Novel Approaches to Bipolar: What Worked, and What Did Not, in 2019


The first part of this series covered updates on traditional psychotropics-lithium, anticonvulsants, antipsychotics, and more. Here, Part 2 examines anti-inflammatories, natural supplements, and mitochondrial therapies.


See Part 1 of this 2-part series: Bipolar Disorder: Practice-Changing Trials from 2019



Recently, I culled the crop of randomized controlled trials from 2019 in bipolar disorder. I was hoping there would be enough to supply a year-end article, but this was a big harvest, so I have broken it into two parts. The first* covered updates on traditional psychotropics-lithium, anticonvulsants, antipsychotics, as well as transcranial magnetic stimulation and thyroid augmentation. This article summarizes more novel approaches to the disorder: anti-inflammatories, natural supplements, and mitochondrial therapies.

N-acetylcysteine: knocked down, but not ELIMINATED

The biggest disappointment of the year was the anti-inflammatory N-acetylcysteine (NAC), which failed in 3 controlled trials of bipolar depression.1-3 NAC is the main antioxidant in the brain, and it showed promise in an earlier controlled trial from 2008.4 What is important to understand is that the new studies are different from the 2008 trial. They focused on full episodes of bipolar depression, and only tested it for 4 to 5 months. In the original study, NAC did not work until month 6, and it worked for patients with subsyndromal depression who were not in a full episode.4

In schizophrenia, where NAC improved negative symptoms, it took even longer to work: 6 to 12 months.5 In practice, it is difficult to know how a treatment is working after such a long stretch, but a pearl from the 2008 study4 can help you figure out who should stay on it. Those who got better felt worse within 4 weeks of stopping it.

Mixed results for anti-inflammatories and mitochondrial therapies

NAC is part of two developing stories in bipolar disorder: inflammation and mitochondrial dysfunction. These pathways are thought to play a causative role in bipolar disorder, and NAC has protective effects in both. Other anti-inflammatories that were put to the test in 2019 had mixed results. On the positive side, two anti-inflammatories that work on the COX-2 pathway, celecoxib and aspirin, had promising results as augmentation agents in bipolar depression, building on prior research with these agents.2,6 Celecoxib was dosed at 200 mg bid as an add-on to escitalopram. Aspirin was dosed high (1000 mg qd) as an add-on to n-acetylcysteine, but a lower dose (81 mg bid) worked in an earlier controlled trial as augmentation of minocycline (100 mg bid), an anti-inflammatory antibiotic.7

The news was not so good for two other anti-inflammatories in 2019. Pioglitazone, an anti-diabetic agent with anti-inflammatory and glutamatergic effects, failed in a small RCT despite succeeding in a similar trial from 2015.8 Likewise, atorvastatin has positive trials in depression and cognition but failed to repeat that success in a small 2019 trial that focused on cognitive function in bipolar and unipolar depression.9 Though primarily used to lower cholesterol, this statin has anti-inflammatory properties that are thought to mediate its psychiatric effects.

What about the mitochondrial theory? That one fell short in 2019. One of the treatment arms in the NAC trials tested a cocktail of 16 nutraceuticals with potential mitochondrial benefits. Although the mix included compounds with known antidepressant effects-coenzyme Q10, acetyl-l-carnitine, and NAC itself-it ultimately failed to separate from placebo.3

The bottom line

The role of NAC in bipolar disorder has been curtailed but not eliminated. It is one of few therapies that can work for subsyndromal depressive symptoms, and those are a common part of this illness, particularly in bipolar II. NAC also protects the kidneys against lithium toxicity, at least in animal studies.10 This antioxidant is low cost, safe, and well-tolerated (constipation is the only adverse effect I have seen in over a thousand trials). The dose is 1000 mg bid, and product recommendations are here.

Celecoxib is one of the better studied anti-inflammatories in depression, both bipolar and unipolar types.11 Although well-tolerated, long-term use of celecoxib can increase the risk of internal bleeding, stroke, heart attacks, and possible nephrotoxicity. Short-term use can minimize those risks, but even then, celecoxib should be reserved for treatment-resistant cases. Aspirin has fewer studies, but fewer risks (stroke and bleeding are the main problems). Aspirin also has a secondary benefit appreciated by many patients with bipolar disorder. It improves sexual dysfunction in men on lithium (240 mg qd).12

*See Dr Aiken’s earlier article, Bipolar Disorder: Practice-Changing Trials from 2019, at


The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for The Depression and Bipolar Workbook and from W.W. Norton & Co. for Bipolar, Not So Much.

Dr Aiken is the Director of the Mood Treatment Center, Editor in Chief of The Carlat Psychiatry Report, and Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He is the author of The Depression and Bipolar Workbook and coauthor, with Jim Phelps, MD, of Bipolar, Not So Much. He can be heard in the weekly Carlat Psychiatry Podcast with his co-host Kellie Newsome, PMH-NP. Dr Aiken is Section Chief of Psychiatric Times.


1. Ellegaard PK, Licht RW, Nielsen RE, et al. The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study. J Affect Disord. 2019;245:1043–1051.

2. Bauer IE, Green C, Colpo GD, et al. A double-blind, randomized, placebo-controlled study of aspirin and n-acetylcysteine as adjunctive treatments for bipolar depression. J Clin Psychiatry. 2018;80(1):18m12200.

3. Berk M, Turner A, Malhi GS, et al. A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo [published correction appears in BMC Med. 2019 Feb 17;17:35]. BMC Med. 2019;17:18.

4. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468–475.

5. Yolland CO, Hanratty D, Neill E, et al. Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia. Aust N Z J Psychiatry. 2019 Dec 11:4867419893439 [Epub ahead of print].

6. Halaris A, Cantos A, Johnson K, Hakimi M, Sinacore J. Modulation of the inflammatory response benefits treatment-resistant bipolar depression: A randomized clinical trial. J Affect Disord. 2020;261:145–152.

7. Savitz JB, Teague TK, Misaki M, et al. Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry. 2018;8:27.

8. Aftab A, Kemp DE, Ganocy SJ, et al. Double-blind, placebo-controlled trial of pioglitazone for bipolar depression. J Affect Disord. 2019;245:957–964.

9. Fotso Soh J, Almadani A, Beaulieu S, et al. The effect of atorvastatin on cognition and mood in bipolar disorder and unipolar depression patients: A secondary analysis of a randomized controlled trial. J Affect Disord. 2020;262:149–154.

10. Efrati S, Averbukh M, Berman S, et al. N-Acetylcysteine ameliorates lithium-induced renal failure in rats. Nephrol Dial Transplant. 2005;20:65-70.

11. Köhler-Forsberg O, N Lydholm C, Hjorthøj C, et al. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139:404–419.

12. Saroukhani S, Emami-Parsa M, Modabbernia A, et al. Aspirin for treatment of lithium-associated sexual dysfunction in men: randomized double-blind placebo-controlled study. Bipolar Disord. 2013;15:650–656.

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