[HYPOTHESIS]
FUNDING: There was no funding for the development and writing of this article. FINANCIAL DISCLOSURES: None of the authors have a conflict of interest related to the content of this article. ADDRESS CORRESPONDENCE TO: Michael Shuman, PharmD, Rosalind Franklin University of Medicine and Science College of Pharmacy, 3333 Green Bay Road, North Chicago, IL 60064; Phone: (847) 578-8700 ext. 7634; Fax: (847) 775-6593; Email: [email protected] KEY WORDS: Antipsychotic, posttraumatic stress disorder, iloperidone, pre-pulse inhibition
Rationale for Iloperidone in the Treatment of Posttraumatic Stress Disorder by MICHAEL D. SHUMAN, PharmD, and IAN R. MCGRANE, PharmD Dr. Shuman is Assistant Professor, Pharmacy Practice, Rosalind Franklin University of Medicine and Science College of Pharmacy, North Chicago, Illinois, and Pharmacy Specialist, Mental Health, Captain James A. Lovell Federal Health Care Center, North Chicago, Illinois; Dr. McGrane is a Clinical Pharmacist, St. Joseph Medical Center, Polson, Montana. Innov Clin Neurosci. 2014;11(5–6):23–25
ABSTRACT Multiple controlled efficacy studies are available to support the use of psychotropic medications in the treatment of posttraumatic stress disorder symptoms. Iloperidone, a recently approved atypical antipsychotic, has yet to be evaluated in such a manner. This unique agent has the highest affinity of all antipsychotics toward alpha-1 receptors. Antagonism of central nervous system alpha-1 receptors has been implicated in certain aspects of posttraumatic stress disorder, as evidenced by the beneficial role of prazosin in treating nightmares. Additional reduction in hypervigilance may occur through blockade of dopamine receptor D2 and serotonin receptors in the 5-HT2 family. Further investigation of iloperidone is warranted in the treatment of patients with posttraumatic stress disorder due to its unique receptor binding profile.
[VOLUME 11, NUMBER 5–6, MAY–JUNE 2014]
PRE-PULSE INHIBITION AND POSTTRAUMATIC STRESS DISORDER Sensorimotor gating is the method by which an individual screens surrounding stimuli in order to filter out extraneous information and focus on what is deemed most relevant. Pre-pulse inhibition (PPI) is the use of a weak prestimulus to attenuate subsequent response to a more intense stimulus and is utilized as a measure for assessing changes in sensorimotor gating.1-4 There is evidence of impaired PPI in posttraumatic stress disorder (PTSD), as manifested by hypervigilance and nightmares.5 A meta-analysis of six studies examined P50 auditory sensory gating, another marker for pulse inhibition, in a population with PTSD. The P50 auditory potential to a second stimulus was suppressed relative to the first in healthy controls; however, five of the six studies found that suppression of the second auditory
Innovations in CLINICAL NEUROSCIENCE
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potential was impaired in patients with PTSD.6 PPI is regulated by multiple neurotransmitters, including norepinephrine. Alpha receptor stimulation attenuates PPI through excess release of norepinephrine.1,7 The alpha-1 antagonist prazosin has been shown to reverse this disruption; these effects are noted in central but not peripheral alpha-1 receptors. The relationship between alpha-2 receptors and PPI is less clear. Alsene et al8,9 found that guanfacine and clonidine both reversed disruptions in PPI when injected into the locus coeruleus. A separate study found that administration of the alpha-2 antagonist and partial 5-HT1A agonist yohimbine produced deficits in PPI, which were attributed to effects on 5-HT1A rather than alpha-2.10
PPI AND ANTIPSYCHOTICS As a class, atypical antipsychotics may exert a beneficial effect on sensorimotor gating through actions on specific neurotransmitters.1,5 Dopamine agonists are known to reduce PPI. Serotonin also functions in regulation of PPI through action on certain serotonin receptors, including 5-HT2.11 Stimulation of these receptors alters PPI, while 5HT2 antagonism may restore proper functioning.
ILOPERIDONE AND PTSD Atypical antipsychotics have affinity for D2, alpha-1, and 5-HT2 receptors, with relative affinity differing between agents.12 Iloperidone is a piperidinylbenzisoxazole derivative and thus structurally unique from other antipsychotic agents.13 Its complex receptor binding on dopamine, 5-HT, alpha, and muscarinic receptors is novel in regards to other antipsychotic medications.12 Oral iloperidone is extensively and rapidly absorbed, achieves peak plasma concentrations in 2 to 4 hours, and reaches concentration steady state in 3 to 4 days. Metabolism is mainly conducted through hepatic enzymes
24
Innovations in CLINICAL NEUROSCIENCE
CYP2D6 and CYP3A4. The parent compound (t1/2 =18h) is reduced to P88 (active) and P95 (inactive) metabolites, which have concentration half-lives of 26h and 23h, respectively. The P88 metabolite is centrally acting and believed to have a similar receptor binding profile to the parent compound. The P95 metabolite binds to peripheral alpha-adrenergic receptors and does not cross the blood brain barrier.14 Compared to all other antipsychotics, iloperidone has the highest binding affinity constant (Ki) for alpha-1 noradrenergic autoreceptors. The degree of magnitude for alpha-1 binding affinity is nearly 10-fold higher relative to the nearest comparative agents (iloperidone Ki =0.31 vs. risperidone and ziprasidone Ki= 2.6, 2.7).12 Though multiple antipsychotics have been assessed for benefit in treating PTSD, a recent review found no controlled trials of iloperidone for the treatment of PTSD.15 At this time, open-label studies or case series on the use of this medication in PTSD could not be found in the literature; one placebo-controlled trial examining the effect of iloperidone on select symptoms of PTSD is currently recruiting patients.16 Iloperidone’s alpha-1 antagonism and moderate elimination half-life may have beneficial effects on the reduction of nightmares in addition to hypervigilant symptoms. This hypothesis is supported by animal data, which found that iloperidone doses of 0.3mg/kg prevented disruptions in PPI caused by the alpha-1 agonist cirazoline.17 We are therefore suggesting that based on its unique receptor profile, iloperidone may have a heretofore undiscovered role in treatment of PTSD.
2.
3.
4.
5.
6.
7.
8.
9.
REFERENCES 1.
Baisley SK, Fallace KL, Rajbhandari AK, Bakshi VP. Mutual independence of 5HT(2) and α1 noradrenergic receptors in
[VOLUME 11, NUMBER 5–6, MAY–JUNE 2014]
mediating deficits in sensorimotor gating. Psychopharmacology. 2012;220:465–79. Braff DL, Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry. 1990; 47: 181– 188. Kemner C, Oranje B, Verbaten MN, van Engeland H. Normal P50 gating in children with autism. J Clin Psychiatry. 2002;63:214–217. Magnée M, Oranje B, van Engeland H, Kahn RS, Kemner C. Crosssensory gating in schizophrenia and autism spectrum disorder : EEG evidence for impaired brain connectivity ? Neuropsychologia. 2009;47:1728–1732. Braff DL, Geyer MA, Swerdlow NR. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology. 2001;156:234–258. Karl A, Malta LS, Maercker A. Meta-analytic review of eventrelated potential studies in posttraumatic stress disorder. Biol Psychol. 2006;71:123–147. Alsene KM, Carasso BS, Connors EE, Bakshi VP. Disruption of prepulse inhibition after stimulation of central but not peripheral alpha-1 adrenergic receptors. Neuropsychopharmacology. 2006;31:2150–2161. Alsene KM, Bakshi VP. Modulation of prepulse inhibition by alpha-2 noradrenergic receptors in the locus coeruleus-medial prefrontal cortex pathway.Program No. 546.11. 2009 Neuroscience Meeting Planner. Washingon, DC: Society for Neuroscience, 2009. Online. https://am2012.sfn.org/skins/main/p df/chapter_abstracts/PTTA09Abstr act_Alsene.pdf. Accessed May 21, 2013. Alsene KM, Bakshi VP. Pharmacological stimulation of locus coeruleus reveals a new antipsychotic-responsive pathway for deficient sensorimotor gating. Neuropsychopharmacology.
10.
11.
12.
2011;36:1656–1667. Powell SB, Palomo J, Carasso BS, Bakshi VP, Geyer MA. Yohimbine disrupts prepulse inhibition in rats via action at 5-HT1A receptors, not alpha2-adrenoceptors. Psychopharmacology. 2005;180:491–500. Adams W, van den Buuse M. Hippocampal serotonin depletion facilitates the enhancement of prepulse inhibition by risperidone: possible role of 5-HT(2C) receptors in the dorsal hippocampus. Neuropharmacology. 2011;61:458–67. Correll CU. From receptor
13.
14.
15.
pharmacology to improved outcomes: individualizing the selecting, dosing, and switching of antipsychotics. Eur Psychiatry. 2010;25 Suppl 2:S12–21. Corbett R, Griffiths L, Shipley JE, et al. Iloperidone: preclinical profile and early clinical evaluation. CNS Drug Reviews. 1997;3:120–147. Scott L. Iloperidone in schizophrenia. CNS Drugs. 2009;23:867–880. Maher AR, Maglione M, Bagley S, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for offlabel uses in adults: a systematic
[VOLUME 11, NUMBER 5–6, MAY–JUNE 2014]
16.
17.
review and meta-analysis. JAMA. 2011;306:1359–1369. U.S. National Institutes of Health. Website. 2013. Online. http://www.clinicaltrials.gov/ct2/res ults?term=iloperidone. Accessed May 21,2013. Barr A, Powell S, Markou A, Geyer M. Illoperidone reduces sensorimotor gating deficits in pharmacological models, but not developmental models, of disrupted prepulse inhibition in rats. Neuropharmacology. 2006;51:457–465.
Innovations in CLINICAL NEUROSCIENCE
25
FUNDING: There was no funding for the development and writing of this article. FINANCIAL DISCLOSURES: None of the authors have a conflict of interest related to the content of this article. ADDRESS CORRESPONDENCE TO: Michael Shuman, PharmD, Rosalind Franklin University of Medicine and Science College of Pharmacy, 3333 Green Bay Road, North Chicago, IL 60064; Phone: (847) 578-8700 ext. 7634; Fax: (847) 775-6593; Email: [email protected] KEY WORDS: Antipsychotic, posttraumatic stress disorder, iloperidone, pre-pulse inhibition
Rationale for Iloperidone in the Treatment of Posttraumatic Stress Disorder by MICHAEL D. SHUMAN, PharmD, and IAN R. MCGRANE, PharmD Dr. Shuman is Assistant Professor, Pharmacy Practice, Rosalind Franklin University of Medicine and Science College of Pharmacy, North Chicago, Illinois, and Pharmacy Specialist, Mental Health, Captain James A. Lovell Federal Health Care Center, North Chicago, Illinois; Dr. McGrane is a Clinical Pharmacist, St. Joseph Medical Center, Polson, Montana. Innov Clin Neurosci. 2014;11(5–6):23–25
ABSTRACT Multiple controlled efficacy studies are available to support the use of psychotropic medications in the treatment of posttraumatic stress disorder symptoms. Iloperidone, a recently approved atypical antipsychotic, has yet to be evaluated in such a manner. This unique agent has the highest affinity of all antipsychotics toward alpha-1 receptors. Antagonism of central nervous system alpha-1 receptors has been implicated in certain aspects of posttraumatic stress disorder, as evidenced by the beneficial role of prazosin in treating nightmares. Additional reduction in hypervigilance may occur through blockade of dopamine receptor D2 and serotonin receptors in the 5-HT2 family. Further investigation of iloperidone is warranted in the treatment of patients with posttraumatic stress disorder due to its unique receptor binding profile.
[VOLUME 11, NUMBER 5–6, MAY–JUNE 2014]
PRE-PULSE INHIBITION AND POSTTRAUMATIC STRESS DISORDER Sensorimotor gating is the method by which an individual screens surrounding stimuli in order to filter out extraneous information and focus on what is deemed most relevant. Pre-pulse inhibition (PPI) is the use of a weak prestimulus to attenuate subsequent response to a more intense stimulus and is utilized as a measure for assessing changes in sensorimotor gating.1-4 There is evidence of impaired PPI in posttraumatic stress disorder (PTSD), as manifested by hypervigilance and nightmares.5 A meta-analysis of six studies examined P50 auditory sensory gating, another marker for pulse inhibition, in a population with PTSD. The P50 auditory potential to a second stimulus was suppressed relative to the first in healthy controls; however, five of the six studies found that suppression of the second auditory
Innovations in CLINICAL NEUROSCIENCE
23
potential was impaired in patients with PTSD.6 PPI is regulated by multiple neurotransmitters, including norepinephrine. Alpha receptor stimulation attenuates PPI through excess release of norepinephrine.1,7 The alpha-1 antagonist prazosin has been shown to reverse this disruption; these effects are noted in central but not peripheral alpha-1 receptors. The relationship between alpha-2 receptors and PPI is less clear. Alsene et al8,9 found that guanfacine and clonidine both reversed disruptions in PPI when injected into the locus coeruleus. A separate study found that administration of the alpha-2 antagonist and partial 5-HT1A agonist yohimbine produced deficits in PPI, which were attributed to effects on 5-HT1A rather than alpha-2.10
PPI AND ANTIPSYCHOTICS As a class, atypical antipsychotics may exert a beneficial effect on sensorimotor gating through actions on specific neurotransmitters.1,5 Dopamine agonists are known to reduce PPI. Serotonin also functions in regulation of PPI through action on certain serotonin receptors, including 5-HT2.11 Stimulation of these receptors alters PPI, while 5HT2 antagonism may restore proper functioning.
ILOPERIDONE AND PTSD Atypical antipsychotics have affinity for D2, alpha-1, and 5-HT2 receptors, with relative affinity differing between agents.12 Iloperidone is a piperidinylbenzisoxazole derivative and thus structurally unique from other antipsychotic agents.13 Its complex receptor binding on dopamine, 5-HT, alpha, and muscarinic receptors is novel in regards to other antipsychotic medications.12 Oral iloperidone is extensively and rapidly absorbed, achieves peak plasma concentrations in 2 to 4 hours, and reaches concentration steady state in 3 to 4 days. Metabolism is mainly conducted through hepatic enzymes
24
Innovations in CLINICAL NEUROSCIENCE
CYP2D6 and CYP3A4. The parent compound (t1/2 =18h) is reduced to P88 (active) and P95 (inactive) metabolites, which have concentration half-lives of 26h and 23h, respectively. The P88 metabolite is centrally acting and believed to have a similar receptor binding profile to the parent compound. The P95 metabolite binds to peripheral alpha-adrenergic receptors and does not cross the blood brain barrier.14 Compared to all other antipsychotics, iloperidone has the highest binding affinity constant (Ki) for alpha-1 noradrenergic autoreceptors. The degree of magnitude for alpha-1 binding affinity is nearly 10-fold higher relative to the nearest comparative agents (iloperidone Ki =0.31 vs. risperidone and ziprasidone Ki= 2.6, 2.7).12 Though multiple antipsychotics have been assessed for benefit in treating PTSD, a recent review found no controlled trials of iloperidone for the treatment of PTSD.15 At this time, open-label studies or case series on the use of this medication in PTSD could not be found in the literature; one placebo-controlled trial examining the effect of iloperidone on select symptoms of PTSD is currently recruiting patients.16 Iloperidone’s alpha-1 antagonism and moderate elimination half-life may have beneficial effects on the reduction of nightmares in addition to hypervigilant symptoms. This hypothesis is supported by animal data, which found that iloperidone doses of 0.3mg/kg prevented disruptions in PPI caused by the alpha-1 agonist cirazoline.17 We are therefore suggesting that based on its unique receptor profile, iloperidone may have a heretofore undiscovered role in treatment of PTSD.
2.
3.
4.
5.
6.
7.
8.
9.
REFERENCES 1.
Baisley SK, Fallace KL, Rajbhandari AK, Bakshi VP. Mutual independence of 5HT(2) and α1 noradrenergic receptors in
[VOLUME 11, NUMBER 5–6, MAY–JUNE 2014]
mediating deficits in sensorimotor gating. Psychopharmacology. 2012;220:465–79. Braff DL, Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry. 1990; 47: 181– 188. Kemner C, Oranje B, Verbaten MN, van Engeland H. Normal P50 gating in children with autism. J Clin Psychiatry. 2002;63:214–217. Magnée M, Oranje B, van Engeland H, Kahn RS, Kemner C. Crosssensory gating in schizophrenia and autism spectrum disorder : EEG evidence for impaired brain connectivity ? Neuropsychologia. 2009;47:1728–1732. Braff DL, Geyer MA, Swerdlow NR. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology. 2001;156:234–258. Karl A, Malta LS, Maercker A. Meta-analytic review of eventrelated potential studies in posttraumatic stress disorder. Biol Psychol. 2006;71:123–147. Alsene KM, Carasso BS, Connors EE, Bakshi VP. Disruption of prepulse inhibition after stimulation of central but not peripheral alpha-1 adrenergic receptors. Neuropsychopharmacology. 2006;31:2150–2161. Alsene KM, Bakshi VP. Modulation of prepulse inhibition by alpha-2 noradrenergic receptors in the locus coeruleus-medial prefrontal cortex pathway.Program No. 546.11. 2009 Neuroscience Meeting Planner. Washingon, DC: Society for Neuroscience, 2009. Online. https://am2012.sfn.org/skins/main/p df/chapter_abstracts/PTTA09Abstr act_Alsene.pdf. Accessed May 21, 2013. Alsene KM, Bakshi VP. Pharmacological stimulation of locus coeruleus reveals a new antipsychotic-responsive pathway for deficient sensorimotor gating. Neuropsychopharmacology.
10.
11.
12.
2011;36:1656–1667. Powell SB, Palomo J, Carasso BS, Bakshi VP, Geyer MA. Yohimbine disrupts prepulse inhibition in rats via action at 5-HT1A receptors, not alpha2-adrenoceptors. Psychopharmacology. 2005;180:491–500. Adams W, van den Buuse M. Hippocampal serotonin depletion facilitates the enhancement of prepulse inhibition by risperidone: possible role of 5-HT(2C) receptors in the dorsal hippocampus. Neuropharmacology. 2011;61:458–67. Correll CU. From receptor
13.
14.
15.
pharmacology to improved outcomes: individualizing the selecting, dosing, and switching of antipsychotics. Eur Psychiatry. 2010;25 Suppl 2:S12–21. Corbett R, Griffiths L, Shipley JE, et al. Iloperidone: preclinical profile and early clinical evaluation. CNS Drug Reviews. 1997;3:120–147. Scott L. Iloperidone in schizophrenia. CNS Drugs. 2009;23:867–880. Maher AR, Maglione M, Bagley S, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for offlabel uses in adults: a systematic
[VOLUME 11, NUMBER 5–6, MAY–JUNE 2014]
16.
17.
review and meta-analysis. JAMA. 2011;306:1359–1369. U.S. National Institutes of Health. Website. 2013. Online. http://www.clinicaltrials.gov/ct2/res ults?term=iloperidone. Accessed May 21,2013. Barr A, Powell S, Markou A, Geyer M. Illoperidone reduces sensorimotor gating deficits in pharmacological models, but not developmental models, of disrupted prepulse inhibition in rats. Neuropharmacology. 2006;51:457–465.
Innovations in CLINICAL NEUROSCIENCE
25
