Pharmacologically-augmented Cognitive Therapies (PACTs) for Schizophrenia.

Schizophrenia Clinical Trial

Official title:

Pharmacologic Augmentation of Neurocognition and Cognitive Training in Psychosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02634684
• Other study ID #: 5R01MH059803-15
• Secondary ID: Eyeblink Study
• Status: Completed
• Phase: Phase 2
• Start date: July 1, 2014
• Est. completion date: August 2020

Study information

• Verified date: August 2021
• Source: University of California, San Diego
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This application seeks renewed support for MH59803, "Dopaminergic substrates of startle gating across species," to extend a clear path of "bench-to-bedside" progress towards a critical paradigm shift in therapeutic models for schizophrenia (SZ) and schizoaffective disorder, depressed type (SZA): the use of Pharmacologic Augmentation of Cognitive Therapies (PACTs). This novel therapeutic strategy for SZ/SZA directly addresses the need for more effective treatments for this devastating disorder. MH59803 has investigated the neural regulation of laboratory-based measures of deficient information processing in SZ/SZA patients, using rodents and healthy human subjects (HS) to explicate the biology of these deficits, and to establish a rational basis for developing novel therapies for SZ/SZA. In its first 9 years, MH59803 studies of the neural regulation of prepulse inhibition (PPI) of startle in rats focused on basic neurobiological and molecular mechanisms. Over the past 2 years of support, MH59803 studies moved "from bench-to-bedside," focusing on dopamine (DA) agonist effects on PPI and neurocognition in HS, and their regulation by genes identified in cross-species studies. These studies detected biological markers that predict PPI-enhancing and pro-cognitive effects of the DA releaser, amphetamine (AMPH) in humans, leading to specific predictions of AMPH effects on PPI, neurocognition and Targeted Cognitive Training in SZ/SZA patients. If confirmed in the present application, these predictions could help transform therapeutic approaches to SZ/SZA. This renewal application of MH59803 thus reflects a logical progression of studies at systems and molecular levels, translated first to HS, and now to potentially transformative therapeutic models in SZ/SZA patients.

Description:

MH59803 demonstrated that AMPH (20 mg p.o.) significantly increased PPI and neurocognitive performance (MATRICS Consensus Cognitive Battery; MCCB) in HS characterized by specific performance-based or genetic biomarkers, including the val/val genotype for the rs4680 polymorphism of catechol-O-methyltransferase (COMT). Mechanistically-informative results were detected in studies of AMPH effects on PPI in rats with high vs. low brain regional Comt expression. Together with several reports of improved neurocognition and no adverse effects of acute or sustained AMPH administration to antipsychotic (AP)-medicated SZ/SZA patients, MH59803 findings provide a strong rationale for the next goal of this application: to test the potential utility of AMPH in a paradigm of biomarker-informed "PACTs". This "next step" is highly innovative - never previously reported, or perhaps even attempted - and consistent with National Institute of Mental Health (NIMH) objectives, directly challenges existing models for SZ/SZA therapeutics. Investigators will determine whether a test dose of 10 mg AMPH p.o. administered to biomarker-identified, AP-medicated SZ/SZA patients generates predicted increases in PPI, MCCB performance, and sensory discrimination learning in a Targeted Cognitive Training (TCT) module. In total, Investigators will leverage knowledge generated through converging cross-species studies in MH59803, to directly advance scientific and clinical domains, by testing the effects of a pro-cognitive drug on neurophysiological and neurocognitive performance, and Targeted Cognitive Training, in biomarker-stratified subgroups of SZ/SZA patients. Aim: To assess acute effects of AMPH (0 vs 10 mg po) on PPI, neurocognition and computerized TCT in AP-medicated SZ/SZA patients. Hypothesis: PPI- and MCCB-enhancing effects of AMPH seen previously in HS will also be detected in SZ/SZA patients, as will TCT-enhancing effects of AMPH. Prediction: In a within-subject, placebo-controlled, randomized design, AMPH (10 mg po) will increase PPI and enhance MCCB and TCT performance in medicated SZ/SZA patients, particularly among those characterized by low basal performance levels and/or the val/val rs4680 COMT polymorphism. Concurrent HS testing will confirm and extend findings of AMPH effects on PPI and neurocognition, and help interpret findings in SZ/SZA patients. In all participants, the aim to assess acute effects of 0 vs. 10 mg po dextroamphetamine (AMPH) on Prepulse Inhibition (PPI), neurocognition MATRICS: Consensus Cognitive Battery; MCCB, and computerized Targeted Cognitive Training (TCT). Hypothesis: AMPH will enhance: 1. PPI 2. neurocognition (MCCB performance) 3. computerized TCT performance in biomarker-identified SZ/SZA patients. 4. The PPI and MCCB-enhancing effects of AMPH seen previously in HS will also be detected in SZ/SZA patients, as will TCT-enhancing effects of AMPH. Prediction: In a within-subject, placebo-controlled, randomized design, AMPH (10 mg po) will increase PPI and enhance MCCB and TCT performance in medicated SZ/SZA patients, particularly among those characterized by low basal performance levels and/or the val/val rs4680 COMT polymorphism. Concurrent HS testing will confirm and extend findings of AMPH effects on PPI and neurocognition, and help interpret findings in SZ/SZA patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: August 2020
• Est. primary completion date: August 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• 18-55 years old:
• Drug Free (No recreational/street drugs)
• Diagnosis of Schizophrenia or Schizoaffective Disorder, Depressed Type
• Must be stable on antipsychotic medication for at least 1 month
• Any medications other than antipsychotic medications need to be stable for at least 1 week

Exclusion Criteria:

• Dominant hand injury
• Hearing impairment at 40 dB
• Irregular menstrual cycle or cycle is no within in 25-35 days (menopausal is eligible)
• EKG, conduction abnormalities confirmed by cardiologist
• Reading component of Wide Range Achievement Test 4 (WRAT4) Score less than 70
• Any serious illness, including: Insulin-dependent diabetes, HIV, AIDS, cancer, stroke, heart attack, uncontrolled hypothyroidism
• Sleep apnea
• A diagnosis of epilepsy or history of seizures with loss of consciousness
• Open/closed head injury with loss of consciousness greater than 1 minute at any time in the lifetime
• Blood pressure: Systolic Blood Pressure < 90 or > 160, Diastolic Blood Pressure < 45 or > 95
• Heart Rate < 55 or > 110
• Current use of Dexatrim or drugs containing phenylephrine (eligible if not used for at least 72 hours prior to participation)
• Current use of St. John's Wort, Milk Thistle (eligible if for at least 1 month)
• Self report of any illicit drug use within the last 30 days
• Positive urine toxicology
• Self-report of any use of ecstasy, lysergic acid diethylamide (LSD), mushrooms, gamma hydroxybutyrate (GHB), ketamine, phencyclidine (PCP), heroin or any intravenous-drugs within past year
• If there is a history of substance abuse/addiction, participant must be in remission for at least 6 months
• Within 1 month of recent psychiatric hospitalization
• Current mania
• Dementia/Alzheimer's diagnosis
• Mania episode meeting criteria outlined in the MINI-International Neuropsychiatric Interview Plus 6.0 (M.I.N.I. plus 6.0) anytime in the lifetime (hypomania/Bipolar II eligible)

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• Dextroamphetamine
Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) and completes approximately 6 hours of testing in the laboratory. One week later, that participant receives a single pill of the alternate comparator and is again tested in the laboratory. Thus, in total, each participant receives one placebo pill and one active pill, separated by one week.
• Placebo
Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) and completes approximately 6 hours of testing in the laboratory. One week later, that participant receives a single pill of the alternate comparator and is again tested in the laboratory. Thus, in total, each participant receives one placebo pill and one active pill, separated by one week.

Locations

Country	Name	City	State
United States	Clinical Teaching Facility (CTF-B102) at UCSD Medical Center	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Diego

Country where clinical trial is conducted

United States, 

References & Publications (32)

Barch DM, Carter CS. Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers. Schizophr Res. 2005 Sep 1;77(1):43-58. — View Citation

Chew ML, Mulsant BH, Pollock BG, Lehman ME, Greenspan A, Mahmoud RA, Kirshner MA, Sorisio DA, Bies RR, Gharabawi G. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008 Jul;56(7):1333-41. doi: 10.1111/j.1532-5415.2008.01737.x. Epub 2008 May 26. — View Citation

Chou HH, Talledo JA, Lamb SN, Thompson WK, Swerdlow NR. Amphetamine effects on MATRICS Consensus Cognitive Battery performance in healthy adults. Psychopharmacology (Berl). 2013 May;227(1):165-76. doi: 10.1007/s00213-012-2948-x. Epub 2013 Jan 12. — View Citation

Dinse HR, Ragert P, Pleger B, Schwenkreis P, Tegenthoff M. Pharmacological modulation of perceptual learning and associated cortical reorganization. Science. 2003 Jul 4;301(5629):91-4. — View Citation

Fisher M, Holland C, Merzenich MM, Vinogradov S. Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia. Am J Psychiatry. 2009 Jul;166(7):805-11. doi: 10.1176/appi.ajp.2009.08050757. Epub 2009 May 15. — View Citation

Fisher M, Holland C, Subramaniam K, Vinogradov S. Neuroplasticity-based cognitive training in schizophrenia: an interim report on the effects 6 months later. Schizophr Bull. 2010 Jul;36(4):869-79. doi: 10.1093/schbul/sbn170. Epub 2009 Mar 5. — View Citation

Goldberg TE, Bigelow LB, Weinberger DR, Daniel DG, Kleinman JE. Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia. Am J Psychiatry. 1991 Jan;148(1):78-84. — View Citation

Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004 Dec 15;72(1):41-51. Review. — View Citation

Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996 Mar;153(3):321-30. Review. — View Citation

Hamidovic A, Dlugos A, Palmer AA, de Wit H. Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine. Psychiatr Genet. 2010 Jun;20(3):85-92. doi: 10.1097/YPG.0b013e32833a1f3c. — View Citation

Hamidovic A, Dlugos A, Palmer AA, de Wit H. Polymorphisms in dopamine transporter (SLC6A3) are associated with stimulant effects of D-amphetamine: an exploratory pharmacogenetic study using healthy volunteers. Behav Genet. 2010 Mar;40(2):255-61. doi: 10.1007/s10519-009-9331-7. Epub 2010 Jan 21. — View Citation

Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76. — View Citation

Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA; CATIE Investigators; Neurocognitive Working Group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry. 2007 Jun;64(6):633-47. — View Citation

Kumari V, Premkumar P, Fannon D, Aasen I, Raghuvanshi S, Anilkumar AP, Antonova E, Peters ER, Kuipers E. Sensorimotor gating and clinical outcome following cognitive behaviour therapy for psychosis. Schizophr Res. 2012 Feb;134(2-3):232-8. doi: 10.1016/j.schres.2011.11.020. Epub 2011 Dec 3. — View Citation

Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005 Sep 22;353(12):1209-23. Epub 2005 Sep 19. Erratum in: N Engl J Med. 2010 Sep 9;363(11):1092-3. — View Citation

Light GA, Swerdlow NR. Neurophysiological biomarkers informing the clinical neuroscience of schizophrenia: mismatch negativity and prepulse inhibition of startle. Curr Top Behav Neurosci. 2014;21:293-314. doi: 10.1007/7854_2014_316. — View Citation

Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. Epub 2003 Apr 25. — View Citation

Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, Essock S, Fenton WS, Frese FJ 3rd, Gold JM, Goldberg T, Heaton RK, Keefe RS, Kraemer H, Mesholam-Gately R, Seidman LJ, Stover E, Weinberger DR, Young AS, Zalcman S, Marder SR. The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008 Feb;165(2):203-13. doi: 10.1176/appi.ajp.2007.07010042. Epub 2008 Jan 2. — View Citation

Pietrzak RH, Snyder PJ, Maruff P. Amphetamine-related improvement in executive function in patients with chronic schizophrenia is modulated by practice effects. Schizophr Res. 2010 Dec;124(1-3):176-82. doi: 10.1016/j.schres.2010.09.012. Epub 2010 Oct 13. — View Citation

Pietrzak RH, Snyder PJ, Maruff P. Use of an acute challenge with d-amphetamine to model cognitive improvement in chronic schizophrenia. Hum Psychopharmacol. 2010 Jun-Jul;25(4):353-8. doi: 10.1002/hup.1118. — View Citation

Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004 Nov;61(11):1136-44. — View Citation

Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57. Review. — View Citation

Shilling PD, Saint Marie RL, Shoemaker JM, Swerdlow NR. Strain differences in the gating-disruptive effects of apomorphine: relationship to gene expression in nucleus accumbens signaling pathways. Biol Psychiatry. 2008 Apr 15;63(8):748-58. Epub 2008 Feb 20. — View Citation

Swerdlow NR, Bhakta S, Chou HH, Talledo JA, Balvaneda B, Light GA. Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis. Neuropsychopharmacology. 2016 Jan;41(2):419-30. doi: 10.1038/npp.2015.162. Epub 2015 Jun 11. — View Citation

Swerdlow NR, Light GA, Sprock J, Calkins ME, Green MF, Greenwood TA, Gur RE, Gur RC, Lazzeroni LC, Nuechterlein KH, Radant AD, Ray A, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Sugar CA, Tsuang DW, Tsuang MT, Turetsky BI, Braff DL. Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS. Schizophr Res. 2014 Feb;152(2-3):503-12. doi: 10.1016/j.schres.2013.12.004. Epub 2014 Jan 7. — View Citation

Swerdlow NR. Are we studying and treating schizophrenia correctly? Schizophr Res. 2011 Aug;130(1-3):1-10. doi: 10.1016/j.schres.2011.05.004. Epub 2011 Jun 8. — View Citation

Swerdlow NR. Beyond antipsychotics: pharmacologically-augmented cognitive therapies (PACTs) for schizophrenia. Neuropsychopharmacology. 2012 Jan;37(1):310-1. doi: 10.1038/npp.2011.195. — View Citation

Talledo JA, Sutherland Owens AN, Schortinghuis T, Swerdlow NR. Amphetamine effects on startle gating in normal women and female rats. Psychopharmacology (Berl). 2009 May;204(1):165-75. doi: 10.1007/s00213-008-1446-7. Epub 2009 Jan 16. — View Citation

Tarasenko M, Perez VB, Pianka ST, Vinogradov S, Braff DL, Swerdlow NR, Light GA. Measuring the capacity for auditory system plasticity: An examination of performance gains during initial exposure to auditory-targeted cognitive training in schizophrenia. Schizophr Res. 2016 Apr;172(1-3):123-30. doi: 10.1016/j.schres.2016.01.019. Epub 2016 Feb 2. — View Citation

Turetsky BI, Calkins ME, Light GA, Olincy A, Radant AD, Swerdlow NR. Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophr Bull. 2007 Jan;33(1):69-94. Epub 2006 Nov 29. Review. — View Citation

Vinogradov S, Fisher M, de Villers-Sidani E. Cognitive training for impaired neural systems in neuropsychiatric illness. Neuropsychopharmacology. 2012 Jan;37(1):43-76. doi: 10.1038/npp.2011.251. Epub 2011 Nov 2. Review. — View Citation

Wilkinson GS, Robertson GJ (2006) WRAT4: Wide Range Achievement Test professional manual, 4th edn Psychological Assessment Resources: Lutz, FL

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Prepulse Inhibition (PPI)	PPI was assessed with 42 trials of 6 types: 118 dB 40 ms pulse alone (P) & the same P preceded 10, 20, 30, 60, or 120 ms by a prepulse (pp) 16 dB over background. Startle magnitude (SM), habituation, latency & latency facilitation were measured to interpret changes in PPI.; %PPI = 100 x [(SM on P trials) - (SM on pp+P trials)] / SM on P trials. Example: SM on P trials = 80 units SM on pp+P trials = 30 units %PPI = 100 x (80-30)/80 = 100 x 50/80 = 62.5%; Greater %PPI mean the reflex has been inhibited to a greater extent in the presence of a pp.; %PPI can't exceed 100: when SM on pp+P trials = 0, then %PPI = 100 x (SM on P trials - 0)/SM on P trials = 100 x 1 = 100%.; However, %PPI can theoretically be infinitely negative since SM on pp+P trials could be infinitely large ("prepulse facilitiation" (PPF)), i.e. SM is potentiated in the presence of a pp. PPF is "normal" at very short & very long pp intervals, but not within a species-specific physiological range of intervals.	two visits, 1 week apart, each visit lasting approximately 6 hours
Secondary	MATRICS Consensus Cognitive Battery Performance (MCCB)	The T-score indicates the performance on a neurocognitive battery of tests. Higher score reflects better performance.	two visits, 1 week apart, each visit lasting approximately 6 hours
Secondary	Targeted Cognitive Training (TCT): PositScience, Inc.	Auditory discrimination learning: Subjects identify direction (up vs. down) of 2 consecutive sound sweeps. Parameters (e.g. inter-sweep interval, sweep duration) are established for subjects to maintain 80% correct responses. On screen and test days, subjects complete 1h of TCT. Analytic software yields the key measures: auditory processing speed (APS) and APS "learning". APS is the shortest inter-stimulus interval at which a subject performs to criteria and APS learning is the difference (ms) between the first APS and the best APS of the subsequent trials. A smaller APS reflects "better" discrimination (i.e., subject correctly identified frequency "sweep" direction despite a smaller ms gap between stimuli) and a larger ms value for APS learning reflects more learning, i.e., faster APS with repeated trials. Limits for APS are capped at 0-to-1000 ms; values for APS learning are capped at (-) 1000-to-APS.	two visits, 1 week apart, each visit lasting approximately 6 hours