Sustained Remission of Positive and Negative Symptoms of Schizophrenia Following Treatment With Eicosapentaenoic Acid

Recently, a membrane phospholipid hypothesis of schizophrenia has been proposed¹ that not only provides an underlying explanation for those aspects of schizophrenia traditionally explained by the dopamine hypothesis, but also can account for many other clinical features. These include the inverse relationship between schizophrenia and some inflammatory disorders; the high resistance to pain shown by some patients; the dramatic remission of symptoms that may occur with pyrexia; the increased risk associated with exposure to viral infections or maternal malnutrition during fetal development; and the difference in severity and prognosis in different countries.² Recent biochemical, cerebral magnetic resonance spectroscopy, and molecular genetics findings suggest that schizophrenia is associated with a cell membrane deficiency of arachidonic acid and docosahexaenoic acid (DHA), arising from excess activity of 1 of the phospholipase A₂ (PLA₂) group of enzymes.^{3 - 7} Thus, there is mounting evidence for the membrane phospholipid hypothesis; however, an important issue for clinicians is whether it has any useful implications for treatment.

Atypical antipsychotics such as clozapine represent a considerable improvement over standard neuroleptics. However, the mechanism of action of clozapine has not adequately been explained on the basis of neurotransmitter actions, and it is therefore interesting that almost 2 decades ago it was suggested that the structure and pharmacological actions of clozapine are consistent with its being a prostaglandin E analog. The E prostaglandins are potent stimulators of cyclic adenosine monophosphate formation, and cyclic adenosine monophosphate inhibits PLA₂.⁸ Furthermore, pharmacotherapy with clozapine has recently been shown to be associated with a dramatic rise in erythrocyte membrane concentrations of certain polyunsaturated fatty acids.⁹ These observations raise the possibility that clozapine may be a successful drug because its primary action is on membrane phospholipid composition.⁷

The phospholipid hypothesis leads to the prediction that treatment with PLA₂ inhibitors should result in clinical improvement in schizophrenia.⁷ Eicosapentaenoic acid (EPA) is a PLA₂ inhibitor¹⁰ which is also a constituent of brain phospholipids and a precursor of DHA. We report the case of an unmedicated patient with schizophrenia in whom treatment with EPA was associated with a dramatic and sustained reduction in both positive and negative symptoms.

A 31-year-old man first came to the attention of our local psychiatric service at the age of 28 years when he was diagnosed as suffering from schizophrenia as defined by the DSM-IV. At that time he was suffering from daily auditory hallucinations and a complex delusional system, both of which started in his early teenage years. Although his profile had always been predominantly one of unremitting positive symptoms, more recently he had also begun to suffer from negative symptoms, including anhedonia and social anxiety and withdrawal. Furthermore, his basic skills in coping with the practicalities of life were not well developed. At the time of diagnosis he was prescribed sulpiride. He only ever took 1 tablet (200 mg) of sulpiride, and immediately discontinued the medication because of a severe extrapyramidal reaction. He refused neuroleptics thereafter, and so has otherwise remained free of antipsychotic medication.

In an attempt to understand his symptoms, he has been a keen participant in several research studies since his first presentation. His case has thus been extremely well documented since 1994. In 1996, he gave full informed consent to enter into an open single-case study of treatment with EPA provided as an emulsion, which delivered as 2 g of EPA per day in a 30-mL dose (Scotia Pharmaceuticals, Stirling, Scotland).

He underwent psychiatric symptom rating just before treatment commenced and then at monthly intervals for 6 months, using the Schedules for the Assessment of Positive Symptoms (SAPS) and Negative Symptoms (SANS).^{11 - 12} There followed a dramatic and sustained improvement in these scores (SAPS: 46, 45, 14, 9, 8, 8, 7 and SANS: 16, 15, 7, 5, 4, 3, 3 at baseline and successive monthly follow-up visits). Interestingly, his general appearance and skin condition were also much improved after only 1 month. He has suffered no adverse effects from this treatment, which he has asked to continue receiving. His condition has continued to improve further since then; 6 months later his SAPS rating has fallen to 4 and his SANS rating remains at 3.

In this case, a dramatic remission of persistent positive and negative symptoms occurred following treatment with EPA. We believe it unlikely that this represented either a spontaneous remission or a placebo response. The patient's clinical profile had remained essentially unchanged during the 2 previous years, and prior to this there is no evidence of spontaneous remission or an episodic quality to his illness. In addition, other research studies that had incorporated a nonpharmacological treatment element had yielded no benefit. Moreover, it is unlikely that the remission was a consequence of extra attention and regular follow-up, as he had received the same regular attention during the 2 previous years in the course of other research studies.

It is important to note that the patient was free of antipsychotic medication. In another study involving 20 patients with schizophrenia, EPA treatment was followed by reductions in both positive symptoms and tardive dyskinesia,^{13 - 14} and preliminary results from double-blind, placebo-controlled trials similarly showed that EPA significantly reduced schizophrenic symptoms.¹⁵ However, patients in these trials were also receiving their regular antipsychotic medication. Our case report has the advantage that this is not a confounding factor.

The choice of EPA as a treatment was informed by the fact that it actively inhibits cytosolic PLA₂,^{2 ,10} as excessive activity of this enzyme, leading to depletion of arachidonic acid and DHA in membrane phospholipids, has been suggested as a key feature in the etiology of schizophrenia. Controlled trials of EPA treatment in antipsychotic drug-free patients are indicated.