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New drug targets for anxiety
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Anxiety: towards new drug targets
Lectures
F~-~ New drug targets for anxiety J. Hagan 1. 1GlaxoSmithKline Pharmaceuticals, Department Biology Psychiatry CEDD, Harlow, Essex, United Kingdom The major anxiety disorders; generalised anxiety disorder (GAD), social anxiety disorder (SAD), post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD) present a significant source of morbidity and patient burden. For example, the 12 month prevalence of GAD in European populations is approximately 2%, being one of the most frequent mental disorders presenting in primary care. Social phobia has a similar prevalence. Treatments have essentially developed in three stages: Barbiturates were superseded by benzodiazepines, but although the development of the benzodiazepines, chlordiazepoxide and diazepam, contributed significantly to treatment and the development of many more benzodiazepine derivatives, efficacy was offset by issues of sedation, tolerance, abuse liability and dependence. Nevertheless, GABAA receptors remain a key focus in the search for new treatments and recent advances point to the importance of the al, a2, a3, a 5 and y GABAA receptor subunits in differentiating the anxiolytic and sedative properties of benzodiazepine agonists. Early evidence demonstrated that the tricyclic antidepressants, such as infipramine, were efficacious in the treatment of panic disorder, pointing to a significant therapeutic role for monoaminergic approaches. More recent studies have reported the successful use of selective serotonin re-uptake inhibitors, such as Paroxetine and Sertraline, in the treatment of PTSD, GAD, panic disorder and OCD. These observations have, in turn, triggered research efforts to identify the downstream receptors involved in mediating these effects. Preclinical data point to a significant role for a number of 5-HT receptors including 5-HT2B, 5-HT2c, 5-HT1B and 5-HT7 receptors. The success of the antidepressants in treating some forms of anxiety highlights the importance of focussing research on the biological domain, or mechanism, rather than on specific symptom clusters, particularly for syndromes such as major depression and anxiety, which are defined on a categorical basis and display high levels of co-morbidity.
Advances in our understanding of underlying pathophysiology for these conditions, although rudimentary, provide further hypotheses and mechanisms that can be tested. In this respect, HPA dysfunction in 50-70% of patients suffering major depression is a clinically robust finding. Molecular approaches to regulating HPA overactivity, such as CRF1, vasopressinlB and melanocortin4 receptor blockade promise therapeutic advances and are supported by substantial preclinical evidence, particularly in the case of CRF1 receptor blockade. Likewise, strong preclinical evidence supports a therapeutic role for NK1 receptor blockade and, together with antagonism of CRF1 receptors, these represent the most clinically advanced peptidergic targets in the field. Amino acid receptors also represent interesting anxiolytic targets. In this respect, both preclinical and clinical evidence supports the hypothesis that group II metabotropic glutamatergic receptor (mGlu2, mGlu3) agonists are anxiolytic. Thus, the mixed mGlu2/3receptor agonist LY35740 displays efficacy in a range of preclinical models, is effective in a model of CO2 induced panic in volunteers and reduces anxiety (HAMA) scores in patients compared to placebo. Following the identification of the highly potent and selective mGluRs receptor antagonist MPEP [2-methyl-6(phenylethynyl)-pyridine] preclinical evidence to support this class of compound as a potential anxiolytic has also been accumulating. Furthermore, knockout and transgenic approaches have facilitated the identification of many other novel targets through phenotypic approaches using conventional behavioural tests. There is therefore a stream of targets currently under evaluation, some of which may yield therapeutic efficacy and superiority compared to available treatments. However, the field faces a number of issues: The models through which potential targets are evaluated remain biased towards those which are sensitive to the actions of benzodiazepines. Non-benzodiazepine compounds, for which clinical efficacy has been shown, only show efficacy in a subset of these models. Therefore both false positive and false negative decisions on new targets are likely. This problem can be offset if targets are advanced to clinical testing on the basis of known pathophysiological mechanisms, genetic risk factors or environmental risk, regardless of activity in conventional behavioural models. However, in the case of anxiety such approaches are hampered by a lack of knowledge concerning the fundamental factors which pre-dispose to anxiety syndromes.
Anxiety: towards new drug targets
Lectures
F~-~ New drug targets for anxiety J. Hagan 1. 1GlaxoSmithKline Pharmaceuticals, Department Biology Psychiatry CEDD, Harlow, Essex, United Kingdom The major anxiety disorders; generalised anxiety disorder (GAD), social anxiety disorder (SAD), post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD) present a significant source of morbidity and patient burden. For example, the 12 month prevalence of GAD in European populations is approximately 2%, being one of the most frequent mental disorders presenting in primary care. Social phobia has a similar prevalence. Treatments have essentially developed in three stages: Barbiturates were superseded by benzodiazepines, but although the development of the benzodiazepines, chlordiazepoxide and diazepam, contributed significantly to treatment and the development of many more benzodiazepine derivatives, efficacy was offset by issues of sedation, tolerance, abuse liability and dependence. Nevertheless, GABAA receptors remain a key focus in the search for new treatments and recent advances point to the importance of the al, a2, a3, a 5 and y GABAA receptor subunits in differentiating the anxiolytic and sedative properties of benzodiazepine agonists. Early evidence demonstrated that the tricyclic antidepressants, such as infipramine, were efficacious in the treatment of panic disorder, pointing to a significant therapeutic role for monoaminergic approaches. More recent studies have reported the successful use of selective serotonin re-uptake inhibitors, such as Paroxetine and Sertraline, in the treatment of PTSD, GAD, panic disorder and OCD. These observations have, in turn, triggered research efforts to identify the downstream receptors involved in mediating these effects. Preclinical data point to a significant role for a number of 5-HT receptors including 5-HT2B, 5-HT2c, 5-HT1B and 5-HT7 receptors. The success of the antidepressants in treating some forms of anxiety highlights the importance of focussing research on the biological domain, or mechanism, rather than on specific symptom clusters, particularly for syndromes such as major depression and anxiety, which are defined on a categorical basis and display high levels of co-morbidity.
Advances in our understanding of underlying pathophysiology for these conditions, although rudimentary, provide further hypotheses and mechanisms that can be tested. In this respect, HPA dysfunction in 50-70% of patients suffering major depression is a clinically robust finding. Molecular approaches to regulating HPA overactivity, such as CRF1, vasopressinlB and melanocortin4 receptor blockade promise therapeutic advances and are supported by substantial preclinical evidence, particularly in the case of CRF1 receptor blockade. Likewise, strong preclinical evidence supports a therapeutic role for NK1 receptor blockade and, together with antagonism of CRF1 receptors, these represent the most clinically advanced peptidergic targets in the field. Amino acid receptors also represent interesting anxiolytic targets. In this respect, both preclinical and clinical evidence supports the hypothesis that group II metabotropic glutamatergic receptor (mGlu2, mGlu3) agonists are anxiolytic. Thus, the mixed mGlu2/3receptor agonist LY35740 displays efficacy in a range of preclinical models, is effective in a model of CO2 induced panic in volunteers and reduces anxiety (HAMA) scores in patients compared to placebo. Following the identification of the highly potent and selective mGluRs receptor antagonist MPEP [2-methyl-6(phenylethynyl)-pyridine] preclinical evidence to support this class of compound as a potential anxiolytic has also been accumulating. Furthermore, knockout and transgenic approaches have facilitated the identification of many other novel targets through phenotypic approaches using conventional behavioural tests. There is therefore a stream of targets currently under evaluation, some of which may yield therapeutic efficacy and superiority compared to available treatments. However, the field faces a number of issues: The models through which potential targets are evaluated remain biased towards those which are sensitive to the actions of benzodiazepines. Non-benzodiazepine compounds, for which clinical efficacy has been shown, only show efficacy in a subset of these models. Therefore both false positive and false negative decisions on new targets are likely. This problem can be offset if targets are advanced to clinical testing on the basis of known pathophysiological mechanisms, genetic risk factors or environmental risk, regardless of activity in conventional behavioural models. However, in the case of anxiety such approaches are hampered by a lack of knowledge concerning the fundamental factors which pre-dispose to anxiety syndromes.