Dietary and nutritional therapies for schizophrenia

Nutritional medicine as mainstream in psychiatry

Psychiatry is at an important juncture, with the current pharmacologically focused model having achieved modest benefits in addressing the burden of poor mental health worldwide. Although the determinants of mental health are complex, the emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of mental disorders suggests that diet is as important to psychiatry as it is to cardiology, endocrinology, and gastroenterology. Evidence is steadily growing for the relation between dietary quality (and potential nutritional deficiencies) and mental health, and for the select use of nutrient-based supplements to address deficiencies, or as monotherapies or augmentation therapies. We present a viewpoint from an international collaboration of academics (members of the International Society for Nutritional Psychiatry Research), in which we provide a context and overview of the current evidence in this emerging field of research, and discuss the future direction. We advocate recognition of diet and nutrition as central determinants of both physical and mental health.

The Emerging Field of Nutritional Mental Health: Inflammation, the Microbiome, Oxidative Stress, and Mitochondrial Function

We live in a transformational moment for understanding the etiology of mental disorders. The previous leap in understanding occurred 60 years ago, which led us to incorporate psychopharmacology into our curricula to address the chemical basis of neurotransmitter function, especially as explained through the then-popular catecholamine hypothesis. The current revolution is broader, consisting of the rapidly accumulating knowledge of how inflammation, microbiome imbalance (gut dysbiosis), oxidative stress, and impaired mitochondrial output affect brain function. Suitable interventions for fighting inflammation, restoring normal gut function, reducing oxidative stress, and improving mitochondrial metabolism incorporate lifestyle variables, including nutrients and probiotics. This article invites readers to stay abreast of this emerging model of the biological basis of mental illness, given that it has particular relevance for those readers interested in alleviating the suffering of individuals with mental disorders. This overview describes the basis for a new field in mental health: nutritional psychiatry/psychology

food microglia
Feeding the beast: Can microglia in the senescent brain be regulated by diet?

Pregnenolone has a plethora of pharmacological properties that validate its use in the augmentation of antipsychotics [1, 2, 3]

Pregnenolone.svg

DHEA (also via its sulfate) shows pro-neurogenic, neuroprotective, sigma-1 receptor agonism, anti-glucocorticoid, NMDAR enhancing, catecholaminergic, antioxidant, anti-inflammatory and immunomodulating activity amongst other promising activities, similarly implicating it as a potential therapy for negative, depressive and anxiety symptoms in schizophrenia [4, 5, 6, 7]

Dehydroepiandrosteron.svg

See more: Neurosteroids as therapeutics

OMEGA-3 PUFAs

Omega-3 fatty acids initially demonstrated beneficial effects. More recent studies attempting to prevent the transition to psychosis in at-risk patients have been less encouraging [Update: but notable in another- see: Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study] but animal models are uncovering a broad range of prophylactic and restorative benefits. Widely available and with few side effects, use of omega-3 PUFAs at an anti-inflammatory dose [2.7 grams or more of omega-3 (EPA + DHA)] is personally encouraged as a simple dietary measure.

From: A meta-analysis of placebo-controlled trials of omega-3 fatty acid augmentation in schizophrenia: Possible stage-specific effects

Omega-3 fatty acids have shown promise as an adjunctive treatment for schizophrenia. However, efficacy across studies has been inconsistent. We conducted a meta-analysis of published controlled studies with the goal of detecting different efficacy profiles at various stages of schizophrenia. An online search was conducted for randomized, double-blind, placebo-controlled clinical trials, and a meta-analysis was conducted. Ten studies met the criteria for inclusion. Among patients in the prodromal phase of schizophrenia, omega-3 supplementation reduced psychotic symptom severity and lowered conversion rates to first-episode psychosis. In patients with first-episode schizophrenia, omega-3 decreased nonpsychotic symptoms, required lower antipsychotic medication dosages, and improved early treatment response rates. Omega-3 had mixed results in patients with stable chronic schizophrenia, with only some patients experiencing significant benefits. Among patients with chronic schizophrenia, use of omega-3 fatty acids both by those experiencing acute exacerbations and those who had discontinued antipsychotic medications resulted in worsening of psychotic symptoms. The data suggest that omega-3 fatty acids may be efficacious in reducing clinical symptoms for patients in the earlier stages of schizophrenia (prodrome and first episode), while producing mixed results for patients in the chronic stages. Based on these results, omega-3 fatty acids would not be recommended for acute exacerbations in patients with chronic schizophrenia nor for relapse prevention after discontinuation of antipsychotics.

From: Pathways of polyunsaturated fatty acid utilization: Implications for brain function in neuropsychiatric health and disease

PUFAs and signaling pathways in the brain

PUFAs can modulate many signal transduction mechanisms in neuronal membranes and the synapse. As serotonin (5-HT1 and 5-HT4), beta-adrenergic and dopamine (D1 and D2) receptors are all coupled to the cAMP messenger system, PUFAs can influence them by increasing adenylate cyclase (Murphy, 1985 and Nicolas et al., 1991) and protein kinase A (Speizer et al., 1991) activity. Animal studies, in piglets (de la Presa Owens and Innis, 1999) and in two generations of rats (Zimmer et al., 1999 and Zimmer et al., 2000b) fed n-3 PUFA deficient diets identify many effects on dopaminergic systems, including lower levels of dopamine (de la Presa Owens and Innis, 1999 and Zimmer et al., 2000b), D2 receptors, D2 receptor mRNA and dopaminergic presynaptic vesicles (Zimmer et al., 2000b), and increased breakdown of dopamine (Zimmer et al., 1998), in the prefrontal cortex. Experimental n-3 PUFA deficiency in rat dams shortly after conception also results in offspring with decreased tyrosine hydroxylase (Kuperstein et al., 2008), the rate-limiting enzyme in dopamine synthesis; fewer detectable dopaminergic neurons in the substantia nigra and ventral tegmentum (Ahmad et al., 2008); and elevated postnatal expression of dopamine receptor genes in rat pups (Kuperstein et al., 2005). After two generations of n-3 PUFA deficiency, rats also exhibit higher dopamine levels, D2 receptor mRNA, D2 receptors, and less release and breakdown of dopamine in the nucleus accumbens (Zimmer et al., 2000a). Conversely, two generations of a high-n-3 PUFA diet increases dopamine levels in rat prefrontal cortex by 40% and elevates D2 receptor binding, while lowering monoamine oxidase B activity in prefrontal cortex and D2 receptor binding in striatum (Chalon et al., 1998). PUFA associations with dopamine also have been implicated in clinical depression (Sublette et al., 2014). Less has been reported concerning dietary PUFA effects on serotonin (5-HT), although, compared with normally fed animals, rats with low brain DHA had decreased 5-HT levels and turnover in frontal cortex (nulliparous females) and higher density of hippocampal 5-HT1A receptors (parous dams) (Levant et al., 2008). Also, in 2-month old male rats, stimulated 5-HT release in the hippocampus was lower in rats fed an n-3 PUFA deficient diet for two generations, and the ability of diet alteration to reverse this deficiency decreased over time after parturition (Chalon, 2006a). However, in adult male mice, n-3 PUFA supplementation was effective in reversing 5-HT levels that had declined by 40–65% as a result of unpredictable chronic mild stress (Vancassel et al., 2008). On the other hand, in one study comparing high saturated fat, high n-3 PUFA, and high n-6 PUFA diets, 5-HT2A receptor and 5-HT transporter binding were most strongly affected by the n-6 PUFA diet (Dubois et al., 2006).

PUFAs also can interact with the phosphoinositide signaling pathway by exerting effects on phospholipase C (Irvine et al., 1979) and protein kinase C (McPhail et al., 1984a and McPhail et al., 1984b), both of which are involved in 5-HT2 and alpha-1 adrenergic mediated signal transduction.

Neurotransmitters affect PUFA turnover, as PLA2 is activated by multiple receptor types – dopamine D2 (Vial and Piomelli, 1995), serotonin 5-HT2 (Berg et al., 1996), glutamate (Tence et al., 1995), and muscarinic acetylcholine (Jones et al., 1996) – to liberate fatty acids from the sn-2 position of phospholipids. In turn, PUFAs also regulate the activity, mRNA expression, and protein levels of multiple PLA2 isoforms (Downes and Currie, 1998, Lister et al., 1988 and Rao et al., 2007a).

Fatty acids that are not recycled back into phospholipids can be metabolized through several pathways, e.g. cyclooxygenase (COX)-2 ( O’Banion, 1999) acts on AA, EPA and DHA ( Serhan et al., 2002) to produce prostanoids (prostaglandins [PGE] and thromboxanes) ( Chang and Karin, 2001 and Kozak et al., 2001), while lipoxygenases produce leukotrienes and lipoxins. PGEs occur in 3 families which have different effects through interactions with specific signaling systems: the PGE-2 family transduces signals via a Gs protein, elevating cAMP levels, whereas the PGE-3 family uses a Gi protein, lowering cAMP, and the PGE-1 family acts through a phosphoinositide signaling system ( Smith, 1992). Eicosanoids, 20-carbon n-6 compounds, and docosanoids, 22-carbon n-3 compounds that include resolvins or neuroprotectins, can have opposing effects on signal transduction and inflammatory processes ( Calder, 2006 and Piomelli, 1994).

Release of neurotransmitters from synaptic vesicles by activation of Ca2+/calmodulin-dependent protein kinase is affected by PUFAs (Piomelli et al., 1989), and Ca-ATPase in neuronal membranes is inhibited by DHA and EPA.

Neuroinflammation

The balance between n-6 and n-3 PUFAs thus can have profound effects on neuroinflammation. For example, as n-3 and n-6 LC-PUFAs compete for membrane insertion, an n-3 PUFA-enriched diet increases production of anti-inflammatory docosanoids and decreases the n-6 content of glial cell membranes, resulting in less substrate available for AA-derived eicosanoid synthesis (Calder, 2006). Some examples with clinical relevance include rodent models of metabolic and behavioral responses to traumatic brain injury, in which n-3 PUFA deficiency states worsened post-injury anxiety-like behavior (Agrawal et al., 2014) and sensorimotor impairments (Russell et al., 2013), and resulted in lower levels of anxiolytic neuropeptide Y1 receptor (Agrawal et al., 2014) and mRNA expression of tissue inhibitor of matrix metalloproteinase-1 (Timp1) (Russell et al., 2013). Supplementation with n-3 PUFAs in the diet prior to experimental injury mitigated the usual sequelae of abnormal levels of brain-derived neurotrophic factor (BDNF), synapsin I, and cAMP responsive element-binding protein (CREB) (Wu et al., 2004), as well as axonal injury, apoptosis (Mills et al., 2011), and cognitive impairments (Mills et al., 2011 and Wu et al., 2004). Moreover, in a mouse model, even after experimental brain injury, an inhibitor of fatty acid amide hydrolase (FAAH) reduced breakdown of the PUFA metabolite anandamide, and thereby mitigated fine motor and working memory impairments and anxiety-like behaviors, concomitantly reducing neurodegeneration and amyloid precursor protein, and upregulating stress-responsive growth factors and heat shock proteins (Tchantchou et al., 2014).

PUFAs as regulators of brain energy

DHA also has been identified as an important regulator of brain energy metabolism, having effects on both glucose uptake and on the density of glucose transporter-1 (GLUT1) in endothelial cell cultures (Pifferi et al., 2007) and in cerebral cortex from rat brain (Pifferi et al., 2005). Neuroimaging in humans with [18F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) has identified correlations between plasma PUFA levels and cerebral metabolic rates for glucose (rCMRglu) in specific brain regions (Sublette et al., 2009).

PUFAs and neuroprotection

The benefits of n-3 LC-PUFAs to neuropsychiatric health are likely afforded, in part, by their neuroprotective properties. DHA and its metabolite NPD1 alter the expression of pro- and anti-apoptotic genes, including Bcl-2, Akt, and Bfl-1 (Akbar and Kim, 2002, Akbar et al., 2005 and Bazan, 2007), positively affecting neuronal survival. Resolvins, too, protect the brain from ischemia (Marcheselli et al., 2003). Dietary DHA also confers neuroprotection by specifically reducing β-amyloid in a mouse model of Alzheimer’s disease (Lim et al., 2005a) and in cytokine-stressed human neural cells (Lukiw et al., 2005), while in an in vivo human study, elevated AA brain uptake was seen with PET, in patients with Alzheimer’s disease compared to healthy volunteers ( Esposito et al., 2007). Conversely, in vivo DHA depletion has been shown to result in decreased brain-derived neurotrophic factor (BDNF) in rodents ( Rao et al., 2007b) and increased neuronal cell death in cell cultures ( Akbar et al., 2005).

“…we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction”

OTHER DIETARY MEASURES

see: Nutritional interventions for the adjunctive treatment of schizophrenia: a brief review.

A Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia and “may effectively target sensory gating deficits and is a promising area for additional research in schizophrenia

In patients with hyperhomocysteinemia, adjunctive administration of B Vitamins [a complex of folic acid, cobalamin (B12), and pyridoxine (B6)] produced improvements in neurocognitive outcomes over placebo.

Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption [8]. L-methylfolate is undergoing clinical trials [9]

Vitamin D may play a role in the pathogenesis of psychiatric illness [10]. Multiple relevant neurotransmitter pathways, immune function and inflammation are all influenced by vitamin D status [11] Developmentally vitamin D deficient animals show increased behavioural deficits in a NMDA antagonist model of schizophrenia and “a transient vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders. [12] Clinical trials are underway to determine if antipsychotic induced weight gain may be related to a vitamin D deficiency [13]

1,25(OH)2D3 has a direct effect on neural stem cell proliferation, survival, and neuron/oligodendrocyte differentiation, thus representing a novel mechanism underlying its remyelinating and neuroprotective effect.

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A significant subgroup of patients may benefit from the initiation of a gluten and casein-free diet.

Despite some limitations – particularly related to bioavailability – supplementation with curcumin may be of benefit. A clinical trial is underway to determine if curcumin nanoparticles will improve behavioral measures and biomarkers of cognition and neuroplasticity in patients with schizophrenia.

A diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine and choline may target multiple relevant pathways and thus provide a broad-spectrum nutraceutical approach to symptom reduction in neurodegenerative conditions [14].

ANTIOXIDANTS

Pharmacotherapeutic strategy to reduce oxidative stress

Clinical trials demonstrated beneficial effects of N-acetylcysteine and omega-3 fatty acids and and vitamins E and C in the treatment of schizophrenia. Furthermore, these studies seem to suggest that antioxidant treatment supports positive outcomes in the early stage of schizophrenia.

a-Lipoic acid, a liphophilic anti-oxidant, shows potential in animal models. [15 , 16]
Lipoic-acid-2D-skeletal.png
N-acetylcysteine is a readily available and potentially effective agent. [17, 18, 19] Actions at mGluR2/3 receptors [20] add to its intriguing pharmacology. [21, 22]

Acetylcysteine2DACS.svgMelatonin displays neurotrophic activity. Administration of melatonin, which also attenuates stress induced changes to the HPA-axis and hippocampus, helps to entrain circadian rhythms and attenuates antipsychotic induced metabolic side-effects [23] is a benign approach to potential symptom reduction.

Microsoft PowerPoint - Hardeland_Mel_BrainInflammaging_Fig1
See more here

Acetyl-L-carnitine administered intravenously has been shown to promote rapid antidepressant responses by acetylation of histone proteins that control the transcription of BDNF and metabotropic glutamate 2 (mGlu2) receptors in the hippocampus and prefrontal cortex [24]. It is also a potent antioxidant. Clinical trials are currently underway (using small doses of 500mg) with the hope of improving cognitive and negative symptom domains.

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OTHERS

Adjunctive L-carnosine produced improvements in executive functions, memory, attention, and motor speed over placebo. [25]

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6g/day of L-lysine added to risperidone has shown superiority over placebo [26] Large doses can deplete intra-cellular L-arginine stores, leading to a reduction in NO [more here]. Actions as a 5-HT4 partial antagonist may also play a role. High doses have demonstrated an anxiolytic effect in humans

Skeletal formula of the L-monocation (positive polar form)Creatine [examine.com]: “Dechent et al (1999) studied the effect of oral creatine supplementation for 4 wk demonstrating a statistically significant increase of mean concentration of total creatine across brain regions. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including schizophrenia and major depression. Recently, Rae et al (2003) reported that creatine supplementation for 6 weeks had a significant positive effect on both working memory and Raven matrices. Several independent lines of evidence suggest the possible involvement of altered cerebral energy metabolism in schizophrenia.

We are performing a double blind cross-over study of creatine in schizophrenia.” [27]

Skeletal formula of creatine

A pilot open study of long term high dose creatine augmentation in patients with treatment resistant negative symptoms schizophrenia found only “mild positive effects on the patients’ symptomatology and behavior” but concluded it “might have beneficial effect on tardive parkinsonism” [28]

Zinc may be an effective augmentation strategy [29]

Zinc can modulate fast-excitatory transmission, facilitate the release of amino butyric acid and potentiate nicotinic acetylcholine receptors. There are also emerging evidences discussing the implication of these neurotransmitters in pathophysiology of schizophrenia. The purpose of this study was to evaluate the efficacy of Zn sulfate as an add-on therapy in the treatment of schizophrenia in a 6-week, double-blind and placebo-controlled trial. Eligible participants were 30 inpatients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Patients were randomly allocated into two equal groups; one group of patients received risperidone 6 mg/day plus capsules of Zn sulfate (each containing 50 mg elemental Zn) three times a day and another group received risperidone 6 mg/day plus placebo. The Positive and Negative Syndrome Scale (PANSS) was applied to assess the psychotic symptoms and aggression risk at baseline, week 2, 4, and 6 of the study. The results of this study showed that both protocols significantly decreased the scores on all subscales of the PANSS and supplemental aggression risk subscale as well as PANSS total score over the study. However, this improvement was significantly higher in Zn sulfate receiving group compared to the placebo group. No major clinical side-effects were detected. It may be concluded that Zn is an effective adjuvant agent in the management of patients with schizophrenia.

See: Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease


Schizophrenia.com details the following:

Sarcosine
D-Serine
N-Acetyl cysteine (NAC)
Melatonin
D-Alanine
B-Vitamins
Omega-3 for Prevention
Prenatal Choline for Prevention

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