Effects of PRX-00023, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial
Rickels K, Mathew S, Banov MD, Zimbroff DL, Oshana S, Parsons EC Jr, et al.;
Commented by , 30 Apr 2008
Aim
To assess the efficacy in treating generalised anxiety disorder (GAD) of PRX-00023 a new 5HT-1A receptor agonist
Hypothesis
PRX-00023 will reduce symptoms of GAD significantly greater than placebo, as measured by the Hamilton Anxiety Inventory (HAM-A).
Method
277 DSM-IV diagnosed sufferers of GAD who had not responded to one week run in of placebo were randomised in double blind fashion to either PRX-00023 or placebo. This was a multi-centre trial lasting 8 weeks. Primary outcome measures were the change in total Hamilton Anxiety Inventory (HAM-A). Secondary measures included the Clinical Global Impression of Improvement (GCI-I), Montgomery-Asberg Depression Rating Scale (MADRS) and the Massachusetts General Hospital Sexual Function Scale (MGH).
Results
There was no significant difference between PRX-00023 and placebo on the primary outcome measure (total HAM-A score). There was a significant reduction in the MADRS compared to placebo, but not any other secondary outcome measure.
Dr Christmas', Dr Hood's and Prof Nutt's comments
The 5HT-1A receptor has long been associated with clinical anxiety disorders. It is located both pre and post-synaptically and is negatively linked to the second messenger cyclic adenosine monophosphate (cAMP) (ref. 1). The presynaptic 5HT-1A autoreceptors in the dorsal raphe, which regulate raphe firing, have been most implicated in anxiety disorders.
Genetically modified "knock out" mice with redundant 5HT-1A receptors have been found to exhibit increased anxiety behaviour (ref. 2). An imaging study in healthy controls found an inverse correlation with the number of 5HT-1A receptors and anxiety traits (the less receptors, the more anxious) (ref. 3).
Our group have also recently shown reduced 5HT 1a receptors in patients with panic disorder (ref. 4). Buspirone is also a 5HT-1A ligand, but a partial agonist; it has been used for the treatment of generalised anxiety disorder for some time. It has, however, not been found to be efficacious for other anxiety disorders (ref. 5, ref. 6).
It may have some effect in speeding the response of major depression to SSRIs (ref. 7) although this has been disputed (ref. 8). Therefore, this paper's finding of an improvement in the MADRS is not completely surprising.
However, as patients with a concurrent major depressive episode were excluded from the study, the MADRS may not have been measuring the "syndrome depression" yet analysis of MADRS sub-items showing most gains in "apparent sadness", "reduced sleep", "pessimistic thoughts" and "suicidal thoughts" – core features of depression.
This is a reminder that without viable biological markers for anxiety or mood disorders, measurement of these entities by questionnaires can be fraught with difficulty. Other agonist drugs targeting the 5HT-1A receptor (such as flesinoxan) (ref. 9) have also failed to have anxiolytic efficacy robustly validated in clinical trials.
One explanation for this may be the large placebo effect often seen in anxiety disorder trials making it hard to prove an additional benefit above this (ref. 10). However, in the case of the 5HT-1A receptor, given that several specific ligands have failed to prove efficacy over a range of disorders, there may be an intrinsic problem with this mechanism to try to treat anxiety disorders.
The balance between pre and post synaptic actions may be critical here; a pre synaptic preponderance may lead to reduced 5HT release so opposing any possible actions at the post synaptic receptor.
References
1. Olivier B, Soudijn W, van Wijngaarden I. The 5-HT1A receptor and its ligands: structure and function. Progress in drug research 1999; 52;103-165
2. Parks CL, Robinson PS, Sibille E, Shenk T, Toth M. Increased anxiety of mice lacking the serotonin1A receptor. Proceedings of the National Academy of Sciences of the United States of America 1998; 95(18); 10734-10739. (Note: Free full text article)
3. Tauscher J, Bagby RM, Javanmard M, Christensen BK, Kasper S, Kapur S. Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers. American Journal of Psychiatry 2001; 158 (8); 1326-1328. (Note: Free full text article)
4. Nash JR, Sargent PA, Rabiner EA, Hood SD, Argyropoulos SV, Potokar JP, et al. A positron emission tomography study of serotonin 5-HT1A receptor availability in untreated and recovered patients with panic disorder. British Journal of Psychiatry 2008; 193 (3); 229-234
5. van Vliet IM, den Boer JA, Westenberg HG, Pian KL. Clinical effects of buspirone in social phobia: a double-blind placebo-controlled study. Journal of Clinical Psychiatry 1997; 58 (4); 164-168
6. Sheehan DV, Raj AB, Sheehan KH, Soto S. Is buspirone effective for panic disorder? Journal of Clinical Psychopharmacology 1990; 10 (1); 3-11
7. Appelberg BG, Syvälahti EK, Koskinen TE, Mehtonen OP, Muhonen TT, Naukkarinen HH. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. Journal of Clinical Psychiatry 2001; 62 (6); 448-452
8. Onder E, Tural U. Faster response in depressive patients treated with fluoxetine alone than in combination with buspirone. Journal of Affective Disorders 2003; 76 (1-3); 223-227
9. van Vliet IM, Westenberg HG, den Boer JA. Effects of the 5-HT1A receptor agonist flesinoxan in panic disorder. Psychopharmacology 1996; 127 (2); 174-180
10. Khan A, Detke M, Khan SR, Mallinckrodt C. Placebo response and antidepressant clinical trial outcome. Journal of Nervous and Mental Disease 2003; 191 (4); 211-218