Azapirones for Attention Deficit Hyperactivity Disorder: A Systematic Review

Abstract

Introduction: No meta-analysis has evaluated azapirones (serotonin_1A receptor partial agonists) as anxiolytics for attention deficit hyperactivity disorder (ADHD).

Methods: Randomized controlled trials (RCTs) and single-arm trials published before October 27, 2015 were retrieved from major healthcare databases and clinical trial registries. Relative risk and 95% confidence intervals were calculated.

Results: 5 RCTs (n=429) and 3 single-arm studies (n=70) were identified. 3 RCTs compared buspirone vs. methylphenidate in children/adolescents, one buspirone patches vs. placebo patches in children/adolescents, and one atomoxetine plus buspirone vs. atomoxetine vs. placebo in adults. The single-arm studies were buspirone trails in children/adolescents. All-cause discontinuation rates and adverse events did not differ between pooled buspirone and methylphenidate groups. No other meta-analyses of buspirone efficacy and safety vs. comparators were conducted due to insufficient data. 2 RCTs found no significant differences in parent and teacher ADHD-Rating Scale total scores between buspirone and methylphenidate, while one reported that methylphenidate improved parent and teacher ADHD-RS total scores vs. buspirone.

Discussion: It remains unclear whether buspirone use has benefit for ADHD patients and therefore further evidence is needed for better clinical use of buspirone in patients with ADHD.

Key words

azapirone - buspirone - attention deficit hyperactivity disorder - systematic review and meta-analysis - guidelines

^* These authors contributed equally to this work.

• References

• 1 Fayyad J, De Graaf R, Kessler R et al. Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 2007; 190: 402-409
• 2 Mostert JC, Onnink AM, Klein M et al. Cognitive heterogeneity in adult attention deficit/hyperactivity disorder: A systematic analysis of neuropsychological measurements. Eur Neuropsychopharmacol 2015;
• 3 Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics 2012; 9: 490-499
• 4 Simon V, Czobor P, Balint S et al. Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry 2009; 194: 204-211
• 5 Higgins JPT, Green S (ed.). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011] The Cochrane Collaboration. 2011 http://handbookcochraneorg/
• 6 Kvarnbrink S, Karlsson T, Edlund K et al. LRIG1 is a prognostic biomarker in non-small cell lung cancer. Acta Oncol 2015; 54: 1113-1119
• 7 Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry 2010; 71: 754-763
• 8 Bolea-Alamanac B, Nutt DJ, Adamou M et al. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2014; 28: 179-203
• 9 Davari-Ashtiani R, Shahrbabaki ME, Razjouyan K et al. Buspirone versus methylphenidate in the treatment of attention deficit hyperactivity disorder: a double-blind and randomized trial. Child Psychiatry Hum Dev 2010; 41: 641-648
• 10 Volkow ND. Long-term safety of stimulant use for ADHD: findings from nonhuman primates. Neuropsychopharmacology 2012; 37: 2551-2552
• 11 Gurer B, Bozkurt M, Neves G et al. The subparietal and parietooccipital sulci: an anatomical study. Clin Anat 2013; 26: 667-674
• 12 Michelson D, Adler L, Spencer T et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 2003; 53: 112-120
• 13 FDA. MEDICATION GUIDE STRATTERA^® . http://wwwfdagov/downloads/Drugs/DrugSafety/ucm089138 2014
• 14 Cortese S, Holtmann M, Banaschewski T et al. Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry 2013; 54: 227-246
• 15 Stuhec M, Svab V. Atomoxetine-induced life-threatening long QT syndrome. Ir J Med Sci 2013; 182: 535-537
• 16 Hirota T, Schwartz S, Correll CU. Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy. J Am Acad Child Adolesc Psychiatry 2014; 53: 153-173
• 17 Cadieux RJ. Azapirones: an alternative to benzodiazepines for anxiety. Am Fam Physician 1996; 53: 2349-2353
• 18 Hensler JG. Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration. Life Sci 2003; 72: 1665-1682
• 19 Kishi T, Meltzer HY, Matsuda Y et al. Azapirone 5-HT1A receptor partial agonist treatment for major depressive disorder: systematic review and meta-analysis. Psychol Med 2014; 44: 2255-2269
• 20 Kishi T, Meltzer HY, Iwata N. Augmentation of antipsychotic drug action by azapirone 5-HT1A receptor partial agonists: a meta-analysis. Int J Neuropsychopharmacol 2013; 16: 1259-1266
• 21 Wilens TE, Biederman J, Faraone SV et al. Presenting ADHD symptoms, subtypes, and comorbid disorders in clinically referred adults with ADHD. J Clin Psychiatry 2009; 70: 1557-1562
• 22 Matheson GK, Pfeifer DM, Weiberg MB et al. The effects of azapirones on serotonin1A neurons of the dorsal raphe. Gen Pharmacol 1994; 25: 675-683
• 23 Newman-Tancredi A, Kleven MS. Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties. Psychopharmacology (Berl) 2011; 216: 451-473
• 24 Taylor DP, Moon SL. Buspirone and related compounds as alternative anxiolytics. Neuropeptides 1991; 19 (Suppl) 15-19
• 25 Wedzony K, Mackowiak M, Fijal K et al. Evidence that conditioned stress enhances outflow of dopamine in rat prefrontal cortex: a search for the influence of diazepam and 5-HT1A agonists. Synapse 1996; 24: 240-247
• 26 Wedzony K, Mackowiak M, Fijal K et al. Ipsapirone enhances the dopamine outflow via 5-HT1A receptors in the rat prefrontal cortex. Eur J Pharmacol 1996; 305: 73-78
• 27 Ohmura Y, Kumamoto H, Tsutsui-Kimura I et al. Tandospirone suppresses impulsive action by possible blockade of the 5-HT1A receptor. J Pharmacol Sci 2013; 122: 84-92
• 28 Coccaro EF, Gabriel S, Siever LJ. Buspirone challenge: preliminary evidence for a role for central 5-HT1a receptor function in impulsive aggressive behavior in humans. Psychopharmacol Bull 1990; 26: 393-405
• 29 Silverstone PH, Lalies MD, Hudson AL. Quetiapine and buspirone both elevate cortical levels of noradrenaline and dopamine in vivo, but do not have synergistic effects. Front Psychiatry 2012; 3: 82
• 30 Castillo C, Ibarra M, Marquez JA et al. Pharmacological evidence for interactions between 5-HT1A receptor agonists and subtypes of alpha 1-adrenoceptors on rabbit aorta. Eur J Pharmacol 1993; 241: 141-148
• 31 Sutherland SM, Adler LA, Chen C et al. An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults with ADHD. J Clin Psychiatry 2012; 73: 445-450
• 32 Alam N, Najam R, Khan SS. Attenuation of methylphenidate-induced tolerance on cognition by buspirone co-administration. Pak J Pharm Sci 2015; 28: 1601-1605
• 33 Mohammadi MR, Hafezi P, Galeiha A et al. Buspirone versus methylphenidate in the treatment of children with attention- deficit/ hyperactivity disorder: randomized double-blind study. Acta Med Iran 2012; 50: 723-728
• 34 Shahrbabaki M, Sabzevari L, Haghdoost A et al. A randomized double blind crossover study on the effectiveness of buspirone and methylphenidate in treatment of attention deficit /hyperactivity disorder in children and adolescents. Iran J Psychiatr 2013; 18: 2284-2292
• 35 Sangal RB, Sangal JM. What is a significant response in drug studies of attention-deficit/hyperactivity disorder: statistical significance is necessary, but is it sufficient?. Psychopharmacol Bull 2003; 37: 50-58
• 36 Gross MD. Buspirone in ADHD with ODD. J Am Acad Child Adolesc Psychiatry 1995; 34: 1260
• 37 Malhotra S, Santosh PJ. An open clinical trial of buspirone in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1998; 37: 364-371
• 38 Niederhofer H. An open trial of buspirone in the treatment of attention-deficit disorder. Hum Psychopharmacol 2003; 18: 489-492
• 39 Balon R. Buspirone for attention deficit hyperactivity disorder?. J Clin Psychopharmacol 1990; 10: 77
• 40 Moher D, Liberati A, Tetzlaff J et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535
• 41 Pattij T, Schoffelmeer AN. Serotonin and inhibitory response control: focusing on the role of 5-HT(1A) receptors. Eur J Pharmacol 2015; 753: 140-145
• 42 Doyle CA, McDougle CJ. Pharmacotherapy to control behavioral symptoms in children with autism. Expert Opin Pharmacother 2012; 13: 1615-1629
• 43 Popper CW. Pharmacologic alternatives to psychostimulants for the treatment of attention-deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 2000; 9: 605-646 viii
• 44 Apter JT, Allen LA. Buspirone: future directions. J Clin Psychopharmacol 1999; 19: 86-93
• 45 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177-188
• 46 Leucht S, Cipriani A, Spineli L et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951-962
• 47 Stuhec M, Munda B, Svab V et al. Comparative efficacy and acceptability of atomoxetine, lisdexamfetamine, bupropion and methylphenidate in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis with focus on bupropion. J Affect Disord 2015; 178: 149-159
• 48 Tanaka H, Tatsuno T, Shimizu H et al. Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain. Gen Pharmacol 1995; 26: 1765-1772
• 49 Newman-Tancredi A, Gavaudan S, Conte C et al. Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol 1998; 21: 245-256
• 50 Zuideveld K, Rusic-Pavletic J, Maas H et al. Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats. J Pharmacol Exp Ther 2002; 303: 1130-1137
• 51 Tsutsui S, Saito T, Katsura N. Double blind comparative study of tandospirone (SM-3997) on neurosis. Placebo controlled dose-finding study. The Clinical Report 1992; 26: 4265-4288
• 52 Uchida H, Mamo DC, Mulsant BH et al. Increased antipsychotic sensitivity in elderly patients: evidence and mechanisms. J Clin Psychiatry 2009; 70: 397-405
• 53 Faraone SV, Biederman J, Spencer TJ et al. Comparing the efficacy of medications for ADHD using meta-analysis. MedGenMed 2006; 8: 4