Diet quality, dietary inflammatory index and body mass index as predictors of response to adjunctive N-acetylcysteine and mitochondrial agents in adults with bipolar disorder: A sub-study of a randomised placebo-controlled trial.

AIMS: We aimed to explore the relationships between diet quality, dietary inflammatory potential or body mass index and outcomes of a clinical trial of nutraceutical treatment for bipolar depression. METHODS: This is a sub-study of a randomised controlled trial of participants with bipolar depression who provided dietary intake data (n = 133). Participants received 16 weeks adjunctive treatment of either placebo or N-acetylcysteine-alone or a combination of mitochondrial-enhancing nutraceuticals including N-acetylcysteine (combination treatment). Participants were followed up 4 weeks post-treatment discontinuation (Week 20). Diet was assessed by the Cancer Council Victoria Dietary Questionnaire for Epidemiological Studies, Version 2, converted into an Australian Recommended Food Score to measure diet quality, and energy-adjusted dietary inflammatory index score to measure inflammatory potential of diet. Body mass index was also measured. Generalised estimating equation models were used to assess whether diet quality, energy-adjusted dietary inflammatory index score and/or body mass index were predictors of response to significant outcomes of the primary trial: depression symptoms, clinician-rated improvement and functioning measures. RESULTS: In participants taking combination treatment compared to placebo, change in depression scores was not predicted by Australian Recommended Food Score, dietary inflammatory index or body mass index scores. However, participants with better diet quality (Australian Recommended Food Score) reported reduced general depression and bipolar depression symptoms (p = 0.01 and p = 0.03, respectively) and greater clinician-rated improvement (p = 0.02) irrespective of treatment and time. Participants who had a more anti-inflammatory dietary inflammatory index had less impairment in functioning (p = 0.01). Combination treatment may attenuate the adverse effects of pro-inflammatory diet (p = 0.03) on functioning. Participants with lower body mass index who received combination treatment (p = 0.02) or N-acetylcysteine (p = 0.02) showed greater clinician-rated improvement. CONCLUSION: These data support a possible association between diet (quality and inflammatory potential), body mass index and response to treatment for bipolar depression in the context of a nutraceutical trial. The results should be interpreted cautiously because of limitations, including numerous null findings, modest sample size and being secondary analyses.

Remote Healing of Bipolar Disorder, Eating Disorder Not Otherwise Specified, Posttraumatic Stress Disorder, Fibromyalgia, and Irritable Bowel Syndrome Through Lifestyle Change.

This case report illustrates the relationship between gut, hormonal, and brain function in that dietary change, mindfulness interventions, and detoxification led to resolution of disabling psychiatric symptoms. In this case, a single Caucasian female resolved her symptoms of bipolar disorder (BD) including psychotic features and suicidality, posttraumatic stress disorder symptoms from childhood torture, disordered eating, fibromyalgia, and irritable bowel syndrome through lifestyle interventions. This patient survived a severe trauma history only to develop alcohol dependence, disordered eating, and depressive symptoms, which were treated with a polypharmaceutical psychiatric approach. She was formally diagnosed with BD after being treated with antidepressants and went on to be treated with up to 15 medications in the ensuing years. Disabled by the side effects of her treatment, she worked with her treating psychiatrist to taper off of 4 medications before she learned of nutritional change through a book authored by the author. After completing 1 mo of these recommendations including dietary change, detox, and meditation, she enrolled in the author's online program and went on to resolve her symptoms, physical and psychiatric, to the extent that BD has been removed from her medical record. She has been symptom free for 1 y. This case is evidence of the potential for self-directed healing and resolution of chronic illness.

Diet and Bipolar Disorder: A Review of Its Relationship and Potential Therapeutic Mechanisms of Action.

OBJECTIVES: It is well accepted that diet quality has an important role in the prevention and treatment of several physical diseases. However, its influence on mental health has received far less attention, although there is increasing evidence to support a relationship with depression. In this narrative review, investigations into the relationship between diet and bipolar disorder are examined and the potential implications in the management and treatment of bipolar disorder are reviewed. METHODS: The authors provide a narrative review of the relevant information. RESULTS: Research is limited, although there are preliminary findings to suggest a relationship between diet and bipolar disorder. Findings from cross-sectional research suggest that people with bipolar disorder consume an unhealthier dietary pattern. This has significant treatment implications as bipolar disorder has a high comorbidity with several physical diseases. In addition, diet also influences several biological processes that are dysregulated in bipolar disorder, namely monoaminergic activity, immune/inflammatory processes, oxidative stress, mitochondrial activity, and neuroprogression. CONCLUSIONS: The role of diet in bipolar disorder requires further attention in research as it presents as a factor that may contribute to the worsening course of this condition and may potentially enhance current treatment outcomes.

Novel nutritional treatment for manic and psychotic disorders: a review of tryptophan and tyrosine depletion studies and the potential of protein-based formulations using glycomacropeptide.

RATIONALE: Current amino acid (AA) mixtures used in acute tryptophan (Trp) and tyrosine (Tyr) plus phenylalanine (Phe) depletion and loading tests are unpalatable and lack specificity. Specificity is improved by reducing content of branched-chain amino acids (BCAA) and palatability to a certain extent by dose reduction. OBJECTIVES: This study aims to identify a palatable naturally occurring alternative(s) to amino acids with the desired BCAA content for use in the above tests. METHODS: A palatable alternative lacking in Trp, Tyr and Phe has been identified in the whey protein fraction caseino-glycomacropeptide (c-GMP). The absence of these three aromatic amino acids renders GMP suitable as a template for seven formulations for separate and combined depletion or loading and a placebo control. The absence of Phe and Tyr enables GMP to provide a unique nutritional therapy of manic and psychotic disorders by inhibition of cerebral dopamine synthesis and release and possibly also by enhancing glutamatergic function, in general, and in patients resistant to anti-psychotic medication, in particular. RESULTS: Seven GMP-based formulations for the above tests are proposed, two of which can be used in the above nutritional therapy and a third formulation as a placebo control in clinical trials. CONCLUSIONS: Development of these formulations should advance the above research and diagnostic tests, open new avenues for neuroscience research on monoamine function, and improve the therapy of bipolar and psychotic disorders and enhance the quality of life of sufferers.

Influence of lifelong dietary fats on the brain fatty acids and amphetamine-induced behavioral responses in adult rat.

The influence of dietary fatty acids (FA) on mania-like behavior and brain oxidative damage were evaluated in rats. First generation of rats born and maintained under supplementation with soybean-oil (SO), fish-oil (FO) or hydrogenated-vegetable-fat (HVF), which are rich in n-6, n-3 and trans (TFA) FA, respectively, until adulthood, were exposed to an amphetamine (AMPH)-induced mania animal model to behavioral and biochemical evaluations. While AMPH caused hyperlocomotion in HVF and, to a less extent, in SO- and FO-groups, a better memory performance was observed in FO group. Among vehicle-groups, HVF increased reactive species (RS) generation and protein-carbonyl (PC) levels in cortex; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. Among AMPH-treated animals, HVF exacerbated RS generation in all evaluated brain areas and increased PC levels in cortex and striatum; FO reduced RS generation in hippocampus and decreased PC levels in hippocampus and striatum. FO was related to higher percentage of polyunsaturated fatty acids (PUFA) and docosahexaenoic acid (DHA) in cortex and striatum, while HVF was associated to higher incorporation of TFA in cortex, hippocampus and striatum, besides increased n-6/n-3 FA ratio in striatum. While a continuous exposure to TFA may intensify oxidative events in brain, a prolonged FO consumption may prevent mania-like-behavior; enhance memory besides decreasing brain oxidative markers. A substantial inclusion of processed foods, instead of foods rich in omega-3, in the long term is able to influence the functionality of brain structures related to behavioral disturbances and weaker neuroprotection, whose impact should be considered by food safety authorities and psychiatry experts.

Plasma levels of n-3 fatty acids in bipolar patients: deficit restricted to DHA.

Epidemiological studies suggest that n-3 polyunsaturated fatty acid (n-3 FA) deficiency is a risk factor for bipolar disorders (BDs). The aim of this study was to determine whether such a deficit does exist in patients with BD and to characterize the overall plasma fatty acid (FA) profile in these patients. Using gas chromatography/mass spectrometry, we measured fasting plasma levels of 15 FAs in 42 patients diagnosed with BD according to DSM-IV criteria and in 57 age- and gender-matched healthy controls. Plasma docosahexaenoic acid (DHA) levels were significantly decreased in bipolar patients (p < 0.001 versus healthy controls). Compared with controls, patients had higher plasma levels of all other FAs, including arachidonic acid (AA, p < 0.001), alpha-linolenic acid (ALA, p < 0.001), and eicosapentaenoic acid (EPA) (p < 0.001). Although in the present study we observed significant DHA deficits in the plasma of bipolar patients our findings do not support the therapeutic use of ALA and/or EPA supplementation. DHA may provide a basis for possible pharmacological intervention in psychiatric disorders at the level of second messengers linked to the phosphatidylinositol cycle. Finally, measurement of FA levels in plasma seems to be more reliable and reproducible than assays of erythrocyte FA content.

Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression.

OBJECTIVE: Studies using augmentation of pharmacotherapies with omega-3 in bipolar disorder have been conducted; however, to date a specific meta-analysis in this area has not been published. Thus, we present the significant findings from meta-analyses of omega-3 in the treatment of bipolar depression and bipolar mania. DATA SOURCES: PubMed, CINAHL, Web of Science, and Cochrane Library databases were searched for clinical trials up to September 1, 2010, using the search terms bipolar disorder OR bipolar depression OR bipolar mania OR mania OR hypomania OR cyclothymia with the search terms omega 3 OR essential fatty acids OR polyunsaturated fatty acids OR DHA OR EPA OR fish oil OR flax oil. Clinical trial registries and gray literature (published or unpublished data not readily accessible via main databases) were also searched. DATA SELECTION: The analysis included randomized controlled studies 4 weeks or longer, with a sample size > 10, written in English, using omega-3 for diagnosed bipolar depression or mania. No criteria were set for age, gender, or ethnicity. DATA EXTRACTION: A random-effects model was used. The model analyzed the standard mean difference between treatment and placebo between baseline and endpoint, combining the effect size (Hedges g) data. Funnel plot and heterogeneity analyses (I²) were also performed. DATA SYNTHESIS: The findings of 5 pooled datasets (n = 291) on the outcome of bipolar depression revealed a significant effect in favor of omega-3 (P = .029), with a moderate effect size of 0.34. On the outcome of mania, 5 pooled datasets (n = 291) revealed a nonsignificant effect in favor of omega-3 (P = .099), with an effect size of 0.20. Minor heterogeneity between studies on the outcome of bipolar depression was found (I² = 30%; P = .213), which was not present on the outcome of bipolar mania (I² = 0%; P = .98). Funnel plot symmetry suggested no significant likelihood of publication bias. Meta-regression analysis between sample size and effect size, however, revealed that studies with smaller sample sizes had larger effect sizes (P = .05). CONCLUSIONS: The meta-analytic findings provide strong evidence that bipolar depressive symptoms may be improved by adjunctive use of omega-3. The evidence, however, does not support its adjunctive use in attenuating mania.

Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials.

OBJECTIVE: Studies using augmentation of pharmacotherapies with nutraceuticals in bipolar disorder (BD) have been conducted and preliminary evidence in many cases appears positive. To date, however, no specialized systematic review of this area has been conducted. We present the first systematic review of clinical trials using nutrient-based nutraceuticals in combination with standard pharmacotherapies to treat BD. A subsequent aim of this report was to discuss posited underlying mechanisms of action. METHODS: PubMed, CINAHL, Web of Science, and Cochrane Library databases, and grey literature were searched during mid-2010 for human clinical trials in English using nutraceuticals such as omega-3, N-acetyl cysteine (NAC), inositol, and vitamins and minerals, in combination with pharmacotherapies to treat bipolar mania and bipolar depression. A review of the results including an effect size analysis (Cohen's d) was subsequently conducted. RESULTS: In treating bipolar depression, positive evidence with large effect sizes were found for NAC (d=1.04) and a chelated mineral and vitamin formula (d=1.70). On the outcome of bipolar mania, several nutraceuticals reduced mania with strong clinical effects: a chelated mineral formula (d=0.83), L-tryptophan (d=1.47), magnesium (d=1.44), folic acid (d=0.40), and branched-chain amino acids (d=1.60). Mixed, but mainly positive, evidence was found for omega-3 for bipolar depression, while no evidentiary support was found for use in mania. No significant effect on BD outcome scales was found for inositol (possibly due to small samples). CONCLUSIONS: BD treatment outcomes may potentially be improved by additional use of certain nutraceuticals with conventional pharmacotherapies. However, caution should be extended in interpreting the large effects of several isolated studies, as they have not yet been replicated in larger trials.

[The role of omega-3 fatty acids in the treatment of bipolar disorders: the current situation]. / De plaats van omega-3-vetzuren bij de behandeling van de bipolaire stoornis. Stand van zaken.

BACKGROUND: There is great interest in the use of omega-3 fatty acids in the treatment of various psychiatric disorders. Epidemiological investigations show that a high consumption of omega-3 fatty acids is in inverse proportion to the prevalence of affective disorders. AIM: To provide an overview of current research reports on the use of omega-3 fatty acids and bipolar disorders. METHOD: Medline was searched with the following MeSH terms: 'mood disorders', 'affective disorders', 'bipolar disorders', 'fish oil', 'unsaturated dietary fats', 'omega-3 fatty acids', 'eicosapentaenoic acid', 'docosahexaenoic acid' and 'alpha-linolenic acid'. results To date, articles have been published about four randomized controlled trials and one open-label study. Omega-3 fatty acids, when added to an existing psychopharmacological maintenance treatment for bipolar disorder, can have a slight beneficial effect on depressive symptoms. There is no clear evidence that this combination has a beneficial effect on manic symptoms. CONCLUSION: Current data on the efficacy of docosahexaenoic acid (dha) and eicosapentaenoic acid (epa) in the treatment of bipolar disorder are insufficient for us to draw definite conclusions that can guide clinical practice. Further investigations are required into the effects of omega-3 fatty acids on the various phases of bipolar disorder.

Omega-3 fatty acids and mood disorders.

OBJECTIVE: This article is an overview of epidemiological and treatment studies suggesting that deficits in dietary-based omega-3 polyunsaturated fatty acids may make an etiological contribution to mood disorders and that supplementation with omega-3 fatty acids may provide a therapeutic strategy. METHOD: Relevant published studies are detailed and considered. RESULTS: Several epidemiological studies suggest covariation between seafood consumption and rates of mood disorders. Biological marker studies indicate deficits in omega-3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression. CONCLUSIONS: Deficits in omega-3 fatty acids have been identified as a contributing factor to mood disorders and offer a potential rational treatment approach. This review identifies a number of hypotheses and studies for consideration. In particular, the authors argue for studies clarifying the efficacy of omega-3 supplementation for unipolar and bipolar depressive disorders, both as individual and augmentation treatment strategies, and for studies pursuing which omega-3 fatty acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), is likely to provide the greatest benefit.

Inositol deficiency diet and lithium effects.

OBJECTIVES: A major hypothesis explaining the therapeutic effect of lithium (Li) in mania is depletion of inositol via inhibition of inositol monophosphatase. However, inositol is also present in the diet. Restriction of dietary inositol could theoretically enhance the effects of Li. METHODS: We used dietary inositol restriction in animal studies and also devised a palatable diet for humans that is 90% free of inositol. RESULTS: Dietary inositol restriction significantly augmented the inositol-reducing effect of Li in rat frontal cortex. Li reduced inositol levels by 4.7%, inositol-deficient diet by 5.1%, and Li plus inositol-deficient diet by 10.8%. However, feeding with the inositol-deficient diet did not enhance the behavioral effect of Li in the Li-pilocarpine seizure model. Fifteen patients participated in an open clinical study of the inositol-deficient diet: six rapid cycling bipolar patients responding inadequately to Li or valproate in different phases of illness; two Li-treated bipolar outpatients with residual symptomatology, and seven inpatient Li-treated bipolar patients in non-responding acute mania. The diet had a major effect in reducing the severity of affective disorder in 10 of the patients within the first 7-14 days of treatment. CONCLUSION: These results suggest that dietary inositol restriction may be useful in some bipolar patients, but controlled replication is necessary.

Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder.

OBJECTIVE: The authors hypothesized that changes in brain membrane composition resulting from omega-3 fatty acid administration in patients with bipolar disorder would result in greater membrane fluidity, as detected by reductions in T(2) values. METHOD: Women with bipolar disorder (N=12) received omega-3 fatty acids for 4 weeks. A cohort of bipolar subjects (N=9) and a group without bipolar disorder (N=12) did not receive omega-3 fatty acids. T(2) values were acquired at baseline and after 4 weeks. RESULTS: Bipolar subjects who received omega-3 fatty acids had significant decreases in T(2). There was a dose-dependent effect when the bipolar omega-3 fatty acid group was subdivided into high- and low-dose cohorts. CONCLUSIONS: Omega-3 fatty acids lowered T(2) values, consistent with the hypothesis that the fluidity of cell membranes was altered. Further studies are needed to clarify the significance of alterations in brain physiology induced by omega-3 fatty acids, as reflected in T(2) values.

Bipolar disorder and cell membrane dysfunction. Progress toward integrative management.

Bipolar disorder (BD) is characterized by periods of abnormally elevated mood (mania) that cycle with abnormally lowered mood (depression). Multiple structural, metabolic, and biochemical abnormalities are evident in the brain's cortex, subcortex, and deeper regions. This disorder is highly genetically conditioned but also highly susceptible to environmental stressors: prenatal or perinatal insults, childhood sexual or physical abuse, challenging life events, substance abuse, and other toxic chemical exposures. Its high morbidity, lost productivity, and suicide risk place a great toll on society. Since World War II, BD has been steadily worsening with earlier age of onset, greater intensity of symptoms, and development of drug resistance. Incidence in children is rising and misdiagnosis is common. Disciplined management of the many risk factors is essential, including cognitive psychotherapy and support from family and community. Lithium has been the foundational treatment, followed by valproate and other mood stabilizers, antidepressants, and anticonvulsants. Several single-nutrient and multinutrient supplements have also proven beneficial. Controlled, double-blind trials show multinutrient combinations of vitamins, minerals, orthomolecules, herbals, and the omega-3 fatty acids EPA and DHA to be effective monotherapy. The molecular action of lithium and valproate converge with nutrients on the level of the cell membrane and its molecular signal transduction systems. This emergent, unified rationale presages effective integrative management of bipolar disorder.

Are fish oils an effective therapy in mental illness--an analysis of the data.

OBJECTIVE: To review the literature regarding the use of fish oils in the treatment of psychiatric illness. METHOD: A Medline search was conducted in September 1999. RESULTS: Five papers have investigated omega-3 fatty acids levels in depression. One study used omega-3 fatty acids as an adjunctive therapy in bipolar disorder. Four studies used fatty acids as an adjunctive therapy in schizophrenia. CONCLUSION: There is a great deal of current research in this field. While omega-3 fatty acids levels may be lowered in depression, there are no data suggesting that omega-3 fatty acids are effective. One paper indicates that omega-3 fatty acids are effective in bipolar disorders. The data on schizophrenia are conflicting. Omega-3 and omega-6 fatty acids have proved effective. Most of the evidence suggests that the main effect is an improvement in negative symptoms. One recent study showed that omega-3 fatty acids had no effect on negative symptoms.

Vanadium: a possible aetiological factor in manic depressive illness.

The effect of Vitamin C in manic-depressive psychosis was assessed by a double-blind, placebo controlled, crossover trial. Both manic and depressed patients were significantly better following a single 3 g dose of Vitamin C than following a placebo. Preliminary results of a double-blind, crossover comparison of normal vanadium intake with reduced intake in manic and depressed subjects are reported. Both manic and depressed patients were significantly better on reduced intake. These results are in keeping with the suggestion that vanadium may be an aetiological factor in manic depressive illness.