A Phase 4 interventional study of N-Acetyl Cysteine and sugar pill in Schizophrenia, Psychotic Disorder NOS and Schizoaffective Disorder, sponsored by Indiana University. Completed at 2 sites in United States. Open to participants aged 16 Years to 35 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-05-08.
Sponsored by Indiana University · Phase 4, Interventional, and Treatment
The primary objective of this study is to determine if NAC, added to existing antipsychotic treatment, is superior to placebo for cortical erosion in patients with early stage psychosis. The primary hypothesis is that there will be significantly less cortical erosion as measured by cortical thickness, cortical volume and cortical white matter density (assessed by DTI) in patients treated for 12 months with NAC as compared to those treated with placebo. The secondary objectives of this study are to determine if 12 months of NAC add-on treatment is superior to placebo for fMRI determined working memory and semantic memory tasks, cortical MR spectroscopy measures (glutathione, N-acetylaspartate, and glutamine/glutamate levels), electrophysiologically determined attention measures (e.g., mismatch negativity, P300), symptoms, functional measures and cognitive functioning.
Schizophrenia is a severe, debilitating illness that typically begins during the teen-age years and early twenties, and worsens over time as it evolves into a chronic, life-long disorder. Existing treatments suppress psychotic symptoms but do not prevent the evolution of underlying disease processes that results in poor, long term outcomes. Recent studies have shown that progressive erosion of cortical mass occurs during the early stages of schizophrenia (1-3). The investigators hypothesize that arresting cortical erosion during the early phases of schizophrenia will prevent subsequent clinical deterioration and the descending course of illness associated with this disorder. The investigators propose to establish a research program that will assess the ability of agents with neuroprotective properties to halt cortical loss and thereby prevent subsequent clinical deterioration.
N-acetyl cysteine (NAC) is an attractive molecule for the proposed study because of two of its mechanistic properties. First, it is an established neuroprotective agent. NAC is a precursor to glutathione which is a primary detoxifier of reactive oxygen and other radical molecules which damage neuronal tissue (4-6). Glutathione deficiencies have been well documented in schizophrenia (7, 8). Second, NAC modulates glutamate release. NMDA hypofunction and altered glutamate release have been hypothesized to contribute to the cortical atrophy observed in early stage schizophrenia (9, 10). NAC has been shown to antagonize both the phencyclidine (PCP) effects of increased frontal glutamate levels and induction of social isolation in rodents (11). PCP is a pharmacological model of schizophrenia. In a controlled clinical trial of patients with chronic schizophrenia, NAC improved mismatch negativity, a pre-attentive measure of cortical information processing that has been consistently implicated in the pathophysiology of schizophrenia and has been shown to correlate with cortical erosion in early stage patients (12, 13). In a double-blind, placebo controlled clinical trial of chronic schizophrenic patients, NAC significantly improved general psychopathology scores, negative symptoms and extrapyramidal symptoms (14). NAC was well tolerated with no significant effects on any safety parameter or adverse events. The favorable tolerability of NAC has been further demonstrated in a recent study conducted at IUSM Riley Hospital in children (ages 4 to 12 years) with autism at relatively high doses (dose range of 900 to 4200 mg/day) in which there were no serious adverse events reported and NAC was well tolerated (15).
The investigators propose to determine if NAC has disease modifying potential in early stage schizophrenia. The investigators hypothesize that NAC will improve measures of cortical integrity in early stage schizophrenia and these brain effects will be related to improvements in negative symptoms and cognitive functioning. Primary outcome measures in the trials will be serial assessments of cortical integrity using magnetic resonance structural (cortical thickness, cortical volume, diffuses tensor imaging, DTI). In addition the investigators will assess the possible effects of NAC treatment on other parameters linked to cortical erosion including fMRI coupled with working memory and semantic memory tasks, MR spectroscopy (cortical glutathione, N-acetylaspartate, and glutamine/glutamate levels) and electrophysiological measures (e.g., mismatch negativity, P300). The investigators will also determine the relationship between effects of NAC on negative symptoms, positive symptoms, functional status, cognition (BACS), and safety parameters; and brain indices.
3,471 studies on the registry are indexed under Schizophrenia; 472 are open to participants now.
This study's enrollment of 60 is below the median of 70 across 2,872 interventional studies indexed under Schizophrenia.
Browse Schizophrenia studies →Indiana University is the lead sponsor of 958 studies on the registry; 200 are open to participants now.
Of its 142 completed or terminated interventional studies of FDA-regulated products, 112 (79%) have results posted.
Counted across the registry records on this site, refreshed daily.
SUBJECTS DIAGNOSED WITH A PSYCHOTIC DISORDER
Inclusion Criteria:
Exclusion Criteria:
HEALTHY CONTROL SUBJECTS
The comparison subjects will consist of 40 healthy normal volunteers recruited from the community who will be age and gender matched to subjects diagnosed with a psychotic disorder entering the NAC treatment study
Inclusion Criteria:
Exclusion Criteria:
NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. This approximate dose was effective and well tolerated in a recent study of treatment refractory obsessive-compulsive disorder by Krystal and colleagues at Yale (16). In addition, a double-blind placebo controlled trial recently completed at IUSM Riley Hospital in children (age 4 to 12 years) with autism spectrum disorders used doses ranging from 900 mg/day to 4200 mg/day and reported no serious adverse events and found the agent well tolerated (15). Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.
Drug: N-Acetyl Cysteine
matched placebo
Other: sugar pill
NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 480 mg of NAC. Dosing will begin at 480 mg/d and titrated up by 480 mg/d each week until a maximum dose of 2880 mg/d (BID) is reached. This approximate dose was effective and well tolerated in a recent study of treatment refractory obsessive-compulsive disorder by Krystal and colleagues at Yale (16). In addition, a double-blind placebo controlled trial recently completed at IUSM Riley Hospital in children (age 4 to 12 years) with autism spectrum disorders used doses ranging from 900 mg/day to 4200 mg/day and reported no serious adverse events and found the agent well tolerated (15). Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose
matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Cortical Thickness
We anticipate that 12 months treatment with NAC as an add-on treatment will show significantly less cortical erosion as measured by cortical thickness than treatment with placebo
Time frame: 12 months
Cortical Volume
We anticipate that 12 months treatment with NAC as an add-on treatment will show a difference in cortical volume than treatment with placebo
Time frame: 12 months
Working Memory
determine if 12 months of NAC add-on treatment is superior to placebo as determined by brain activity during n-back working memory task during fMRI.
Time frame: Baseline and 12 months
Number of Participants With Glutamine/Glutamate Level Changes
Identify number of participants with 12 months of NAC treatment who had glutamine/glutamate level changes as measured by cortical magnetic resonance spectroscopy measures.
Time frame: 12 months
Attention Measures
determine if 12 months of NAC add-on treatment is superior to placebo for attention measures (e.g., mismatch negativity, P300) as measured by electrophysiology methods. Electrophysiology measures will be recorded from a 64 channel, silver/silver-chloride scalp electrode montage.
Time frame: 12 months
Symptoms of a Psychotic Disorder
Determine if 12 months of NAC add-on treatment is superior to placebo for symptom management of a psychotic disorder as assessed by the Positive and Negative Syndrome Scale (PANSS). The PANSS is a semi-structured interview, containing 30 items that assess positive, negative, and general psychopathology symptoms. Positive symptoms=7 items, negative symptoms=7 items, and general psych.=16 items. Scores for each item range from 1-absent to 7-extreme. To calculate total score, all items on the scale are summed to yield a score from 30-210,a lower score reflecting fewer symptoms. To calculate factor scores various items from positive, negative, and general psych. are summed together to yield Cognitive/Disorganized, Negative, and Positive factor scores. Cog/Disorg factor scores sum 7 items, ranging from 7-49. Neg factor scores sum 7 items, ranging from 7-49. Pos factor scores sum 8 items, ranging from 8-56. For all factor scores a lower score reflects less symptom severity.
Time frame: 12 months
Cognitive Functioning
determine if 12 months of NAC add-on treatment is superior to placebo for cognitive functioning as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). The BACS is a battery specifically designed to measure treatment-related changes in cognition by utilizing 6 tasks, and has alternate forms, thus minimizing practice effects. Each task generates a raw score (with a higher score indicating better performance): verbal memory 0-75; digit sequencing 0-28; token motor task 0-100; semantic\&letter fluency 0-148; symbol coding 0-110; and tower of London 0-22. The raw scores are used to generate a composite score that is calculated by summing t-scores derived by comparisons with a normative sample of 404 healthy controls. The six brief assessments' t-scores, are summed, and averaged to provide a composite t-score. The composite score min and max are between -43 and 100. A higher score indicating better cognitive performance.
Time frame: Baseline and 12 months
Functional Status
determine if 12 months of NAC add-on treatment is superior to placebo for functional measures as measured by the Personal and Social Performance Scale (PSP). The PSP scale is a 100-point, single item, clinician rated scale to assess 4 domains of functioning, including personal and social relationships, socially useful activities, self care and disturbing and aggressive behaviors. A score from 0-100 is generated, with a higher score representing better performance.
Time frame: Baseline and 12 months
Mismatch Negativity Voltage Differences
Determine if 12 months of NAC add-on treatment is superior to placebo for attention measures as measured by the voltage of the Mismatch Negativity (MMN) of the event-related potential. The voltage of the peak MMN response was measured at the Fz electrode site.
Time frame: 12 months
Symptoms of a Psychotic Disorder
determine if 12 months of NAC add-on treatment is superior to placebo for symptom management of a psychotic disorder as assessed by the Clinical Global Impressions Severity Scale (CGI-S). The CGI-S is used for repeated evaluations of global psychopathology and is a 7 point Likert scale rating severity on a scale of 1 (normal, not ill) to 7 (very severely ill).
Time frame: 12 months
| Milestone | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| Started | 30 | 30 |
| Completed | 14 | 18 |
| Not completed | 16 | 12 |
We anticipate that 12 months treatment with NAC as an add-on treatment will show significantly less cortical erosion as measured by cortical thickness than treatment with placebo
| mm | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| Left Total Cortical Thickness at 52 Weeks | 2.53 ± 0.03 | 2.54 ± 0.03 |
| Right Total Cortical Thickness at 52 weeks | 2.51 ± 0.03 | 2.52 ± 0.03 |
| Left Caudal Middle Frontal Thickness at 52 Weeks | 2.59 ± 0.04 | 2.57 ± 0.04 |
| Right Caudal Middle Frontal Thickness at 52 Weeks | 2.49 ± 0.04 | 2.49 ± 0.05 |
| Left Middle Temporal Thickness at 52 Weeks | 2.84 ± 0.04 | 2.87 ± 0.05 |
| Right Middle Temporal Thickness at 52 Weeks | 2.91 ± 0.04 | 2.95 ± 0.05 |
| Left Superior Parietal Thickness at 52 Weeks | 2.16 ± 0.03 | 2.21 ± 0.04 |
| Right Superior Parietal Thickness at 52 Weeks | 2.17 ± 0.03 | 2.18 ± 0.04 |
determine if 12 months of NAC add-on treatment is superior to placebo as determined by brain activity during n-back working memory task during fMRI.
| Bold signal change | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| Baseline pre exposure to NAC | 0.299 ± .20 | 0.356 ± .24 |
| 6 months exposure to NAC | 0.351 ± .24 | 0.398 ± .28 |
| 12 months exposure to NAC | 0.315 ± .185 | 0.406 ± .23 |
Identify number of participants with 12 months of NAC treatment who had glutamine/glutamate level changes as measured by cortical magnetic resonance spectroscopy measures.
| Participants | NAC Treated Early Psychosis Patients | Placebo Group |
|---|---|---|
| Number of Participants With Glutamine/Glutamate Level Changes | 18 | 0 |
determine if 12 months of NAC add-on treatment is superior to placebo for attention measures (e.g., mismatch negativity, P300) as measured by electrophysiology methods. Electrophysiology measures will be recorded from a 64 channel, silver/silver-chloride scalp electrode montage.
| Hz | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| EEG Alpha power | 3.81 ± 0.40 | 4.18 ± 0.73 |
| EEG Delta power | 2.96 ± 0.25 | 3.46 ± 0.35 |
| EEG Gamma power | 0.37 ± 0.03 | 0.47 ± 0.05 |
| EEG Theta power | 1.33 ± 0.30 | 1.33 ± 0.35 |
| Auditory Steady State Response 40 Hz | 0.05 ± 0.01 | 0.06 ± 0.01 |
Determine if 12 months of NAC add-on treatment is superior to placebo for symptom management of a psychotic disorder as assessed by the Positive and Negative Syndrome Scale (PANSS). The PANSS is a semi-structured interview, containing 30 items that assess positive, negative, and general psychopathology symptoms. Positive symptoms=7 items, negative symptoms=7 items, and general psych.=16 items. Scores for each item range from 1-absent to 7-extreme. To calculate total score, all items on the scale are summed to yield a score from 30-210,a lower score reflecting fewer symptoms. To calculate factor scores various items from positive, negative, and general psych. are summed together to yield Cognitive/Disorganized, Negative, and Positive factor scores. Cog/Disorg factor scores sum 7 items, ranging from 7-49. Neg factor scores sum 7 items, ranging from 7-49. Pos factor scores sum 8 items, ranging from 8-56. For all factor scores a lower score reflects less symptom severity.
| scores on a scale | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| PANSS Total Score at 52 Weeks | 46.79 ± 2.24 | 56.44 ± 2.32 |
| PANSS Cognitive/Disorganized Factor at 52 Weeks | 11.09 ± 0.68 | 13.68 ± 0.70 |
| PANSS Negative Symptom Factor at 52 Weeks | 10.35 ± 1.02 | 13.22 ± 1.06 |
| PANSS Positive Symptom Factor at 52 Weeks | 14.77 ± 1.05 | 16.38 ± 1.09 |
determine if 12 months of NAC add-on treatment is superior to placebo for cognitive functioning as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). The BACS is a battery specifically designed to measure treatment-related changes in cognition by utilizing 6 tasks, and has alternate forms, thus minimizing practice effects. Each task generates a raw score (with a higher score indicating better performance): verbal memory 0-75; digit sequencing 0-28; token motor task 0-100; semantic\&letter fluency 0-148; symbol coding 0-110; and tower of London 0-22. The raw scores are used to generate a composite score that is calculated by summing t-scores derived by comparisons with a normative sample of 404 healthy controls. The six brief assessments' t-scores, are summed, and averaged to provide a composite t-score. The composite score min and max are between -43 and 100. A higher score indicating better cognitive performance.
| scores on a scale | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| BACS Composite Score Baseline | 26.91 ± 3.22 | 27.70 ± 3.35 |
| BACS Composite Score at 52 Weeks | 30.03 ± 3.22 | 29.37 ± 3.36 |
determine if 12 months of NAC add-on treatment is superior to placebo for functional measures as measured by the Personal and Social Performance Scale (PSP). The PSP scale is a 100-point, single item, clinician rated scale to assess 4 domains of functioning, including personal and social relationships, socially useful activities, self care and disturbing and aggressive behaviors. A score from 0-100 is generated, with a higher score representing better performance.
| scores on a scale | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| PSP Adjusted Score at Baseline | 62.51 ± 2.26 | 64.46 ± 2.35 |
| PSP Adjusted Score at 52 Weeks | 64.51 ± 2.33 | 65.44 ± 2.42 |
Determine if 12 months of NAC add-on treatment is superior to placebo for attention measures as measured by the voltage of the Mismatch Negativity (MMN) of the event-related potential. The voltage of the peak MMN response was measured at the Fz electrode site.
| microvolts | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| Mismatch Negativity Voltage Differences | -2.51 ± 0.28 | -3.44 ± 0.38 |
We anticipate that 12 months treatment with NAC as an add-on treatment will show a difference in cortical volume than treatment with placebo
| mm^3 | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| Total Cortical Gray Matter Volume at 52 Weeks | 233.0 ± 5.2 | 235.8 ± 6.0 |
| Total Cortical White Matter Volume at 52 Weeks | 423.8 ± 11.5 | 418.5 ± 13.1 |
determine if 12 months of NAC add-on treatment is superior to placebo for symptom management of a psychotic disorder as assessed by the Clinical Global Impressions Severity Scale (CGI-S). The CGI-S is used for repeated evaluations of global psychopathology and is a 7 point Likert scale rating severity on a scale of 1 (normal, not ill) to 7 (very severely ill).
| scores on a scale | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| Symptoms of a Psychotic Disorder | 2.78 ± 0.18 | 3.00 ± 0.19 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| N-Acetyl Cysteine | — | 3/30 (10%) | 28/30 (93.3%) |
| Sugar Pill | — | 2/30 (6.7%) | 27/30 (90%) |
| Event | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| Psychosis ExacerbationPsychiatric disorders | 2/30 | 2/30 |
| Asthma ExacerbationRespiratory, thoracic and mediastinal disorders | 1/30 | 0/30 |
| Event | N-Acetyl Cysteine | Sugar Pill |
|---|---|---|
| Weight GainMetabolism and nutrition disorders | 3/30 | 6/30 |
| Nausea and VomitingGastrointestinal disorders | 3/30 | 5/30 |
| Depressed MoodPsychiatric disorders | 4/30 | 4/30 |
| HeadacheNervous system disorders | 3/30 | 2/30 |
| SedationGeneral disorders | 2/30 | 3/30 |
| InsomniaGeneral disorders | 3/30 | 2/30 |
| Illness ExacerbationPsychiatric disorders | 3/30 | 0/30 |
| DizzinessNervous system disorders | 2/30 | 3/30 |
| Upper Respiratory InfectionInfections and infestations | 2/30 | 3/30 |
| Suicidal IdeationPsychiatric disorders | 0/30 | 2/30 |
| Age, Categorical(Participants) | N-Acetyl Cysteine | Sugar Pill | Total |
|---|---|---|---|
| <=18 years | 2 | 1 | 3 |
| Between 18 and 65 years | 28 | 29 | 57 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | N-Acetyl Cysteine | Sugar Pill | Total |
|---|---|---|---|
| Mean | 22.2 ± 4.2 | 25.0 ± 5.2 | 23.1 ± 4.8 |
| Sex: Female, Male(Participants) | N-Acetyl Cysteine | Sugar Pill | Total |
|---|---|---|---|
| Female | 7 | 6 | 13 |
| Male | 23 | 24 | 47 |
| Region of Enrollment(participants) | N-Acetyl Cysteine | Sugar Pill | Total |
|---|---|---|---|
| United States | 30 | 30 | 60 |
This study is completed, as verified in Apr 2019. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Indiana University