Therapeutic Effectiveness of Galphimia glauca vs. Lorazepam in Generalized Anxiety Disorder. A Controlled 15-Week Clinical Trial

Abstract

Galphimia glauca Cav. has demonstrated anxiolytic activity attributable to nor-seco-triterpenes denominated galphimines, the most active of which is galphimine-B. Galphimine-B inhibits ventral tegmental area dopaminergic neurons and interacts with the serotoninergic system of the dorsal hippocampus. A previous clinical study that administered a G. glauca herbal medicinal product for 4 weeks evidenced high percentages of therapeutic effectiveness and safety in patients with generalized anxiety disorder. Based on the previous findings, the goal of the present study was to evaluate the effectiveness, safety, and tolerability of G. glauca herbal medicinal product administered during 15 weeks in patients with generalized anxiety disorder. Study design: double-blind, randomized, lorazepam-controlled clinical trial. Study subjects: adult males and females, ambulatory, diagnosed with generalized anxiety disorder, with 20 or more points on the Hamilton anxiety scale, without data of depression, and without anxiolytic treatment in the previous month. Interventions were as follows. Experimental treatment: G. glauca herbal medicinal product in capsules containing the dry extract of G. glauca standardized in 0.175 mg of galphimine-B, one or two capsules twice a day, during 12 weeks plus 3 withdrawal weeks, and control treatment: lorazepam 0.5 mg with the same presentation and posology. Primary outcome: anxiolytic effectiveness (≥ 50 % reduction of initial Hamilton anxiety scale score). Secondary outcomes: tolerability and safety. One hundred ninety-one patients initiated the study with 94 in the experimental group. One hundred four patients concluded the study, 51 of these in the experimental group. Anxiolytic effectiveness, measured as 0 in a negative case and as 1 in a positive case, was assessed 593 times in the experimental group and 631 in the control; the mean effectiveness observed was 0.686 ± 0.019 vs. 0.588 ± 0.019 (repeated-measures ANOVA; p = 0.0003). In the same way, G. glauca-herbal medicinal product diminished the score in the Hamilton anxiety scale to 11.51 ± 8.27 points and lorazepam to 12.40 ± 8.07 points (repeated-measures ANOVA; p = 0.05). The tolerability analysis, which comprised patients who concluded the treatment plus 11 patients who withdrew due to adverse reactions did not show differences between treatments (p = 0.35), nor did therapeutic safety demonstrate differences between groups (p = 0.21). There were no cases of tolerance, intoxication, dependence, or suppression syndrome. We concluded that G. glauca herbal medicinal product, standardized in 0.175 mg of galphimine-B and administered for 15 weeks to patients with generalized anxiety disorder, showed greater anxiolytic effectiveness than that obtained with lorazepam, with high percentages of therapeutic tolerability and safety.

Key words

Galphimia glauca - Malpighiaceae - nor-seco-triterpenes - herbal medicinal product - generalized anxiety disorder - randomized controlled clinical trial

• References

• 1 American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edition. Text revision. Washington, DC: American Psychiatric Association; 2000: 429-484
• 2 Leray E, Camara A, Drapier D, Riou F, Bougeant N, Pelissolo A, Lloyd KR, Bellamy V, Roelandt JL, Millet B. Prevalence, characteristics and comorbidities of anxiety disorders in France. Results from the “Mental Health in General Population” Survey (MHGP). Eur Psychiatry 2011; 26: 339-345
• 3 DuPont RL, Rice DP, Miller LS, Shiraki SS, Rowland CR, Harwood HJ. Economic costs of anxiety disorders. Anxiety 1996; 2: 167-172
• 4 Regier DA, Rae DS, Narrow WE, Kaelber CT, Schatzberg AF. Prevalence of anxiety disorders and their comorbidity with mood and addictive disorders. Br J Psychiatry Suppl 1998; 34: 24-28
• 5 Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51: 8-19
• 6 Marks SL, Wegelin JA, Bourgeois JA, Perkins J. Anxiety disorders in rural primary care: use of the MINI to estimate prevalence in clinic patients. J Health Care Poor Underserved 2010; 21: 680-690
• 7 Caballero L, Bobes J, Vilardaga I, Rejas J. Clinical prevalence and reason for visit of patients with generalized anxiety disorder seen in the psychiatry out-patient clinics in Spain. Results of the LIGANDO study. Actas Esp Psiquiatr 2009; 37: 17-20
• 8 Feltner DE, Crockatt JG, Dubovsky SJ, Cohn CK, Shrivastava RK, Targum SD, Liu-Dumaw M, Carter CM, Pande AC. A randomized, double blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003; 23: 240-249
• 9 Bielski RJ, Bose A, Chang CC. A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder. Ann Clin Psychiatry 2005; 17: 65-69
• 10 Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ. WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disoders, Zohar J, Hollander E, Kasper S, Möller HJ, Bandelow B, Allgulander C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF, Lader M, Lecrubier Y, Lépine JP, Liebowitz MR, Lopez-Ibor JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders – first revision. World J Biol Psychiatry 2008; 9: 248-312
• 11 Uzun S, Kozumplik O, Jskovljevic M, Sedic B. Side effects of treatment with benzodiazepines. Psychiatr Danub 2010; 22: 90-93
• 12 Neale G, Smith AJ. Self-harm and suicide associated with benzodiazepine usage. Br J Gen Pract 2007; 57: 407-408
• 13 Lader M. Effectiveness of benzodiazepines: do they work or not?. Expert Rev Neurother 2008; 8: 1189-1191
• 14 Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand 2008; 118: 69-86
• 15 Filter ER, Gorczynski L, Fernandes JR. Fatal intoxication with a selective serotonin reuptake inhibitor, lorazepam, and codeine. Am J Forensic Med Pathol 2007; 28: 361-363
• 16 Străulea AO, Chiriţă V. The withdrawal syndrome in benzodiazepine dependence and its management. Rev Med Chir Soc Med Nat Iasi 2009; 113: 879-884
• 17 Tortoriello J, Romero O. Plants used by Mexican traditional medicine with presumable sedative properties: an ethnobotanical approach. Arch Med Res 1992; 23: 111-116
• 18 Tortoriello J, Lozoya X. Effect of Galphimia glauca methanolic extract on neuropharmacological tests. Planta Med 1992; 58: 234-236
• 19 Tortoriello J, Ortega A. Sedative effect of galphimine B, a nor-seco-triterpenoid from Galphimia glauca . Planta Med 1993; 59: 398-400
• 20 González-Cortazar M, Tortoriello J, Álvarez L. Norsecofriedelanes as spasmolytics, advances of structure-activity relationships. Planta Med 2005; 71: 711-716
• 21 Prieto-Gómez B, Tortoriello J, Vázquez-Álvarez A, Reyes-Vázquez C. Galphimine B modulates synaptic transmission on dopaminergic ventral tegmental area neurons. Planta Med 2003; 69: 38-43
• 22 Jiménez-Ferrer E, Herrera-Ruiz M, Ramírez-García R, Herrera-Arellano A, Tortoriello J. Interaction of the natural anxiolytic Galphimine-B with serotonergic drugs on dorsal hippocampus in rats. J Ethnopharmacol 2011; 137: 724-729
• 23 Herrera-Ruíz M, Jiménez-Ferrer JE, De Lima TCM, Avilés-Montes D, Pérez-García D, González-Cortazar M, Tortoriello J. Anxiolytic and antidepressant-like activity of a standardized extract from Galphimia glauca . Phytomedicine 2006; 13: 23-28
• 24 Herrera-Ruíz M, González-Cortazar M, Jiménez-Ferrer E, Zamilpa A, Álvarez L, Ramírez G, Tortoriello J. Anxiolytic effect of natural galphimines from Galphimia glauca and their chemical derivatives. J Nat Prod 2006; 69: 59-61
• 25 Herrera-Arellano A, Jiménez-Ferrer E, Zamilpa A, Morales-Valdéz M, García-Valencia CE, Tortoriello J. Efficacy and tolerability of a standardized herbal product from Galphimia glauca on generalized anxiety disorder. A randomized, double-blind clinical trial controlled with lorazepam. Planta Med 2007; 73: 713-717
• 26 Comisión Permanente de la Farmacopea. Farmacopea de los Estados Unidos Mexicanos, 8th edition, Vol. 1. Cuauhtémoc: Comisión Permanente FEUM; 2004
• 27 Davidson JR, Feltner DE, Dugar A. Management of generalized anxiety disorder in primary care: identifying the challenges and unmet needs. Primary Care Companion J Clin Psychiatry 2010; 12 pii: PCC.09r00772
• 28 Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Dienel A, Schläfke S. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of subsyndromal anxiety disorder: a randomized, double blind, placebo controlled trial. Int Clin Psychopharmacol 2010; 25: 277-287
• 29 Allgulander C, Nutt D, Detke M, Erickson J, Spann M, Walker D, Ball SG, Russell JM. A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder. J Psychopharmacol 2008; 22: 417-425
• 30 Davidson JR, Bose A, Korotzer A, Zheng H. Escitalopram in the treatment of generalized anxiety disorder: double blind, placebo controlled, flexible-dose study. Depress Anxiety 2004; 19: 234-240
• 31 Davidson J, Allgulander C, Pollack MH, Hartford J, Erickson JS, Russell JM, Perahia D, Wohlreich MM, Carlson J, Raskin J. Efficacy and tolerability of duloxetine in elderly patients with generalized anxiety disorder: a pooled analysis of four randomized, double-blind, placebo-controlled studies. Hum Psychopharmacol 2008; 23: 519-526
• 32 Lydiard RB, Rickels K, Herman B, Feltner DE. Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder. Int J Neuropsychopharmacol 2010; 12: 229-241