Indsendt af
Københavns Universitet
Abstract
Depression, chronic pain, stress and the associated cognitive disturbances is an accelerating global health problem. Denmark is in an attractive position to exploit present scientific understanding to improve diagnostics and create the foundation for tailoring treatment regimens for the individual patient. There are huge financial and social benefits for improving treatment of these diseases. Further there are both short and long term growth opportunities for the pharmaceutical industry and for small to medium sized MedTech companies.
Challenges and opportunities
Depression and chronic pain disorder represent some of the most common and proliferating health problems worldwide with profound impact on society and quality of life for the inflicted individuals. According to WHO predictions depression will be the largest healthcare economic burden to society worldwide by year 2020. Chronic pain is a strong predictor of depressive symptoms in humans, and individuals with depression are prone to develop chronic pain. Thus, co-occurrence rates of 30-60 % between depression and pain have been reported, suggesting shared biological underpinnings.
Although the interface of depression and chronic pain has been recognized by clinicians for decades, clinical trials of drugs developed to treat chronic pain conditions typically do not encompass the affective components of pain (unpleasantness, fear and worrying). This is striking since efficacy against the affective components of pain is an important determinant of the clinical outcome in terms of improved quality of life.
Stress precipitates and aggravates both depression and pain, and a sensitized stress response is found in both conditions. Since these disorders are themselves stressful by nature, a vicious cycle often ensues (Fig. 1). However, it is still unclear why some individuals are highly vulnerable to stress exposure, while others show a remarkable level of resilience. Stress also impairs cognitive function (e.g. attention and memory). Considering that chronic pain and depression are tightly related to stress, it is therefore not surprising that these disorders are frequently accompanied by cognitive disturbances. Conversely, abnormal cognitive function has been suggested as a predictive biomarker for increased stress vulnerability. It is noteworthy that brain circuitry involved in the affective component of pain shows striking overlap with the circuits regulating mood, stress response and cognitive function.
A systematic investigation of the links between depression, chronic pain, stress sensitivity and cognitive function is necessary to identify vulnerability traits that are present before emergence of depressive and/or chronic pain states. Such an investigation will enable earlier interventions to prevent disease onset and progression, as well as more personalized treatment.
Need for innovation and project objectives
Considering the paucity of novel drugs to treat depression and chronic pain it is pertinent to exploit already approved drugs to develop new treatment strategies. Both depression and chronic pain represent heterogeneous etiologies that converge to become manifest as specific symptom clusters, which are then used as diagnostic criteria. Similarly, the treatment of both disorders is mostly based on symptoms rather than etiology. Accordingly, many patients do not benefit from first- or second-line drugs, and multiple drugs are often tried before sufficient symptom relief is obtained. The lack of knowledge of the etiologies, as well as the general ignorance of pathological processes responsible for depression, calls for targeted research into the pathological basis of symptomatic states of depression.
A better understanding of the etiology of and links between depression, chronic pain, stress sensitivity and cognitive function would lead to identification of phenotypic markers that predict: 1) vulnerability to development of comorbid conditions and 2) responsiveness to specific drugs.
This would lead to a therapeutic paradigm shift towards more individualized treatment, leading to improved prevention, diagnosis and more targeted treatment, thereby shortening the ‘time-to-efficacy’, speeding up the process of rehabilitation - including improved quality of life and ability to work, and consequently reducing the burden to health care and social systems.
To create the foundation for individual treatment of these diseases innovation is needed within theoretical and experimental science. Possible focus areas:
- Quantification of individual differences between monoamine excitatory and inhibitory receptors
- Medical imaging in 2D, 3D and 4D
- Functional correlation between cellular markers and disease progression
- Genetic, epigenetic, proteomic and metabolomic profiling
- Development of model compounds for selective interference with neuronal signaling pathways
- Incorporation of existing animal models and development of novel models (incl. behavioral assays in rodents). Parallel investigations of rodents and humans will provide information regarding the translational value of the rodent findings, as well as back-translation to improve the usability of animal models.
- Biomarkers (eg. profiling of neurotransmission; mathematical modeling of EEG patterns)
- Statistics
To achieve a short term (3-5 years) innovative value it is essential that close links are established between academia, clinical research and the pharmaceutical industry. Further to exploit the identified biomarkers in novel Point-of-Care devices it is important that collaborations are established with MedTech companies and selected GTS institutes.
Danish prerequisites
Denmark has strong scientific presence within neuroscience, patient databases, pharmaceutical industry with CNS focus, and a fast developing MedTech industry.
Effects and potentials
Effect, short term (3-5 years): Integral to the increased understanding of the pathophysiology of the described neurological disorders will be identification of quantifiable biomarkers allowing design of an efficacious treatment regimen (consisting of individual or combinations of existing drugs) for the individual patient. Identification of biomarkers (ex. profiling of neurotransmission; mathematical modeling of EEG patterns) opens for development of Point-of-Care technologies.
Present first-line medical treatment of depression and chronic pain only show effect in approx. 30% of the patients – an improved efficacy will provide tremendous benefits to patients and society.
Intelligent design of drug-drug combinations is expected to become essential within most therapeutic areas in the future. EU has thus an open IMI call with the topic: “Development of drug-drug combinations”. The present scientific endeavor has the potential to provide a “handle” for designing such combinations within the area of CNS related diseases.
Effect, long term (>3-10 years): The pharmaceutical industry is heavily interested in obtaining novel animal models for drug profiling. Present models translate insufficiently to the human situation. Identification of quantifiable biomarkers is essential when stratifying patients for clinical trials and subsequent commercialization of drugs may require accompanying bioassay.
Beyond the human market there is an increasing interest within the veterinary area to provide improved treatment of chronic pain.