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Omega-3 fatty acids as a psychotherapeutic agent for a pregnant
schizophrenic patient
a a b ,
*
Kuan-Pin Su , Winston W. Shen , Shih-Yi Huang
a
Departments of Psychiatry, Taipei Medical University Wan Fang Hospital and School of Medicine, Taipei, Taiwan b
Institute of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan
Received 7 February 2001; accepted 22 May 2001
Abstract
Because of the potential adverse events and teratogenesis of antipsychotic drugs, it is important to find a safe and effective treatment for pregnant women with severe mental illness. The membrane hypothesis of schizophrenia provides a rationale to treat symptoms of schizophrenia with omega-3 PUFAs. We report a 30-year-old married woman with chronic schizophrenia, who experienced an episode of acute exacerbation of psychotic symptoms during pregnancy. After entering into an open trial of omega-3 PUFAs monotherapy, she showed a dramatic improvement in both positive and negative symptoms of schizophrenia and a significant increase of omega-3 PUFA composition in erythrocyte membrane. There were no adverse effects in this treatment. Thus, omega-3 PUFAs could be both beneficial and therapeutic to pregnant schizophrenic women. 2001 Elsevier Science B.V. All rights reserved.
Keywords: Omega-3 polyunsaturated fatty acids (PUFAs); Pregnancy; Schizophrenia; Teratogenesis; Ecosapentaenoic acid (EPA); Docosahexaenoic acid (DHA)
1. Introduction PUFAs are classified into two main groups, omega-3 (or
n23) and omega-6 (or n26) families. The parent fatty acid
Because of teratogenesis and other adverse events in the of omega-3 family is alpha-linolenic acid (ALA; 18:3n2
fetus, avoidance of pregnancy and withholding of drug 3), and that of n26 family is linoleic acid (LA; 18:2n26).
therapy during pregnancy are commonly suggested to Omega-3 PUFAs are found in plant and marine sources,
minimize the risk of fetal drug exposure. However, these such as marine-derived omega-3 PUFAs including high
suggestions are not often possible in treating a pregnant levels of ecosapentaenoic acid (EPA; 20:5n23) and
woman who has a serious psychiatric illness. Once a docosahexaenoic acid (DHA; 22:6n23). Unlike saturated
decision to offer pharmacotherapy is made, the clinicians fatty acids, omega-3 PUFAs are found to have many health
face lots of limitations and considerations, including benefits in neonates and women in pregnancy and
lacta-efficacy of the drugs available, the anticipated response of tion. Recently, one preliminary double-blind,
placebo-con-the individual patient, and placebo-con-the overall toxicity profile of placebo-con-the trolled trial (Stoll et al., 1999) seems to suggest the
drug for the mother and fetus (Committee on Drugs, omega-3 PUFAs could improve the outcome, especially
American Academy of Pediatrics, 2000). Thus, to find a for the prevention of recurrent depression (Su et al., 2000a)
safe and effective pharmacotherapy for the severe in the bipolar patients. We therefore reviewed the effects of
psychiatrically ill pregnant women is clinically important. omega-3 PUFAs on psychiatric disorders (Su et al.,
The use of omega-3 polyunsaturated fatty acids 2000b): Horrobin et al. (1994) proposed membrane
hy-(PUFAs) in pregnant women is increasingly common. The pothesis of schizophrenia, which was supported by
reveal-ing the abnormalities of omega-3 PUFAs in the frontal cortex of the postmortem brain tissue (Horrobin et al.,
*Corresponding author. Tel.: 1886-2-2736-1661; fax:
1886-2-2737-1991) and red cell membrane (Yao et al., 1994), as well as
3112.
E-mail address: [email protected] (S.-Y. Huang). an association between dietary omega-3 PUFAs intake and
0924-977X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. P I I : S 0 9 2 4 - 9 7 7 X ( 0 1 ) 0 0 0 9 8 - 0
findings not only suggested a possible etiology for schizo- evening dosing. phrenia, but also give the rationale to treat schizophrenic
patients with omega-3 PUFAs. Therefore, omega-3 PUFAs 2.2. Fatty acids analysis of red blood cells
could be promising therapeutic alternatives for psychiatric
patients during pregnancy and lactation (Freeman, 2000). Blood samples were analyzed for individual fatty acids
Here, we are reporting a case of unmedicated pregnant with gas chromatography of methyl esters. Individual fatty
schizophrenic patient successfully treated with omega-3 acids were identified by comparison of gas
chromatog-PUFAs (EPA / DHA). The patient had a dramatic reduction raphy (Lipid Standards, FAMEs) (Sigma Co., St. Louis,
in both positive and negative symptoms of schizophrenia MO, USA). The step-by-step procedures are described
and a significant change in red blood cell membrane elsewhere (Edwards et al., 1998; Maes et al., 1999).
omega-3 PUFA compositions.
3. Results 2. Experimental procedures
Fig. 1 depicts that there had been no changes in the 2.1. Case report
PANS S scores before omega-3 PUFA treatment (week 4 to week 0) and that the treatment with omega-3 PUFAs led Miss A, a 30-year-old married woman who came to our
to remarkable improvements in both positive and negative psychiatric service for her acute exacerbation of auditory /
symptoms of schizophrenia between weeks 2 and 4. The visual hallucinations, bizarre delusion and sleep /
behav-improvement persisted from week 4 to the following ioural disturbance.
months. She received haloperidol therapy after the delivery Since age 25 years, Miss A had persistent hallucinations
and her condition has continued to maintain stable. and a complex delusional system, including when she was
Prior to treatment with omega-3 PUPA, the patient had pregnant with her first child. Since she was 28 years old,
abnormally low erythrocyte membrane levels of all the the patient also has had obvious negative symptoms of
major long-chain omega-3 and omega-6 fatty acids. As schizophrenia, including anhedonia and social withdrawal.
shown in Table 1, omega-3 PUFA treatment produced a Due to stigma, her families deprived her of professional
significant change of omega-3 PUFA compositions,
treatment. During the first trimester of this pregnancy, her
omega-3 / omega-6 ratios, and AA / EPA ratios in erythro-psychotic symptoms and behavioural disturbance
worse-cyte membrane. ned, therefore, her obstetrician referred her to us for
psychiatric care.
In mental status examination, Miss A looked anxious
and agitated. She had vivid auditory / visual hallucinations 4. Discussion
and florid delusions. Her mood was depressed. Her speech
was relevant and coherent, but her thought form was Miss A showed remarkable improvements in both
impaired. She was orientated to time, place and person. positive and negative symptoms of schizophrenia after
She had intact recent memory as shown in her ability to receiving omega-3 fatty acids. The results of this patient’s
recall three objects in 5 min. The abilities in speech, mental status examination had remained unchanged for
language comprehension, and naming objects, were intact. three previous years, and the clinical course showed no
She had no history of substance abuse, or any medical or evidence of spontaneous remission or any episodic
im-surgical condition that might account for her psychiatric provement of her illness. It is unlikely that the remission
symptoms. The Axis I diagnosis in DSM-IV (American was a consequence of clinical attention of the regular
Psychiatric Association, 1994) was schizophrenic disorder, follow-up visits, for the patient had received the same
paranoid type. regular attention 4 weeks before she enrolled to this study.
Miss A refused medication, but she and her husband The limitations of this study are the absence of the
gave written informed consent to enter into an open single- control group and the possibility of the placebo response. It
case trial with EPA / DHA. The patient received 4 g of EPA is important to address that up to 50% of placebo response
and 2 g of DHA per day. She was rated with the Positive may be expected when a new or controversial medication
and Negative Symptoms Scale (PANSS; Kay et al., 1987) is used regardless of prior history. These limitations could
1 month before treatment and during the treatment until be improved in the future study by using placebo lead-in
her delivery. The ratings were carried out biweekly for the duration with blind rater or the double-blind controlled
first 2 months and then monthly for 6 months. trial.
Miss A was also monitored for laboratory assessments To date, no psychotropic drug has been approved to be
of erythrocyte fatty acid compositions on week 0 (before safe during pregnancy. Psychiatrists are thus faced with a
psy-Fig. 1. Patient’s Positive and Negative Symptoms Scale (PANSS) on 4 weeks (24 weeks), 2 weeks (22 weeks) before receiving omega-3 PUFAs; the beginning (0 week) and 2, 4, 6, 8 and 12 weeks after treatment.
chotropic drug for pregnant patients. Knowledge of risks mine and serotonin (Malnoe et al., 1990; Delion et al.,
of psychotropic medications to the fetus of prenatal 1996). These may be the mechanisms, in addition to the
exposure is incomplete. It is neither feasible nor ethical to receptor-blocking profile, to contribute to the therapeutic
design the prospective, case-control studies for the risks of effect in schizophrenia (Horrobin, 1998).
psychotropic drugs to both mother and child during The essential fatty acids (EFAs) of the omega-3 and
pregnancy. Thus, the appropriate data from observation omega-6 families play important roles during pregnancy.
studies and alternative, non-drug treatments are important. During pregnancy, accretion of maternal, placental and
Based on the data of lower levels of omega-3 PUFA fetal tissue occurs and consequently the EFAs
require-compositions in red blood cells (Yao et al., 1994), brain ments are high. Furthermore, the fetal requirements for
(Horrobin et al., 1991) and cultured skin fibroblasts arachidonic acid (AA) and DHA are especially high in the
(Mahadik et al., 1996) in schizophrenic patients, the last trimester of pregnancy because of the rapid synthesis
hypothesis of deficient uptake or excessive breakdown of of brain tissue (Clandinin et al., 1980; Martinez, 1992).
membrane omega-3 PUFAs in schizophrenia is proposed DHA, for example, accumulates in the fetal brain three to
(Horrobin et al., 1994). The results in the open trial of five times more rapidly during the last 3 months of
‘add-on’ studies and one case report of monotherapy (Peet pregnancy than it does during the first months of gestation
et al., 1996; Shah et al., 1998; Puri and Richardson, 1998; (Nettleton, 1993) for it performs many membrane
func-Richardson et al., 2000) revealed that the omega-3 fatty tions in neuronal synapse and photoreceptor outer
seg-acids are associated with the improvement in the PANS S ments (Sastry, 1985). At birth, the infant’s plasma contains
scores and the Abnormal Involuntary Movement Scale more DHA and AA than mother’s plasma does (Carnielli
(AIMS; Guy, 1976). But the exact mechanism is unknown. et al., 1996; Leaf et al., 1992).
One hypothesis is that omega-3 PUFAs actively inhibits Since omega-3 PUFAs are thought to be both beneficial
cytosolic phosphlipase 2 (PLA ) (Richardson et al., 2000;2 and therapeutic to pregnant schizophrenic women, we are
Gattaz et al., 1995; Ross et al., 1997). The other hypothesis now conducting a double-blind controlled trial. Hopefully,
is that the omega-3 PUFAs can normalize the altered the trial of omega-3 PUFAs may help shed some light on
Pre Test (week 0) Test 1 (week 4) Test 2 (week 8) SFA(%) 16:0 15.86 7.99 8.44 18:0 4.87 4.47 5.73 MUFA (%) 16:1 4.93 5.95 4.72 18:1 66.68 70.95 69.77 PUFA, n23 (%) 18:3 0.41 0.90 1.31 18:4 0.12 1.11 1.69 20:5 (EPA) 0.09 1.28 0.42 22:6 (DHA) 0.12 0.25 0.42 PUFA, n26 (%) 18:2 6.68 6.86 7.27 20:4 (AA) 0.07 0.23 0.25 Ratio (%) n23 / n26 0.11 0.50 0.51 AA / EPA 0.78 0.18 0.59 PUFA / UFA 0.10 0.12 0.13 PUFA / SFA 0.37 0.85 0.80 PUFA / MUFA 0.11 0.14 0.15 MUFA / SFA 3.45 6.17 5.26 SFA / total (%) 20.73 12.46 14.17 PUFA / total (%) 7.67 10.64 11.34 MUFA / total (%) 71.61 76.90 74.49
SFA, saturated fatty acids; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; EPA, ecosapentaenoic acid; DHA, docosahexaenoic acid; AA, arachidonic acid.
minergic and serotonergic neurotransmission in the rat frontal cortex.
Acknowledgements
J. Neurochem. 66, 1582–1591.
Edwards, R., Peet, M., Shay, J., Horrobin, D., 1998. Omega-3
polyunsatu-The work was supported by the grants NSC 89-2320-B- rated fatty acid levels in the diet and in red blood cell membranes of
038-046 from the National Science Council, TMC88-Y05- depressed patients. J. Affect. Disord. 48, 149–155.
A121 from the Taipei Medical University, and China Freeman, M.P., 2000. Omega-3 fatty acids in psychiatry: a review. Ann.
Clin. Psychiatry 12, 159–165.
Chemical and Pharmaceutical Company, Taipei, Taiwan.
Gattaz, W.F., Schmitt, A., Maras, A., 1995. Increased platelet
phospholip-The authors thank Li-Chia Chen, Tsung-Ta Liu, Chin-Hua
ase A activity in schizophrenia. Schizophr. Res. 16, 1–6.2
Liu, Hui-Ting Yang and Hsin Chein for data collection. Guy, W., 1976. NCDEU Assessment manual for psychopharmacology.
Department of Health, Education and Welfare, Washington, DC. Horrobin, D.F., Manku, M.S., Hillman, H., Iain, A., Glen, A.I.M., 1991.
Fatty acid levels in the brains of schizophrenics and normal controls.
References Biol. Psychiatry 30, 795–805.
Horrobin, D.F., Glen, A.I., Vaddadi, K., 1994. The membrane hypothesis American Psychiatric Association, 1994. Diagnostic and Statistical Manu- of schizophrenia. Schizophr. Res. 13, 195–207.
al of Mental Disorders, 4th Edition (DSM-IV), Washington, DC. Horrobin, D.F., 1998. The membrane phospholipid hypothesis as a Carnielli, V.P., Wattimena, D.J.L., Luijendijk, I.H.T., Doerlage, A., De- biochemical basis for the neurodevelopmental concept of
schizophre-genhart, H.J., Sauer, P.J.J., 1996. The very low birth weight premature nia. Schizophr. Res. 30, 193–208.
infant is capable of synthesizing arachidonic and docosahexaenoic Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative acids from linoleic and linolenic acids. Pediatr. Res. 40, 169–174. syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, Clandinin, M.T., Chappell, J.E., Leong, S., Heim, T., Swyer, P.R., 261–276.
Chance, G.W., 1980. Intrauterine fatty acid accretion rates in human Leaf, A.A., Leighfield, M.J., Costeloe, K.L., Crawford, M.A., 1992. brain: implications for fatty acid requirements. Early Hum. Dev. 4, Long-chain polyunsaturated fatty acids and fetal growth. Early Hum.
121–129. Dev. 30, 183–191.
Committee on Drugs, American Academy of Pediatrics, 2000. Use of Maes, M., Christophe, A., Delanghe, J., Altamura, C., Neels, H., Meltzer, psychoactive medication during pregnancy and possible effects on the H.Y., 1999. Lowered omega-3 polyunsaturated fatty acids in serum fetus and newborn. Pediatrics 105, 880–887. phospholipids and cholesteryl esters of depressed patients. Psychiatr. Delion, S., Chalon, S., Guilloteau, D., Besnard, J.C., Durand, G., 1996. Res. 85, 275–291.
Scheffer, R.E., 1996. Plasma membrane phospholipid fatty acid acid changes accompanying symptom remission in a patient with composition of cultured skin fibroblasts from schizophrenic patients: schizophrenia treated with eicosapentaenoic acid. Eur. Neuro-comparison with bipolar patients and normal subjects. Psychiatr. Res. psychopharmacol. 10, 189–193.
63, 133–1342. Ross, B.M., Hudson, C., Erlich, J., Warsh, J.J., Kish, S.J., 1997. Increased Malnoe, A., Milon, H., Reme, C., 1990. Effect of in vivo modulation of phospholipid breakdown in schizophrenia. Arch. Gen. Psychiatry 54,
membrane docosahexaenoic acid levels on the dopamine-dependent 487–494.
adenylate cyclase activity in the rat retina. J. Neurochem. 55, 1480– Sastry, P.S., 1985. Lipids of nervous tissue: composition and metabolism.
1485. Prog. Lipid Res. 24, 69–176.
Martinez, M., 1992. Tissue levels of polyunsaturated fatty acids during Shah, S., Vankar, G.K., Telang, S.D., Ramchand, C.N., Peet, M., 1998. early human development. J. Pediatr. 120, S129–S138. Eicosapentaenoic acid (EPA) as an adjunct in the treatment of Mellor, J.E., Laugharne, J.D.E., Peet, M., 1996. Omega-3 fatty acid schizophrenia. Presented at the 9th Schizophrenia Winter Workshop,
supplementation in schizophrenic patients. Hum. Psychopharmacol. Davos, Switzerland.
11, 39–46. Stoll, A.L., Severus, W.E., Freeman, M.P., Rueter, S., Zboyan, H.A., Nettleton, J.A., 1993. Are n23 fatty acids essential nutrients for fetal and Diamond, E., Cress, K.K., Marangell, L.B., 1999. Omega 3 fatty acids infant development? J. Am. Diet. Assoc. 93, 58–64. in bipolar disorder: a preliminary double-blind, placebo-controlled Peet, M., Laugharne, J.D.E., Mellor, J., Ramchand, C.N., 1996. Essential trial. Arch. Gen. Psychiatry 56, 407–412.
fatty acid deficiency in erythrocyte membranes from chronic schizo- Su, K.P., Huang, S.Y., Shen, W.W., 2000a. Is omega 3 fatty acids phrenic patients, and the clinical effects of dietary supplementation. beneficial in depression but not mania? Arch. Gen. Psychiatry 57, 716. Prostaglandins Leukot. Essent. Fatty Acids 55, 71–75. Su, K.P., Huang, S.Y., Shen, W.W., 2000b. Effects of polyunsaturated fatty Puri, B.K., Richardson, A.J., 1998. Sustained remission of positive and acids on psychiatric disorders. Am. J. Clin. Nutr. 72, 1241.
negative symptoms of schizophrenia following treatment with Yao, J.K., van Kammen, D.P., Welker, J.A., 1994. Red blood cell eicosapentaenoic acid. Arch. Gen. Psychiatry 55, 188–189. membrane dynamics in schizophrenia: II. Fatty acid composition. Richardson, A.J., Easton, T., Pun, B.K., 2000. Red cell and plasma fatty Schizophr. Res. 13, 217–226.
