getting ‘the nac’ of treatment: a literature review of n ...€¦ · • n-acetylcysteine (nac)...

Getting ‘the NAC’ of treatment: a Literature

Review of N-acetylcysteine (NAC) in Schizophrenia

Sandy BaptieLMPS Pharmacist Resident 2019-20

Background• N-acetylcysteine (NAC) is a medication indicated to treat acetaminophen

overdose and as a mucolytic in cystic fibrosis and chronic obstructive pulmonary disease

• NAC is relevant to psychiatry for novel uses and may be beneficial in refractory conditions

• Over the past few years, emerging evidence is showing uses in psychiatric and neurologic disorders

• Current recruiting studies are underway• NAC treatment appears to be safe and tolerable• Further well designed, larger controlled trials are needed for specific

psychiatric and neurological disorders

Acetylcysteine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Sept 14 2019N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011 Mar; 36(2): 78–86.

N-Acetylcysteine (NAC)Mechanism of Action

-NAC a prodrug converted to cysteine in bloodstream-Cysteine is precursor to antioxidant glutathione (GSH)-Administration of acetylcysteine replenishes glutathione stores

Dosage Formulations

-Effervescent Tablet-Capsule-Vials of IV solution for oral, inhalation, IV

Adherence Very unpleasant taste and odorAdministration A: Bioavailability very low (6-10%)

D: Vd: 0.47 L/kg; 66-87% protein boundM: Hepatic. De-acetylated by the liver to cysteine and subsequently metabolized.

Half-Life: 5.6 hours (adults), 11 hours (neonates)E: Urine excretion 13-38%

Cost $3.90 for 10mL vial of 200mg/mL, comes as a pack of 10 vials (Pharmacare)

Lexicomp N-acetylcysteine

Acetylcysteine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Sept 14 2019Dean, O et al. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011 Mar; 36(2): 78–86.

Natural Health Product• 500mg, 600mg, extra strength (1000mg) product available over the

counter• Natural Factors states pure NAC in product• Advertised uses: respiratory function, chronic bronchitis, antioxidant

https://www.amazon.ca/s?k=n-acetylcysteine&ref=nb_sb_noss

Mechanism of NAC in Psychiatry• Theoretical Mechanism of Action of NAC related to pathology of

Schizophrenia:– Studies reporting chronic schizophrenia associated with

glutathione (GSH) deficiency in CSF and oxidative stress associated with impaired metabolism of glutathione

– Schizophrenia abnormal metabolism of dopamine and glutamate– Postmortem assay of caudate nucleus decrease of GSH– NAC = precursor to the antioxidant glutathione, involved in

detoxification of reactive oxygen and other radical species– NAC shown to have anti-inflammatory properties that targets

oxidative stress – NAC postulated to help regulate amount of glutamate present in

the extracellular space and facilitate dopamine release

Dean, O et al. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011 Mar; 36(2): 78–86.

Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia -a double-blind, randomized, placebo-controlled trial. Biological Psychiatry 2008;64(5):361-8.

PICOP Patients with schizophreniaI Adjunctive N-acetylcysteine (NAC)C Adjunctive PlaceboO Symptoms of psychosis (schizophrenia)

(PANSS)

PANSS minimum clinically important difference (MCID):• Total PANSS score:15.3-point (34.0%) change from baseline

Hermes ED, Sokoloff D, Stroup TS, Rosenheck RA. Minimum clinically important difference in the Positive and Negative Syndrome Scale with data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). J Clin Psychiatry. 2012 Apr;73(4):526-32. doi: 10.4088/JCP.11m07162.

Literature SearchDatabases Search Terms

Medline, Google Scholar, Clinical Trials database, PubMed, Cochrane Library

(N-acetylcysteine OR NAC OR Acetylcysteine), (Psychiatric disorder OR psychosis OR schizophrenia OR schizophrenic disorder OR (disorder, schizophrenic)

• 13 total RCTs: 2 RCTs Included• 3 included in reported MA excluded• 8 non-relevant conditions excluded• 2 RCT measuring non-relevant outcomes

• 2 SR/MA, 1 Cochrane Review: 1 Meta-analysis included• 1 Cochrane Review excluded

• non-relevant comparators• 1 Meta-analysis excluded

• Retracted, errors that undermine conclusions drawn• 1 Meta-analysis included 2018

Conus, et al. 2017

Conus P, Seidman L, Fournier M, et al. N-Acetylcysteine in a double-blind randomized placebo controlled trial: toward biomarker-guided treatment in earlyPsychosis. Schizophrenia Bulletin. 10/2017; 44(2) 317-327

Conus, et al. 2017

Method • Double-blind, randomized, placebo-controlled 2-center trial (USA, Switzerland), intention to treat analysis

Participants • N = 63 early psychosis patients Duration • 2009 – 2014; treatment for 6 months, monthly visits, 1 month

follow up visitIntervention& Comparator

• NAC effervescent tablets (900mg) at a dosage of 2700 mg/day (morning: 1800mg; evening: 900mg) adjunct to standard medication (antipsychotics reported in chlorpromazine equivalents)

VS• Standard medication (antipsychotics reported in

chlorpromazine equivalents)


Conus, et al. 2017Inclusion Exclusion• Male or female aged 18–40• Having a psychotic disorder,

defined by reaching the “psychosisthreshold” subscale on the Comprehensive Assessmentof At Risk Mental States scale (CAARMS)

• Less than 12 months of treatment for psychosis

• Sufficient stability to participate in the study

• Presence of clinically significant medical illnesses (including peptic ulcer)

• Organic mental disease • Severe cerebral trauma• Mental retardation (IQ <70)• Pregnancy/ lactation• Current treatment with antioxidants

(Vitamin E, selenium, multivitamins) • Substance induced psychosis

Conus, et al. 2017

Outcomes • 1o Outcome• PANSS Negative

• 2o Outcome:• Symptoms

• PANSS Positive• PANSS General

• Functional• Global Assessment of Functioning (GAF)• Social Functioning Assessment Scales (SOFAS)

• 2o Outcome: Redox Markers• Brain GSH• Blood GSH


Conus, et al. 2017


Population Baseline NAC (N=31) Comparator (N=30)Mean Age 26.1 24.7Male sex – no (%) 26 (84%) 21 (70%)Smoking – no (%) 11 (56%) 17 (45%)Duration of Psychosis, mean 2.3 years 2.0 yearsSchizophrenia – no (%) 21 (67%) 19 (61%)Schizoaffective Disorder – (%) 3 (9.67%) 4 (13.33%)Other – (%) 7 (22.58%) 7 (23.33%)Chlorpromazine Equivalents (mean) 309mg 309mgPositive PANSS 14.3 15.0Negative PANSS 15.6 17.3Blood Glutathione mM 0.77 0.84Brain Glutathione mM 0.87 1.12

Conus, et al. 2017 PANSS Outcomes

Outcome β (estimate of NAC effect VS placebo)

Standard Error P Value

PANSS Negative 0.161 0.237 0.50PANSS Positive 0.176 0.207 0.39PANSS General 0.598 0.359 0.09

Conus P, Seidman L, Fournier M, et al. N-Acetylcysteine in a double-blind randomizedplacebo controlled trial: toward biomarker-guided treatment in earlyPsychosis. Schizophrenia Bulletin. 10/2017; 44(2) 317-327

Conus, et al. 2017 Glutathione Results


Outcome at 6 months

NAC (N=13)

Placebo(N=12)

Overall Difference

P Value

Blood Glutathione (%)

+18.8 -1.9 +17 0.05

Brain Glutathione(%)

+26.6 -4.6 +28 0.005

Conus, et al. 2017 Adverse Drug Reactions


Category of side effects (Symptoms) NAC (n = 31) Placebo (n = 30)p-

values

2 months 6 months2 months

6 months

Neurologic(Tremor, Rigidity, Akathisia)

0.16 0.22 0.18 0.20.95

Autonomic(Dry mouth, Increased salivation, Nausea, Constipation)

0.32 0.72 0.59 0.33 0.19

Cardiovascular (Hypotension, Hypertension, Oedema)

0.36 0.17 0.18 0.07 0.1

Psychological(Emotional indifference, Sedation)

0.28 0.39 0.59 0.27 0.27

Sexual function(Diminished sexual desire, Orgasmic dysfunction, Erectile dysfunction, Ejaculatory dysfunction)

0.32 0.17 0.41 0.07 0.72

Limitations

• Methodological– Small sample size– Analyzed various forms of psychoses together– Adjunct medications were various types of second generation

antipsychotics

• Clinical– Already modest baseline negative symptoms levels – Chlorpromazine equivalents may not correlate well with second

generation antipsychotics

Breier, et al 2018

Breier A; Liffick, Emily; Hummer, Tom A et al. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 09 2018 199:395-402

Breier, et al. 2018Method • Double-blind, placebo-controlled randomized trialParticipants • 60 patients with DSM-IV diagnosis of schizophrenia,

schizophreniform, schizoaffective or psychosis not otherwise specified

Duration • 52 weeks duration of treatment Intervention & Comparator

• NAC initiated at 600 mg/day and then increased over 1st 4 weeks until max dose of 1800mg BID capsules, added to stable schizophrenia medication (chlorpromazine equivalents)

VS• Stable schizophrenia medication (chlorpromazine

equivalents)

Breier A; Liffick, Emily; Hummer, Tom A et al. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 199:395-402, 2018 09

Breier, et al. 2018


Inclusion Criteria Exclusion Criteria• Male or Female age 16 – 35 • Within 3 years of 1st onset of non-

affective, non-substance use induced psychosis

• IQ < 70• Current Substance Use Disorder• Pregnancy• Serious medical disorders

Breier, et al. 2018Outcomes • 1o Outcome

• PANSS Score• PANSS Total• PANSS Positive• PANSS Negative• PANSS General

• 2o Outcome• Personal and Social Performance Scale (PS)• Clinical Global Impressions Severity Scale (CGI-S)• Brief Assessment of Cognition in Schizophrenia (BACS)


Breier, et al. 2018 Study CharacteristicsPopulation Baseline NAC (N=30) Comparator (N=30)Age 22.2 25.0Male sex no (%) 77% 80%White ethnicity 10 (33%) 11 (37%)Duration of Psychosis 1.3 years 1.4 yearsSchizophrenia 16 (53%) 25 (83%)Schizoaffective 4 (13%) 1 (3%)Schizophreniform 6 (20%) 2 (7%)Psychosis NOS 4 (13% 2 (7%)PANSS Total Score, mean 56.7 56.4Illness Duration 1.3 years 1.4 yearsChlorpromazine Equivalents 105.4mg 126.5mg


Breier, et al. 2018 Results

Ratings Least Squares Mean (Standard Error)

F (P)

Baseline 52 Weeks Time x GroupPANSS Total

NAC 56.21 (2.13) 46.79 (2.24) 14.7(<0.001)Placebo 56.77 (2.21) 56.44 (2.32)

PANSS General

NAC 13.34 (0.64) 11.09 (0.68) 13.7(<0.001)Placebo 13.26 (0.67) 13.68 (0.70)

PANSS Negative

NAC 13.89 (0.97) 10.35 (1.02) 5.1(0.024)Placebo 14.47 (1.01) 13.22 (1.06)

PANSPositive

NAC 16.99 (1.01) 14.77 (1.05) 1.4(0.23)Placebo 17.40 (1.05) 16.38 (1.09)

Breier Alan; Liffick, Emily; Hummer, Tom A et al. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 199:395-402, 2018 09

Breier, et al. 2018 Results

Ratings LSM (SE) F (P)Baseline 52 Weeks Time x Group

BACS NAC 26.91 (3.22) 30.03 (3.22) 0.5 (0.47)Placebo 27.70 (3.35) 29.37 (3.36)

PSP NAC 62.51 (2.26) 64.51 (2.33) 0.3 (0.60)Placebo 64.46 (2.35) 65.44 (2.42)

CGI NAC 3.17 (0.18) 2.78 (0.18) 1.7 (0.19)Placebo 3.23 (0.18) 3.00 (0.19)

Breier Alan; Liffick, Emily; Hummer, Tom A et al. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 199:395-402, 2018 09

Intention to Treat?

Limitations• Methodological

– Analyzed various forms of psychosis together – Differences in baseline psychosis diagnoses– Did not analyze for type of medication (adjunctive mood stabilizers,

antidepressants) – Allowed to switch to other psychotropic medications – High attrition rate – Questionable Intention to Treat– High dosage NAC utilized– Utilization of chlorpromazine equivalent doses

• Clinical– Subject age may limit generalizability to older populations– Early in their diagnosis – A 10 point decrease in PANSS may not be clinically significant

Zeng, et al (2018)

Zeng, et al. 2018Design Meta-analysis of 3 RCTs

Number N= 307 patients, mean age 34.9 years, 59.6% ♂Population Adult physically healthy patients with diagnosis of schizophrenia in acute

phase of the illness receiving treatment with antipsychoticsSelection Criteria All RCTs up to September 10 2017

Intervention + Comparator

Adjunctive NAC VS Control Group• Farokhina et al: NAC 500mg BID x 7 days, then 1000mg BID

x remainder 7 weeks po adjunct to Risperidone ~4mgVS Risperidone ~4mg (2-6mg)

• Zhang, et al: NAC 6000mg adjunct to Risperidone (1-6mg) VS Risperidone 1-6mg

• Berk, et al: NAC 1000mg po BID (capsules) adjunct to Chlorpromazine Equivalents of ~716mgVS Chlorpromazine Equivalents ~598mg

Outcomes • 1o: Clinical efficacy using Positive and Negative Syndrome Scale (PANSS)• 2o: Any cause discontinuation rate• 2o: Adverse Drug Reactions

Zeng, et al. N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2018;137: 391–400

Meta-Analysis Study CharacteristicsFarokhina, et al 2013(Iran)July 2011- February 2013

• Randomized, double-blind, placebo controlled, parallel-group study

• N= 42 patients chronic schizophrenia, PANSS >60 in the active phase of their illness N= 21 NAC, N=21 comparator

• Treatment for 8 weeks• Average age 33, male 65%, 100% inpatient• SS margin of change= 5 points • 10 outcome: difference in decrease of PANSS negative

scoreZhang, et al 2015(In Chinese)

• Randomized, double-blind, placebo-controlled study• N= 121 patients with schizophrenia • Treatment for 8 weeks• Average age 33.9, male 52.1%, inpatient % not reported

Berk et al 2008(Australia)November 2002- July 2005

• Randomized, multicentre, double-blind, placebo-controlled study

• N= 140 patients with schizophrenia and PANSS > 54; N= 69 for NAC, N= 71 for comparator

• Treatment for 24 weeks• Average age 37, 70% male, 95% outpatient• 10 outcome: PANSS Total score


Meta-analysis Results

Outcome PANSS Study (Subjects) I2 (%) SMD (95% CI) P ValuePANSS Total Score

3 (247) 84 -0.74 (-1.43, -0.06)

0.03

PANSS Positive Score

3 (247) 66 -0.16 (-0.62, 0.29)

0.48

PANSS Negative Score

3 (247) 93 -0.59 (-2.00, 0.10)

0.08

PANSS General Score

3 (247) 59 -0.20 (-0.62, 0.21)

0.34


Meta-analysis Results

Outcome Study (Subjects) I2 (%) RR (95% CI) P ValueDiscontinuationRate

3 (307) 0 0.96 (0.65, 1.43) 0.84

Drowsiness 2 (167) 0 1.79 (0.67, 4.79 0.25Headache 2 (186) 5 0.92 (0.49, 1.72) 0.78Constipation 2 (186) 0 0.83 (0.48, 1.45) 0.51Diarrhea 2 (186) 0 1.56 (0.87, 2.80) 0.14Nausea 2 (186) 29 1.08 (0.52, 2.24) 0.83


AMSTAR Meta-analysis1. Did the research questions and inclusion criteria for the review include the components of PICO?

Yes

2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?

PartialYes

3. Did the review authors explain their selection of the study designs for inclusion in the review?

Yes

4. Did the review authors use a comprehensive literature search strategy? PartialYes

5. Did the review authors perform study selection in duplicate? Yes6. Did the review authors perform data extraction in duplicate? Yes7. Did the review authors provide a list of excluded studies and justify the exclusions? No8. Did the review authors describe the included studies in adequate detail? Partial

Yes9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?

Yes

Shea, et al 2017 AMSTAR BMJ. 2017 Sep 21;358:j4008.

AMSTAR Meta-analysis10. Did the review authors report on the sources of funding for the studies included in the review?

No

11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?

Yes

12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?

No

13. Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review?

No

14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?

No

15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?

No

16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?

Yes

Shea, et al 2017 AMSTAR BMJ. 2017 Sep 21;358:j4008.

Limitations• Methodological

– Only 3 RCTs included in MA – Slightly different primary outcomes (PANSS negative VS PANSS Total score)– Low quality meta-analysis (AMSTAR)– 2/3 studies used intention to treat analysis– Unclear if studies restricted use of other antioxidants– Various dosing schedules of NAC– Short study duration (8 weeks) for two of the studies– Utilization of various antipsychotics, chlorpromazine equivalents

• Clinical– Statistically significant margin of change (5) may not be clinically important– Research conducted from Australia, China, Iran may not be reflective of Canadian

population– Only physically healthy patients were recruited in the RCTs– Unsure of NAC product equivalency in all trials

Conclusion

• Recommendation for NAC use:– Adherent, non-pregnant, otherwise healthy

relatively young patients with early schizophrenia displaying primarily negative symptoms, where efficacy and adherence can be monitored

Questions?

References• Dean O, Giorlando F, Berk, Michael, et al. N-acetylcysteine in psychiatry: current

therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011 Mar; 36(2): 78–86.

• Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia - a double-blind, randomized, placebo-controlled trial. Biological Psychiatry 2008;64(5):361-8. [PUBMED: 18436195]

• Zeng, W, Zhang Q-E, Cai D-B, et al. N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials. Acta PsychiatrScand. 2018; 137: 391–400

• Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, Henry DA. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017 Sep 21;358:j4008.

• Berk M, Copolov D, Dean O et al. N-acetyl cysteine as a glutathione precursor for schizophrenia–a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008;64:361–368. 29.

References• Breier, Alan; Liffick, Emily; Hummer, Tom A et al. Effects of 12-month, double-blind

N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 09/2018;199:395-402.

• Acetylcysteine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Sept 14 2019

• Danivas, V and Venkatasubramanian, G. Current perspectives on chlorpromazine equivalents: Comparing apples and oranges! Indian J Psychiatry. 2013 Jun; 55(2): 207–208.

• Hermes ED, Sokoloff D, Stroup TS, Rosenheck RA. Minimum clinically important difference in the Positive and Negative Syndrome Scale with data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). J Clin Psychiatry. 2012 Apr;73(4):526-32. doi: 10.4088/JCP.11m07162.

Berk, et al. 2008. N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial

Design Randomized, multicentre, double-blind, placebo-controlled studyMethods Allocation: randomized

Blindness: double blind. No further detailsDuration: 24 weeksSetting: mixed, but 95% were outpatients

Participants Diagnosis: Schizophrenia (DSM-IV): (PANSS) total score of 55, or at ≥ 2 of the positive and/or negative items being 3, or Clinical Global Impression-Severity (CGI-S) ≥ 3.N = 140; 84 completed treatmentSex: 70% maleAge: average age 37 yearsExclusion: abnormal renal, hepatic, thyroid, hematological findings; a systemic medical disorder, pregnancy, on mood stabilizers, on antioxidants

Interventions 1. NAC 1g po BID. N = 692. Placebo. N = 71 (usual antipsychotics medication)

Outcomes PANSS: improvement in PANSS total, PANSS neg, PANSS general, not in Posscale. Effect Size 0.43-0.57CGI-S & CGI-I: showed improvementAdverse events: NSSDrop out rates: NSS

Berk, et al. 2008. Biol Psyc 64(6)

Berk 2008 Risk of BiasBias Judgement Support for judgement

Random sequence generation (selection bias)

Low Risk Simple randomization

Allocation concealment (selection bias)

Low Risk Independent coordinated generated sequence

Blinding of personnel and participants

Low Risk Double-blind

Blinding of outcome assessment (detection bias)

Low Risk Raters blinded

Incomplete outcome data (attrition bias)

Low Risk 135/140 participants available for LOCF analysis

Selective reporting (reporting bias) Low Risk Main outcomes reported

Berk, et al. 2008. Biol Psyc 64(6)

getting ‘the nac’ of treatment: a literature review of n ...€¦ · • n-acetylcysteine (nac)...

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