Pharmacologically-augmented Cognitive Therapies (PACTs) for Schizophrenia.

NCT02634684 | Completed Phase 2 Results DMC

• 2 other identifiers: 5R01MH059803-15Eyeblink Study
• Study Type: interventional
• Target: 82
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Schizophrenia

Keywords

Schizophrenia; Schizoaffective Disorder; Mental Disorders; Anti-Dyskinesia Agents; Antiparkinson Agents; Central Nervous System Agents; Dopamine Agents; Excitatory Amino Acid Agents; Excitatory Amino Acid Antagonists; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Pharmacologic Actions; Physiological Effects of Drugs; Therapeutic Uses; Prepulse inhibition; Neurocognition; Working memory; Dextroamphetamine; MATRICS Consensus Cognitive Battery; Pharmacologic Augmentation of Cognitive Therapies; Sensory discrimination learning; Targeted Cognitive Training; rs4680 polymorphism of catechol-O-methyltransferase (COMT)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• MATRICS Consensus Cognitive Battery Performance (MCCB)

  two visits, 1 week apart, each visit lasting approximately 6 hours

• Targeted Cognitive Training (TCT): PositScience, Inc.

  two visits, 1 week apart, each visit lasting approximately 6 hours

Study Arms (2)

dextroamphetamine

ACTIVE COMPARATOR

Drug: Dexedrine, dextroamphetamine, d-amphetamine. Dosage form, frequency and duration: Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) 30 minutes after arriving at the lab. The participant then completes approximately 6 hours of testing in the laboratory. The participant stays at the lab for 7.5 hours in order to monitor physical condition in case the participant received the active pill 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.

Drug: Dextroamphetamine; Drug: Placebo

Placebo

PLACEBO COMPARATOR

Drug: Dexedrine, dextroamphetamine, d-amphetamine Dosage form, frequency and duration: Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) 30 minutes after arriving at the lab. The participant then completes approximately 6 hours of testing in the laboratory. The participant stays at the lab for 7.5 hours in order to monitor physical condition in case the participant received the active pill 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.

Drug: Dextroamphetamine; Drug: Placebo

Interventions

Dextroamphetamine DRUG

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.

Also known as: d-amphetamine, Dexedrine

Placebo; dextroamphetamine

Placebo DRUG

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; dextroamphetamine

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Diego: lead

Study Sites (1)

Clinical Teaching Facility (CTF-B102) at UCSD Medical Center

San Diego, California, 92103, United States

Location

Related Publications (32)

• Swerdlow NR. Beyond antipsychotics: pharmacologically-augmented cognitive therapies (PACTs) for schizophrenia. Neuropsychopharmacology. 2012 Jan;37(1):310-1. doi: 10.1038/npp.2011.195. No abstract available.

  PMID: 22157876 BACKGROUND

• 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. doi: 10.1016/j.schres.2004.12.019.

  PMID: 16005384 BACKGROUND

• 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.

  PMID: 19448187 BACKGROUND

• 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.

  PMID: 19269924 BACKGROUND

• 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.

  PMID: 26851143 BACKGROUND

• 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.

  PMID: 22048465 BACKGROUND

• 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.

  PMID: 18510583 BACKGROUND

• 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.

  PMID: 23314393 BACKGROUND

• 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. doi: 10.1056/NEJMoa051688. Epub 2005 Sep 19.

  PMID: 16172203 BACKGROUND

• 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. doi: 10.1126/science.1085423.

  PMID: 12843392 BACKGROUND

• 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. doi: 10.1176/ajp.148.1.78.

  PMID: 1984711 BACKGROUND

• Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996 Mar;153(3):321-30. doi: 10.1176/ajp.153.3.321.

  PMID: 8610818 BACKGROUND

• 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. doi: 10.1016/j.schres.2004.09.009.

  PMID: 15531406 BACKGROUND

• 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.

  PMID: 20414144 BACKGROUND

• 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.

  PMID: 20091113 BACKGROUND

• Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76. doi: 10.1093/schbul/13.2.261.

  PMID: 3616518 BACKGROUND

• 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. doi: 10.1001/archpsyc.64.6.633.

  PMID: 17548746 BACKGROUND

• 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.

  PMID: 22138048 BACKGROUND

• 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. doi: 10.1073/pnas.0931309100. Epub 2003 Apr 25.

  PMID: 12716966 BACKGROUND

• 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.

  PMID: 24850080 BACKGROUND

• 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.

  PMID: 18172019 BACKGROUND

• 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.

  PMID: 20947305 BACKGROUND

• 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.

  PMID: 20521327 BACKGROUND

• 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. doi: 10.1001/archpsyc.61.11.1136.

  PMID: 15520361 BACKGROUND

• 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.

  PMID: 9881538 BACKGROUND

• 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. doi: 10.1016/j.biopsych.2007.10.015. Epub 2008 Feb 20.

  PMID: 18083141 BACKGROUND

• 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.

  PMID: 21645998 BACKGROUND

• 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.

  PMID: 26062785 BACKGROUND

• 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.

  PMID: 24405980 BACKGROUND

• 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.

  PMID: 19148623 BACKGROUND

• 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. doi: 10.1093/schbul/sbl060. Epub 2006 Nov 29.

  PMID: 17135482 BACKGROUND

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

  BACKGROUND

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders; Mental Disorders

Interventions

Dextroamphetamine

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders

Intervention Hierarchy (Ancestors)

Amphetamine; Amphetamines; Phenethylamines; Ethylamines; Amines; Organic Chemicals

Results Point of Contact

• Title: Neal Swerdlow, M.D., Ph.D.
• Organization: UC San Diego

nswerdlow@health.ucsd.edu

619-543-6270

Study Officials

• Neal R. Swerdlow, M.D., Ph.D.

  UC San Diego

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry and Director of the Research Residency Track at the University of California, San Diego, School of Medicine.

Study Record Dates

• First Submitted: December 14, 2015
• First Posted: December 18, 2015
• Study Start: July 1, 2014
• Primary Completion: August 1, 2020
• Study Completion: August 1, 2020
• Last Updated: August 17, 2021
• Results First Posted: August 16, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)