Omega-3 polyunsaturated fatty acids in the treatment of schizophrenia.

Most studies have shown reduced levels of polyunsaturated fatty acids, particularly docosahexaenoic acid and arachidonic acid, in the cell membranes of red blood cells from schizophrenic patients. This has led to research interest in the possible therapeutic benefits of omega-3 fatty acids in schizophrenia. There is evidence from double-blind placebo-controlled trials that omega-3 fatty acids might prevent conversion from a prodromal state into first episode psychosis, and reduce the antipsychotic drug requirement in first episode patients. Results in chronic and acutely relapsing schizophrenia have been mixed. The problems associated with single nutrient studies are discussed. Nutrients are normally ingested in complex combinations, and they interact with each other in their normal metabolic and physiological functions. It is likely that optimal nutritional treatment will involve complex combinations of nutrients, preferably as part of a healthy balanced diet rather than by using supplements. However, such approaches have been little evaluated in mental health..

Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder.

OBJECTIVE: To compare therapeutic effects of eicosapentaenoic acid (EPA), fluoxetine and a combination of them in major depression. METHOD: Sixty outpatients with a diagnosis of major depressive disorder based on DSM-IV criteria and a score >or=15 in the 17-item Hamilton Depression Rating Scale (HDRS) were randomly allocated to receive daily either 1000 mg EPA or 20 mg fluoxetine, or their combination for 8 weeks. Double dummy technique was used to double blind the study. Patients were assessed at 2 week intervals. Change in HDRS was the primary outcome measure. RESULTS: Analysis of covariance for HDRS at week 8 across treatment groups was performed in 48 patients who completed at least 4 weeks of the study, with the last observation carried forward. Treatment, age of onset and baseline HDRS had a significant effect on HDRS at week 8. EPA + fluoxetine combination was significantly better than fluoxetine or EPA alone from the fourth week of treatment. Fluoxetine and EPA appear to be equally effective in controlling depressive symptoms. Response rates (>or=50% decrease in baseline HDRS) were 50%, 56% and 81% in the fluoxetine, EPA and combination groups, respectively. CONCLUSIONS: In the present 8 week trial EPA and fluoxetine had equal therapeutic effects in major depressive disorder. EPA + fluoxetine combination was superior to either of them alone.

Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry.

OBJECTIVE: To determine if the available data support the use of omega-3 essential fatty acids (EFA) for clinical use in the prevention and/or treatment of psychiatric disorders. PARTICIPANTS: The authors of this article were invited participants in the Omega-3 Fatty Acids Subcommittee, assembled by the Committee on Research on Psychiatric Treatments of the American Psychiatric Association (APA). EVIDENCE: Published literature and data presented at scientific meetings were reviewed. Specific disorders reviewed included major depressive disorder, bipolar disorder, schizophrenia, dementia, borderline personality disorder and impulsivity, and attention-deficit/hyperactivity disorder. Meta-analyses were conducted in major depressive and bipolar disorders and schizophrenia, as sufficient data were available to conduct such analyses in these areas of interest. CONSENSUS PROCESS: The subcommittee prepared the manuscript, which was reviewed and approved by the following APA committees: the Committee on Research on Psychiatric Treatments, the Council on Research, and the Joint Reference Committee. CONCLUSIONS: The preponderance of epidemiologic and tissue compositional studies supports a protective effect of omega-3 EFA intake, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mood disorders. Meta-analyses of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p = .02). The results were highly heterogeneous, indicating that it is important to examine the characteristics of each individual study to note the differences in design and execution. There is less evidence of benefit in schizophrenia. EPA and DHA appear to have negligible risks and some potential benefit in major depressive disorder and bipolar disorder, but results remain inconclusive in most areas of interest in psychiatry. Treatment recommendations and directions for future research are described. Health benefits of omega-3 EFA may be especially important in patients with psychiatric disorders, due to high prevalence rates of smoking and obesity and the metabolic side effects of some psychotropic medications.

The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schizophrenia.

Although schizophrenia is normally regarded as a brain disease, there is clear evidence that schizophrenia is strongly associated with a variety of physical conditions. These include an increased rate of the metabolic syndrome and its physical complications including diabetes and coronary heart disease, and a reduced rate of rheumatoid arthritis. It is argued that these associations may point to a commonality of some aetiological factors. Evidence implicating omega-3 fatty acids in all of these disorders is presented. The associations may derive either from genetic or from environmental factors, including nutrition. Further investigation of these associations may give important clues regarding the aetiology of schizophrenia.

Omega-3 fatty acids in the treatment of psychiatric disorders.

The importance of omega-3 fatty acids for physical health is now well recognised and there is increasing evidence that omega-3 fatty acids may also be important to mental health. The two main omega-3 fatty acids in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have important biological functions in the CNS. DHA is a major structural component of neuronal membranes, and changing the fatty acid composition of neuronal membranes leads to functional changes in the activity of receptors and other proteins embedded in the membrane phospholipid. EPA has important physiological functions that can affect neuronal activity. Epidemiological studies indicate an association between depression and low dietary intake of omega-3 fatty acids, and biochemical studies have shown reduced levels of omega-3 fatty acids in red blood cell membranes in both depressive and schizophrenic patients. Five of six double-blind, placebo-controlled trials in schizophrenia, and four of six such trials in depression, have reported therapeutic benefit from omega-3 fatty acids in either the primary or secondary statistical analysis, particularly when EPA is added on to existing psychotropic medication. Individual clinical trials have suggested benefits of EPA treatment in borderline personality disorder and of combined omega-3 and omega-6 fatty acid treatment for attention-deficit hyperactivity disorder. The evidence to date supports the adjunctive use of omega-3 fatty acids in the management of treatment unresponsive depression and schizophrenia. As these conditions are associated with increased risk of coronary heart disease and diabetes mellitus, omega-3 fatty acids should also benefit the physical state of these patients. However, as the clinical research evidence is preliminary, large, and definitive randomised controlled trials similar to those required for the licensing of any new pharmacological treatment are needed.

Polyunsaturated fatty acid levels in red cell membranes of unmedicated schizophrenic patients.

There are several reports of reduced levels of polyunsaturated fatty acids (PUFA), particularly arachidonic acid (AA) and docosahexaenoic acid (DHA), in membrane phospholipid from various tissues including red blood cells (RBC) taken from schizophrenic patients. However, reports have not been entirely consistent and most studies have been confounded by the potential effects of environmental factors including antipsychotic medication and diet. We measured PUFA levels in RBC from two separate groups of unmedicated patients and control subjects from India and Malaysia, populations which have substantial differences in diet. We found no significant difference in levels of AA between patients and control subjects in either population. Levels of adrenic acid were significantly reduced, and levels of DHA significantly increased in both clinical populations. However, diet-related differences in DHA between the populations from India and Malaysia were much greater than differences between schizophrenic patients and controls. It is concluded that reduced RBC membrane levels of AA and DHA are not pathognomic of schizophrenia but that variations in cell membrane fatty acid levels are an epiphenomenon which may reflect underlying abnormalities of phospholipid and fatty acid metabolism and their interaction with environmental factors including medication and diet.

International variations in the outcome of schizophrenia and the prevalence of depression in relation to national dietary practices: an ecological analysis.

BACKGROUND: Dietary variations are known to predict the prevalence of physical illnesses such as diabetes and heart disease but the possible influence of diet on mental health has been neglected. AIMS: To explore dietary predictors of the outcome of schizophrenia and the prevalence of depression. METHOD: Ecological analysis of national dietary patterns in relation to international variations in outcome of schizophrenia and prevalence of depression. RESULTS: A higher national dietary intake of refined sugar and dairy products predicted a worse 2-year outcome of schizophrenia. A high national prevalence of depression was predicted by a low dietary intake of fish and seafood. CONCLUSIONS: The dietary predictors of outcome of schizophrenia and prevalence of depression are similar to those that predict illnesses such as coronary heart disease and diabetes, which are more common in people with mental health problems and in which nutritional approaches are widely recommended. Dietary intervention studies are indicated in schizophrenia and depression.

Diet, diabetes and schizophrenia: review and hypothesis.

BACKGROUND: Diabetes is more common in people with schizophrenia than in the general population. AIMS: To explore the possible reasons for the association between diabetes and schizophrenia. METHOD: Diet and other lifestyle factors in patients with schizophrenia were reviewed as risk factors for diabetes. RESULTS: People with schizophrenia show features of the metabolic syndrome at the onset of illness, before treatment. They also eat a poor diet, take little exercise and have high rates of smoking. Food intake may be increased further by antipsychotic medication. Nutritional factors appear to have a key role in the development of diabetes in patients with schizophrenia and may also affect the outcome and severity of schizophrenia. A common pathway through which diet might contribute to the development of both diabetes and schizophrenia is proposed. CONCLUSIONS: Lifestyle factors may influence outcomes in both diabetes and schizophrenia. Lifestyle interventions are the key to improving the long-term health of people with schizophrenia.

Nutrition and schizophrenia: beyond omega-3 fatty acids.

There are now five placebo-controlled trials of EPA in the treatment in schizophrenia, and four of these have given positive or partly positive findings. A cross-national ecological analysis of international variations in outcome of schizophrenia in relation to national dietary practices, showed that high consumption of sugar and of saturated fat is associated with a worse long-term outcome of schizophrenia. It is known that a high sugar, high fat diet leads to reduced brain expression of brain-derived neurotrophic factor (BDNF) which is responsible for maintaining the outgrowth of dendrites. Low brain BDNF levels also lead to insulin resistance which occurs in schizophrenia and is associated with diseases of the metabolic syndrome. It appears that the same dietary factors which are associated with the metabolic syndrome, including high saturated fat, high glycaemic load, and low omega-3 PUFA, may also be detrimental to the symptoms of schizophrenia, possibly through a common mechanism involving BDNF.

Dietary sugar and polyunsaturated fatty acid consumption as predictors of severity of schizophrenia symptoms.

A previous epidemiological study found an association between high sugar consumption and two year outcome of schizophrenia. The primary aim of the present pilot study was to assess the possible relationship between dietary sugar intake and the severity of schizophrenic symptoms in a group of 20 patients. A significant negative correlation (r = -0.54, p = 0.02) between dietary sugar and severity of schizophrenic symptoms, appears to be confounded by the effect of medication. Patients taking the antipsychotic drug clozapine consumed almost twice as much sugar as those taking other antipsychotic agents, (235.4+/-92.6 g/day versus 143+/-59, p = 0.02) and had less severe symptoms. Consumption of other nutrients showed no association with clozapine treatment. In a secondary analysis, severity of schizophrenic symptoms correlated with dietary intake of polyunsaturated fatty acids (r = -0.54, p = 0.02) and this was independent of the effect of medication. This finding is consistent with earlier studies.

Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results.

It has been hypothesised that polyunsaturated fatty acids (PUFA) play an important role in the aetiology of schizophrenia and depression. Evidence supporting this hypothesis for schizophrenia includes abnormal brain phospholipid turnover shown by 31P Magnetic Resonance Spectroscopy, increased levels of phospholipase A2, reduced niacin skin flush response, abnormal electroretinogram, and reduced cell membrane levels of n-3 and n-6 PUFA. In depression, there is strong epidemiological evidence that fish consumption reduces risk of becoming depressed and evidence that cell membrane levels of n-3 PUFA are reduced. Four out of five placebo-controlled double- blind trials of eicosapentaenoic acid (EPA) in the treatment of schizophrenia have given positive findings. In depression, two placebo-controlled trials have shown a strong therapeutic effect of ethyl-EPA added to existing medication. The mode of action of EPA is currently not known, but recent evidence suggests that arachidonic acid (AA) if of particular importance in schizophrenia and that clinical improvement in schizophrenic patients using EPA treatment correlates with changes in AA.

Nutrition and schizophrenia: an epidemiological and clinical perspective.

There is well accepted evidence that the long-term outcome of schizophrenia is better in developing than in developed countries. Socio-cultural factors, which are as yet unidentified, have been postulated to explain this. There is also disputed evidence that schizophrenia was rare in indigenous populations and increased when they came into contact with Western or industrialised cultures, and that there was an increase in the rate of schizophrenia during the Industrial Revolution. These epidemiological and historical findings point to diet as a possible mediating factor in schizophrenia. Ecological studies have indicated that a worse outcome of schizophrenia is associated with higher consumption of saturated fat and sugar. It is also known that schizophrenic patients have increased insulin resistance and are at increased risk of developing diabetes and coronary heart disease. These findings suggest a new paradigm for our understanding of the causation and treatment of schizophrenia.

A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs.

BACKGROUND: In depressed patients, low blood levels of eicosapentaenoic acid are seen. We tested the antidepressive effect of ethyl-eicosapentaenoate in these patients. METHODS: We included 70 patients with persistant depression despite ongoing treatment with an adequate dose of a standard antidepressant. Patients were randomized on a double-blind basis to placebo or ethyl-eicosapentaenoate at dosages of 1, 2, or 4 g/d for 12 weeks in addition to unchanged background medication. Patients underwent assessment using the 17-item Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, and the Beck Depression Inventory. RESULTS: Forty-six (88%) of 52 patients receiving ethyl-eicosapentaenoate and 14 (78%) of 18 patients receiving placebo completed the 12-week study with no serious adverse events. The 1-g/d group showed a significantly better outcome than the placebo group on all 3 rating scales. In the intention-to-treat group, 5 (29%) of 17 patients receiving placebo and 9 (53%) of 17 patients receiving 1 g/d of ethyl-eicosapentaenoate achieved a 50% reduction on the Hamilton Depression Rating Scale score. In the per-protocol group, the corresponding figures were 3 (25%) of 12 patients for placebo and 9 (69%) of 13 patients for the 1-g/d group. The 2-g/d group showed little evidence of efficacy, whereas the 4-g/d group showed nonsignificant trends toward improvement. All of the individual items on all 3 rating scales improved with the 1-g/d dosage of ethyl-eicosapentaenoate vs placebo, with strong beneficial effects on items rating depression, anxiety, sleep, lassitude, libido, and suicidality. CONCLUSION: Treatment with ethyl-eicosapentaenoate at a dosage of 1 g/d was effective in treating depression in patients who remained depressed despite adequate standard therapy.

A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms.

The objective was to test effects of ethyl eicosapentaenoate (E-E) on persistent ongoing symptoms in patients receiving different types of anti-schizophrenic drugs, typical antipsychotics, new atypical antipsychotics, and clozapine. 115 patients with DSM-IV-defined schizophrenia were studied, 31 on clozapine, 48 on new atypical drugs and 36 on typical antipsychotics. Placebo or 1, 2 or 4 g/day of E-E was given for 12 weeks in addition to the background medication. The main assessment was change from baseline to 12 weeks on the PANSS and its sub-scales. There were no treatment-related side effects or adverse biochemical or haematological effects. Patients on 2 and 4 g/day E-E showed significant reductions in triglyceride levels which had been elevated by clozapine. In patients given 2 g/day E-E there were improvements on the PANSS and its sub-scales, but there was also a large placebo effect in patients on typical and new atypical antipsychotics and no difference between active treatment and placebo. In patients on clozapine, in contrast, there was little placebo response, but a clinically important and statistically significant effect of E-E on all rating scales. This effect was greatest at 2 g/day. There was a positive relationship between improvement on rating scales and rise in red blood cell arachidonic acid concentration.