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Letter to the Editor

Use of Omega-3 Polyunsaturated Fatty Acids as Augmentation Therapy in Treatment-Resistant Schizophrenia

Alfredo B. Cuéllar-Barboza, MD; Jorge A. Sánchez-Ruiz, MD; and Paola M. Corral, MD

Published: May 4, 2017

Use of Omega-3 Polyunsaturated Fatty Acids as Augmentation Therapy in Treatment-Resistant Schizophrenia

To the Editor: Fish oil supplements containing omega-3 fatty acids are among the most commonly used nutraceuticals,1 and while their role as augmentation therapy has been studied in schizophrenia, their benefits are not as clear in treatment-resistant cases. We present a case report of a treatment-resistant patient with schizophrenia who achieved remission with omega-3 fatty acid supplementation.


Case report. Mr A is a 52-year-old Mexican man of white ancestry diagnosed with schizophrenia during his early 20s. According to his family and historical records, he struggled during the initial 5 years of his schizophrenia diagnosis with poor response to several trials of typical antipsychotics and 2 complete trials of electroconvulsive therapy in the context of numerous inpatient treatments. He achieved partial remission with clozapine for approximately 15 years with no blood count abnormalities or impairing side effects. However, negative symptoms presented insidiously, and he became severely impaired, meriting institutionalized care for the next 5 years.

We received an interconsultation 3 years ago after he suffered an acute pulmonary embolism secondary to deep vein thrombosis that required a 5-day stay in the intensive care unit (Brief Psychiatric Rating Scale2 [BPRS] score = 76). Clozapine 600 mg was suspended, and Mr A was switched to haloperidol 20 mg with partial response in hallucinatory behavior and disorganization (BPRS score = 62) but poor response to negative symptoms and extrapyramidal side effects. Several treatment strategies were implemented, including switching to amisulpride 800 mg (8 weeks), asenapine 20 mg (8 weeks), and risperidone 6 mg. The latter was better tolerated, and after 8 weeks of treatment, we started a flupentixol 20-mg augmentation trial; this last option proved the most beneficial (BPRS score = 44).

A year ago, we started omega-3 fatty acid supplementation (eicosapentaenoic acid [EPA] 2,936 mg/day, docosahexaenoic acid [DHA] 1,068 mg). After 4 weeks, we observed an important increase of speech quantity and content. After a 10-week period, Mr A started taking care of himself with little help, drawing, having complex conversations, having more of an appetite, and visiting church and restaurants with help (BPRS score = 20). He presently remains in this state. Mr A and his family agreed to share his case.


Omega-3 polyunsaturated fatty acids (PUFAs) are essential substrates of neuronal membrane metabolism and redox regulation.3 Abnormalities in omega-3 PUFA concentrations contribute to increased inflammatory states in response to psychological stress, potentially contributing to psychiatric disorders.4,5

Omega-3 PUFA supplementation in schizophrenia has shown positive results in 3 clinical trials.6-8 In contrast to Mr A’s case, patients were not treatment-resistant and were younger with significantly shorter illness duration.6-8 Our observation of beneficial effects of omega-3 PUFAs in residual symptoms also contrasts with negative findings by Fenton and colleagues9 in a randomized, double-blind, placebo-controlled clinical trial of supplementation for cognitive impairment and residual symptoms. Studies by Bentsen et al10,11 may hold the key to this discrepancy, as they found a bimodal distribution of omega-3 PUFAs in patients with schizophrenia and different response to supplementation depending on baseline measures. We hypothesize that some, but not all, treatment-resistant patients with omega-3 PUFA deficiencies may benefit greatly from its supplementation. Unfortunately, we did not measure baseline levels in our patient.

The most promising use of omega-3 PUFAs in recent schizophrenia literature explores augmentation therapy in individuals at ultra-high risk for psychosis12-15 or after a first-episode psychosis16,17 with predominantly positive results. Successful preventive measures in patients prone to psychosis will hopefully reduce our need to study treatment-resistant patients like Mr A.


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2. Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychol Rep. 1962;10:799-812.

3. Clandinin MT, Chappell JE, Heim T, et al. Fatty acid utilization in perinatal de novo synthesis of tissues. Early Hum Dev. 1981;5(4):355-366. PubMed doi:10.1016/0378-3782(81)90016-5

4. Simopoulos AP. Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nutr. 1991;54(3):438-463. PubMed

5. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002;21(6):495-505. PubMed doi:10.1080/07315724.2002.10719248

6. Arvindakshan M, Ghate M, Ranjekar PK, et al. Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr Res. 2003;62(3):195-204. PubMed doi:10.1016/S0920-9964(02)00284-0

7. Jamilian H, Solhi H, Jamilian M. Randomized, placebo-controlled clinical trial of omega-3 as supplemental treatment in schizophrenia. Glob J Health Sci. 2014;6(7 spec no):103-108. PubMed doi:10.5539/gjhs.v6n7p103

8. Sivrioglu EY, Kirli S, Sipahioglu D, et al. The impact of omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol: an open-label pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(7):1493-1499. PubMed doi:10.1016/j.pnpbp.2007.07.004

9. Fenton WS, Dickerson F, Boronow J, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry. 2001;158(12):2071-2074. PubMed doi:10.1176/appi.ajp.158.12.2071

10. Bentsen H, Osnes K, Refsum H, et al. A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. Transl Psychiatry. 2013;3:e335. PubMed doi:10.1038/tp.2013.110

11. Bentsen H, Solberg DK, Refsum H, et al. Bimodal distribution of polyunsaturated fatty acids in schizophrenia suggests two endophenotypes of the disorder. Biol Psychiatry. 2011;70(1):97-105. PubMed doi:10.1016/j.biopsych.2011.02.011

12. Amminger GP, Schäfer MR, Schlögelhofer M, et al. Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nat Commun. 2015;6:7934. PubMed doi:10.1038/ncomms8934

13. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154. PubMed doi:10.1001/archgenpsychiatry.2009.192

14. PaweŠ‚czyk T, Grancow M, Kotlicka-Antczak M, et al. Omega-3 fatty acids in first-episode schizophrenia: a randomized controlled study of efficacy and relapse prevention (OFFER): rationale, design, and methods. BMC Psychiatry. 2015;15(1):97. PubMed doi:10.1186/s12888-015-0473-2

15. Markulev C, McGorry PD, Nelson B, et al. NEURAPRO-E study protocol: a multicentre randomized controlled trial of omega-3 fatty acids and cognitive-behavioural case management for patients at ultra high risk of schizophrenia and other psychotic disorders[published online ahead of print August 16, 2015]. Early Interv Psychiatry. 10.1111/eip.12260 PubMed

16. PaweŠ‚czyk T, Grancow-Grabka M, Kotlicka-Antczak M, et al. A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. J Psychiatr Res. 2016;73:34-44. PubMed doi:10.1016/j.jpsychires.2015.11.013

17. Emsley R, Chiliza B, Asmal L, et al. A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophr Res. 2014;158(1-3):230-235. PubMed doi:10.1016/j.schres.2014.06.004

Alfredo B. Cuéllar-Barboza, MDa,b

Jorge A. Sánchez-Ruiz, MDa

Paola M. Corral, MDa

aDepartment of Psychiatry, University Hospital, Universidad Autónoma de Nuevo León, Monterrey, Mexico

bDepartment of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota

Potential conflicts of interest: None.

Funding/support: None.

Published online: May 4, 2017.

Patient consent: The patient and his family consented to publish this case report.

Prim Care Companion CNS Disord 2017;19(3):16l02040

© Copyright 2017 Physicians Postgraduate Press, Inc.

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