In my previous blog on anxiety, I discussed how the treatments available for anxiety disorders have modest efficacy or severe side-effects. Furthermore many patients do not respond to first line pharmacological treatments (principally antidepressants). Psychological approaches (such as cognitive-behavioural therapy) are often limited in availability. As a result of this, benzodiazepines are frequently used for short-term management of anxiety symptoms. It can be argued that benzodiazepines are probably the most effective and well tolerated medications for anxiety; nevertheless, their long-term use is not recommended due to the unfavourable risk profile.
At the Sussex Drug Discovery Centre with the support of the Medical Research Council (MRC) we are currently studying a new generation of anxiolytic drugs.
These drugs, similarly to benzodiazepines, act as positive modulators of GABAA receptors, the main inhibitory mechanism in the mammalian brain, but are selective for the ‘anxiolytic’ subpopulation of the receptor. This approach may result in a drug with significantly less liabilities and ultimately improved risk-benefit profile.
I will focus on 5 key characteristics that a new ideal anxiolytic drug should possess to be superior to existing first-line treatments and benzodiazepines.
- Be active on all anxiety disorders and over the range of severity.The most common anxiety disorders are generalised anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder and post-traumatic stress disorder1. They all share common psychological and physical symptoms but differ in having characteristic features. The ideal drug should be active on all diseases and be effective in reducing both psychological and physical symptoms including the acute presentation of symptoms, which are common in all anxiety disorders.
- Have a rapid onset of action. Antidepressants, currently the first line treatment for anxiety, typically need 2 to 4 weeks to show benefits and this has obvious repercussions on the management of acute symptoms. On this point, the ideal anxiolytic drug should be similar to fast acting benzodiazepines which are effective in less than half an hour.
- Do not interfere with daily life. Antidepressants are associated with a number of physical side-effects: abdominal pain, weight gain, loss of libido, headache and nausea. Interestingly, anxiety is also included in the list of potential side-effects for antidepressants, in particular in the first weeks of treatment. Benzodiazepines at anxiolytic doses may induce sedation, dizziness and memory impairment. We believe that our approach which targets the anxiolytic subpopulation of GABAA receptors will result in a drug with a clean anxiolytic profile devoid of sedation side-effects2.
- Not be associated with the development of physical dependence or tolerance. Problems upon discontinuation of treatment after long-term use are common to antidepressant and benzodiazepines. Up to a third of people who stop SSRIs and SNRIs have withdrawal symptoms which can last between 2 weeks and 2 months. These include a number of physical symptoms and additionally the possibility of developing rebound anxiety. Benzodiazepine long-term use has been associated with both physical dependence and tolerance (the need to increase the dose to obtain similar therapeutic effect). Sudden discontinuation from benzodiazepine treatment is even more problematic with a withdrawal syndrome that again includes rebound anxiety as a common symptom. The mechanism underpinning benzodiazepine dependence and tolerance is still a matter of discussion but there is general consensus that it probably involves some sort of neuroadaptation of the GABAergic synapses which constitute one-third of the synapses of the whole human brain. It has been argued that selective GABAA modulators may be superior in avoiding these neuroadaptation processes3, but in reality more studies are necessary to characterise selective modulators in models of dependence and tolerance.
- Not have a potential for addiction and abuse. It has been estimated that approximately 0.1–0.2% of the adult population abuse or are dependent upon benzodiazepines. Individuals with potential for abuse tend to cluster into two categories: alcohol or drugs-dependent outpatients and people suffering from anxiety disorders. Many studies – including drug self-administration models in several species and studies with human connoisseurs ‘familiar’ with recreational drugs – have indicated that selective GABAA modulators targeting only the anxiolytic subtype may again be superior in avoiding addiction and abuse4. Interestingly, studies on the neural bases of the addictive properties of benzodiazepines seems to confirm the results in animal models5.
Blog written by Alessandro Mazzacani
- Anxiety disorders, post-traumatic stress disorder, and obsessive–compulsive disorder, D. S. Baldwin et al., Medicine, 2016, 44 (11), pages 664–671.
- TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an Agonist Selective for α2- and α3-Containing GABAA Receptors, Is a Nonsedating Anxiolytic in Rodents and Primates, J. Atack et al., The Journal of Pharmacology and Experimental Therapeutics, 2006, 316(1), pages 410-422
- Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?, C. H. Vinkers and B. Oliver, Advances in Pharmacological Sciences, 2012, doi:10.1155/2012/416864
- Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes, Uwe Rudolph and Frédéric Knoflach, NATURE REVIEWS DRUG DISCOVERY, 2011, 10, pages 685-697
- Neural bases for addictive properties of benzodiazepines, M. Brown et al., NATURE, 2010, 463, pages 769-775