The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: An open label trial

Berk, Michael; Dean, Olivia; Cotton, Sue; Gama, Clarissa Severino; Kapczinski, Flávio; Fernandes, Brisa S.; Kohlmann, Kristy; Jeavons, Sue; Hewitt, Karen; Allwang, Christine; Cobb, Heidi; Bush, Ashley I.; Schapkaitz, Ian; Dodd, Seetal; Malhi, Gin S

doi:10.1016/j.jad.2011.06.005

Cited by 161 publications

(103 citation statements)

References 48 publications

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“…Additional open-label data support the use of adjunctive riluzole and adjunctive NAC (109,110). Patients in a small, open-label, imaging study reported improvements in depressive symptoms with riluzole (level 3) (109), while data from a large (n = 149), eight-week, open-label trial found significant improvement in depressive symptoms with adjunctive NAC in patients with BD I, II, or NOS depression (110).…”

Section: Novel or Experimental Agentsmentioning

confidence: 99%

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013

et al. 2012

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Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O’Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI, Lafer B, Birmaher B, Ha K, Nolen WA, Berk M.  Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013.  Bipolar Disord 2012: 00: 000–000. © 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd.The Canadian Network for Mood and Anxiety Treatments published guidelines for the management of bipolar disorder in 2005, with updates in 2007 and 2009. This third update, in conjunction with the International Society for Bipolar Disorders, reviews new evidence and is designed to be used in conjunction with the previous publications.The recommendations for the management of acute mania remain largely unchanged. Lithium, valproate, and several atypical antipsychotic agents continue to be first‐line treatments for acute mania. Monotherapy with asenapine, paliperidone extended release (ER), and divalproex ER, as well as adjunctive asenapine, have been added as first‐line options.For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, as well as olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first‐line options. Lurasidone monotherapy and the combination of lurasidone or lamotrigine plus lithium or divalproex have been added as a second‐line options. Ziprasidone alone or as adjunctive therapy, and adjunctive levetiracetam have been added as not‐recommended options for the treatment of bipolar depression. Lithium, lamotrigine, valproate, olanzapine, quetiapine, aripiprazole, risperidone long‐acting injection, and adjunctive ziprasidone continue to be first‐line options for maintenance treatment of bipolar disorder. Asenapine alone or as adjunctive therapy have been added as third‐line options.

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Section: Novel or Experimental Agentsmentioning

confidence: 99%

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013

et al. 2012

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“…N-acetylcysteine was supplied by Zambon (Milan, Italy), and encapsulated by DFC-Pharmamed Pty Ltd (Sydney, Australia) in accordance with Good Manufacturing Practice guidelines. The choice of dose was based on that used in our previous trials of adjunctive N-acetylcysteine in schizophrenia 14 and bipolar disorder, 10,15 which have appeared to be efficacious and well tolerated in both trials, and is also distanced by a fair margin from the maximum dose of 5,000 mg/d used in published trials. 16 To facilitate double-blinding, the trial medications (both N-acetylcysteine and placebo) were dispensed in identical numbers and capsule formulations in sealed containers by the trial pharmacist.…”

Section: Participant Recruitment and Allocationmentioning

confidence: 99%

“…[6][7][8][9][10] We therefore aimed to test its efficacy in the acute treatment of major depressive disorder (MDD) by conducting a randomized, placebo-controlled trial of N-acetylcysteine as adjunctive treatment. Specifically, we hypothesized that addition of N-acetylcysteine would reduce MontgomeryAsberg Depression Rating Scale (MADRS) 11 scores (primary outcome) in comparison to placebo.…”

mentioning

confidence: 99%

The Efficacy of AdjunctiveN-Acetylcysteine in Major Depressive Disorder

Berk

Dean²,

Cotton³

et al. 2014

J. Clin. Psychiatry

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Objective: Major depressive disorder (MDD) is one of the most common psychiatric disorders, conferring considerable individual, family, and community burden. To date, treatments for MDD have been derived from the monoamine hypothesis, and there is a paucity of emerging antidepressants, especially with novel mechanisms of action and treatment targets. N-acetylcysteine (NAC) is a redox-active glutathione precursor that decreases inflammatory cytokines, modulates glutamate, promotes neurogenesis, and decreases apoptosis, all of which contribute to the neurobiology of depression.Method: Participants with a current episode of MDD diagnosed according to DSM-IV-TR criteria (N = 252) were treated with NAC or placebo in addition to treatment as usual for 12 weeks and were followed to 16 weeks. Data were collected between 2007 and 2011. Results:The omnibus interaction between group and visit for the Montgomery-Asberg Depression Rating Scale (MADRS), the primary outcome measure, was not significant (F 1,520.9 = 1.98, P = .067), and the groups did not separate at week 12 (t 360.3 = −1.12, P = .265). However, at week 12, the scores on the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) differed from placebo (P = .03). Among participants with a MADRS score ≥ 25, NAC separated from placebo at weeks 6, 8, 12, and 16 (P < .05). Additionally, the rate of change between baseline and week 16 was significant (t 221.03 = −2.11, P = .036). NAC treatment was superior to placebo at week 16 for secondary readouts of function and clinical impression. Remission and response were greater in the NAC group at week 16, but not at week 12. The NAC group had a greater rate of gastrointestinal and musculoskeletal adverse events. Conclusions:Being negative at the week 12 end point, and with some positive secondary signals, the study provides only limited support for the role of NAC as a novel adjunctive therapy for MDD. These data implicate the pathways influenced by NAC in depression pathogenesis, principally oxidative and inflammatory stress and glutamate, although definitive confirmation remains necessary.Trial Registration: www.anzctr.org.au Identifier: ACTRN12607000134426 Clin Psychiatry 2014;75(6):628-636 J

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“…memantine, cytidine, riluzole) in bipolar depression. [23,24] There is also preliminary evidence on the efficacy of N-acetylcysteine, a glutathione precursor with neuroprotective effects which also affects glutamatergic neurotransmission, [25] whereas other mitochondrial enhancers, acetyl-L-carnitine and α-lipoic acid were not superior to placebo as an add-on treatment. [26] Although the treatment of cognitive dysfunction in BD has only recently been recognized as an important unmet need, many agents have been already tested with mixed results.…”

Section: Current Limitations and Future Perspectives In Drug Developmmentioning

confidence: 99%

Challenges with bipolar disorder drug discovery

Konstantakopoulos

2016

Expert Opinion on Drug Discovery

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The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: An open label trial

Cited by 161 publications

References 48 publications

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013

The Efficacy of AdjunctiveN-Acetylcysteine in Major Depressive Disorder

Challenges with bipolar disorder drug discovery

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