal study in which maternal emotional state was measured during each pregnancy trimester and after pregnancy. When the offspring was 14-15 years old, HPA-axis function was measured through establishing a saliva day-time cortisol profile. Severity of depressive symptoms was measured with the Children's Depression Inventory. Repeated measurements regression analysis and ordinary least-squares regression analyses indicated that maternal anxiety at 12-22 weeks of pregnancy was in female and male offspring associated with a diurnal cortisol profile that was attenuated due to elevated cortisol secretion in the evening. Moreover, in female adolescents this flattened cortisol curve was associated with depressive symptoms. Our results indicate that maternal anxiety during pregnancy enhances neurobiological vulnerability to depressive symptoms, possibly by altering (or ‘programming") foetal physiology. If our results can be replicated in future research they may lead to a re-orientation of the target of primary prevention and treatment of depressive symptoms. Preliminary results of a study on the association between prenatal exposure to maternal anxiety and cortisol stress responsivity during inoculation in the four month old will be presented.

There is now good evidence from several prospective studies that antenatal maternal stress, anxiety or depression can have long term consequences for the development of the fetus and the child. There can be a wide range of effects and both behavioural and cognitive outcomes can be altered. Such fetal programming is independent of the postnatal environment, although the nature of maternal care may have a modifying influence. The effects are clinically significant; about 15% of behavioural problems such as attention deficit/hyperactivity disorder may be attributable to prenatal stress. Not all children are affected, and those that are can be affected in different ways. Presumably there is an interaction with the genetic predisposition, but this has not yet been studied. There is little agreement about the gestational windows of vulnerability, which are probably different for different outcomes. Also we do not know the nature of the stress which is most harmful, although there is some evidence that stress due to a bad relationship with the partner is damaging, and anxiety has greater influence than depression.

In animal models there is good evidence for the mediating effects of the HPA axis in both mother and fetus. In humans the evidence is less clear. Several studies have found little or no association between anxiety or depression and maternal cortisol in later pregnancy. However we have found an inverse association between amniotic fluid cortisol and child cognitive ability at 17 months, which is only apparent in insecurely attached children.

The intrauterine environment is likely to play a key role in the etiology of psychopathology because the brain is particularly sensitive during the entire gestation as it undergoes the most rapid period of development. Neurodevelopmental deficits, such as attention problems, are a manifestation of these brain disturbances, which can in the end be linked to disorders, the most common being Attention Deficit Hyperactivity Disorder (ADHD). Animal models provide strong evidence in support for programming. Human studies present added complexity as genetic predisposition in mothers can increase the risk of e.g. pregnancy smoking or distress, thus, the effect may be carried entirely or in part by genetic transmission. However, neither genes nor environment operate in isolation, but rather in a complex interplay. Although ADHD has been the focus of intense research, little is known about the gene-environment interaction because such studies require very large sample sizes to be sufficiently statistically powered, thus necessitating multi-site collaborations. This presentation covers methodological difficulties associated with gene-environment studies and some of the ways in which our team has tackled these challenges. Data is presented on common maternal lifestyle factors during pregnancy and their relation to mental health problems in children, particularly ADHD, in a backdrop of genetic predisposition.

The development of decision making paradigms has prompted a consideration that an underlying deficit may assist in explaining substance dependence. However, despite these advances, little progress has been made in accounting for large inter-subject variance within previous studies. This failure continues to undermine many of the previous attempts to explain individual difference.

A study was undertaken to develop methods for analysing and describing individual response behaviours within a decision-making task. In addition, the effect of task manipulations such as feedback, penalties and practice were examined. Substitute medication maintained adults males were recruited for this study.

Findings from this research offer new insight into a possible link between task design and the response behaviours exhibited. This study emphasised the importance of individual response behaviours, and the necessity to consider individual data as a route to understanding concepts drawn from between groups analysis. Significant issues are raised that might impact on other existing paradigms and implications are proposed in relation to the assessment and treatment of substance dependence.

In April 2007 a European twinning project started between Cyprus and Germany, in order to assist Cyprus as a new Candidate Country in the implementation and harmonisation with the European Community's legislation, by evaluating the governmental drug services in Cyprus and their coordination and promoting the improvement and introduction of new drug treatment services. A field investigation studied parameters as population in need, treatment demand and coverage, as well as high risk patterns and their trend over the last years, showing an individual place of Cyprus in the international drug ranking, with the highest prevalence of cannabis and second highest on ecstasy abuse and one of the smallest in opiates and amphetamine consumption. Nevertheless heroin remains the primary drug of abuse in persons seeking treatment, although Cyprus was until 2008 the only country of the European Union without a substitution treatment. Furthermore this project studies in detail the current availability of the governmental drug facilities, their structure and coordination as well as the legal framework in which they operate, showing a still adapting drug care system, trying to keep up with the increasing special needs of the Cypriot population, but offering the presuppositions for an efficient and good functioning drug care system in the future.

Long-lasting memories that associate environmental stimuli with the effects of alcohol are known to be a main cause of relapse and are a major challenge in the treatment of alcohol addiction. It is reasonable to hypothesize that disrupting consolidated alcohol-related memories might help to prevent relapses. The reconsolidation theory states that a consolidated memory could again become labile and susceptible to disruption by protein synthesis inhibition or NMDA-antagonism after memory retrieval. This has been shown for cocaine- and morphine-associated memories in several recent studies. The aim of our investigations was to examine in an animal model for cue-induced relapse to alcohol-seeking behavior whether the behavioral impact of previously conditioned alcohol associated cues is significantly reduced by blocking the reconsolidation of learned alcohol associations. We show that reconsolidation of alcohol memories is disrupted by post-retrieval ICV-administration of the protein synthesis inhibitor anisomycin. Similarly, post-retrieval i.p.-administration of the NMDA antagonist MK-801 reduced alcohol seeking behavior during the following test day as compared to vehicle treated rats. Pharmacological disruption of reconsolidation of alcohol-associated memories may thus provide a potential therapeutic strategy for the prevention of relapse in alcohol addiction.

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.

As the chronic disease model is now accepted as the model to treat individuals in the community in the UK, it has become important to recognise that individuals tend to present with more than one concomittant problem (comorbidity). A increasing patient centred approach to treatment and recovery has helped to recognise the dual concept of pain and dependence within the clinical environment. There is an ever increasing prevalence of this dual presentation and this has helped to effectively manage individuals with a substance misuse history and associated chronic pain and others treated for their chronic pain with strong analgesic and subsequently experiencing substance misuse and dependence problems.

This presenation aims to provide the literature overview of these populations, clinical characteristics and problems presenting in a pain and dependence clinic in Scotland. Several models of practice will also be presented.

German epidemiological data (Poser and Havemann-Reinecke 2002) showed 12% of all addicted treated patients in Lower Saxony being dependent from prescribed opioid analgesics.

Here we report new clinical data of 150 patients being treated because of dependence on the opioid analgesic tramadol. The documents of these patients were evaluated to social-, family-, pain- and addiction development - data, psychiatric and somatic diseases; suicidality, source of tramadol (prescription: "legal", black market: "illegal" ), withdrawl symptoms, therapy.

Neuroimaging provides insight into the main biological mechanisms underlying drug and alcohol dependence. Cardinal symptoms of drug dependence are the development of tolerance against drug effects, withdrawal symptoms, drug craving, reduced control over drug intake and harmful consequences of drug consumption. Brain imaging studies support the hypothesis that tolerance development can be understood as a neuroadaptive mechanism to ensure homeostasis during chronic drug intake. When drug consumption is suddenly interrupted during detoxification, the loss of homeostasis can manifest as a withdrawal syndrome. While tolerance development reduces the effects of chronic drug intake, sensitization is a neuroadaptive process that increases the effects of a drug dose. Brain imaging studies indicate that sensitisation and drug craving are associated with neuroadaptive processes in the brain reward system. This lecture gives a short review about the neurobiological background of opioid addiction

It is important to remember that patients who misuse substances experience pain just as acutely, and probably more so, than “normal” patients. Their lives are chaotic and difficult and they often suffer from concurrent mental health problems. This in itself increases stress and distress and may make their experience of pain worse. Their coping mechanisms are heavily biased towards use of chemicals to deal with distress and they may not respond easily to non-pharmaceutical measures for pain control. Addiction is a chronically relapsing illness and we should expect our patients to respond accordingly. If a patient who has been stable and productive becomes unstable and chaotic again, this is not an indication of therapeutic failure and a signal to retreat and disengage; it means we have to change our management and try again.

Addiction and chronic pain are rarely curable, just as diabetes is rarely curable. We are tasked with helping these patients to best manage their chronic diseases and we should expect setbacks as much as we enjoy success.

We can use any technique we would use in pain uncomplicated by addiction. Thus we use unconventional analgesics such as tricyclic antidepressants and anticonvulsants for neuropathic pain. Regular paracetamol and short course NSAIDs have the same benefits in musculoskeletal pain. Physical approaches such as physiotherapy, TENS (transcutaneous electrical nerve stimulation) and acupuncture have their place. Behavioural modification with psychology is vital. Opioids do have analgesic effects in opioid misusers, even though popular myths have many patients believing otherwise.

About 13 percent of older individuals have symptoms of depression, and other researchers have speculated that vitamin D may be linked to depression. Underlying causes of vitamin D deficiency such as less sun exposure as a result of decreased outdoor activity, different housing or clothing habits and decreased vitamin intake may be secondary to depression, but depression may also be the consequence of poor vitamin D status. Moreover, poor vitamin D status causes an increase in serum parathyroid hormone levels. Overactive parathyroid glands are frequently accompanied by symptoms of depression that disappear after treatment of the condition. We recently measured blood levels of vitamin D and parathyroid hormone and assessed symptoms of depression among 1,282 community residents age 65 to 95 and found a strong decrease in vitamin D level and increase in parathyroid hormone level (Hoogendijk et al., Arch Gen Psychiat 2008;65(5):508-512). This finding may be important to patients because both low blood vitamin D levels and high parathyroid hormone levels can be treated with higher dietary intake of vitamin D or calcium and increased sunlight exposure. Moreover light treatment has been used successfully to treat seasonal affective disorder. Taking these two lines of studies together, sunlight may have an antidepressant effect via the eye-biological clock tract and via the skin-vitamin D-tract. Interestingly, the biological clock is located in the hypothalamus, where vitamin D receptor is most abundant.

The objective of the present study was to examine the cross-sectional relation between serum 25-hydoxyvitamin D (25(OH)D) levels and depression in obese subjects, and to assess the effect of vitamin D supplementation on depressive symptoms. 441 subjects (body mass index 28 - 47 kg/m2, 159 men and 282 women, aged 21 - 70 years) were recruited by advertisements or from the out-patient clinic at the University Hospital of North Norway, and in a double blind controlled trial randomized to 20.000 or 40.000 IU vitamin D per week versus placebo for 1 year.

Subjects with serum 25(OH)D levels < 40 nmol/L scored significantly higher (more depressive traits) than those with serum 25(OH)D levels ≥ 40 nmol/L on the Beck Depression Inventory (BDI) total (6.0 (0 - 23) versus 4.5 (0 - 28) (median and range)) and the BDI subscale 1 - 13 (2.0 (0 - 15) versus 1.0 (0 - 29.5)) (P < 0.05). In the two groups given vitamin D, but not in the placebo group, there was a significant improvement in BDI scores after one year. There was a significant decrease in serum parathyroid hormone in the two vitamin D groups, without a concomitant increase in serum calcium.

It appears to be a relation between serum levels of 25(OH)D and symptoms of depression. Supplementation with high doses of vitamin D seems to ameliorate these symptoms, indicating a possible causal relationship.

Our group has pioneered research indicating that Developmental vitamin D (DVD) deficiency (a candidate risk factor for schizophrenia) alters both brain development and function. We have convergent evidence indicating a disturbance in dopamine signalling in this model. 1stly the superior colliculus (the proto-basal ganglia) is the initial site where the vitamin D receptor is expressed in foetal brain; 2ndly we show a reduction in Catechol-O-methyl transferase (a major metabolic enzyme for dopamine) in these foetal brains; 3rdly dopamine metabolites in the DVD deplete neonatal brain reflect this enzymatic change. When we allow these animals to mature under vitamin D normal conditions we repeatedly observe alterations in both spontaneous and psychomimetic enhanced locomotion. Consistent with the theme of persistent changes in dopamine signalling in this model we now present new data showing that dopamine transporter density and/or affinity are altered in DVD deplete female offspring whilst DA 1 receptor density and dopamine cell number are reduced in DVD deplete male offspring (all P< 0.05 n>8).

Our most recent studies indicate that Nurr-1, a nuclear transcription regulator important in both bone and dopamine neuron development and survival may be a molecular mediator of these processes. Nurr-1 is upregulated by parathyroid hormone (PTH). PTH levels are 2-3 fold greater in vitamin D deficient Dams across gestation. Most importantly we have just shown that Nurr-1 is dose-dependently upregulated by parathyroid hormone (PTH) in a neuroblastoma cell line.