Adjunctive nutrients in first‐episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms

Aim The effects of nutrient‐based treatments, including adjunctive vitamin or antioxidant supplementation, have been explored extensively in long‐term schizophrenia. However, no systematic evaluation of trials in “first‐episode psychosis” (FEP) has been conducted, despite the potential benefits of using these treatments during the early stages of illness. Therefore, we aimed to review all studies examining efficacy, tolerability and the biological mechanisms of action, of nutrient supplementation in FEP. Methods A systematic review of electronic databases was conducted from inception to July 2017. All information on feasibility, clinical outcomes and mechanistic findings from nutrient supplementation clinical trials was extracted and systematically synthesized. Results Eleven studies with a total of 451 patients with FEP (from 8 independent randomized controlled trials) were eligible for inclusion. Six studies examined omega‐3 fatty acids, with inconsistent effects on psychiatric symptoms. However, mechanistic studies found significant improvements in hippocampal neuronal health and brain glutathione. Antioxidants “n‐acetyl cysteine” (n = 1) and vitamin C (n = 2) also improved oxidative status in FEP, which was associated with reduced psychiatric symptoms. No benefits were found for vitamin E (n = 1). Finally, one study trialling the amino acid taurine, showed significant improvements in positive symptoms and psychosocial functioning. Conclusion There is preliminary evidence that taurine improves outcomes in FEP, whereas effects of omega‐3 and antioxidant vitamins/amino‐acids are inconsistent; perhaps mainly benefitting patients with high levels of oxidative stress. Future studies should evaluate multifaceted dietary and supplementation interventions in FEP; targeting‐specific nutritional deficits and the range of aberrant biological processes implicated in the disorder.


| INTRODUCTION
First-episode psychosis (FEP) refers to the first 2 to 5 years of a psychotic disorder, such as schizophrenia. The mainstay of treatment is antipsychotic medications, which reduce "positive symptoms" (eg, hallucinations and delusions) within weeks per month (Malla et al., 2006). However, 80% of patients relapse within 5 years (Robinson, Woerner, McMeniman, Mendelowitz, & Bilder, 2004), and only 1 in 6 achieve full recovery (Jääskeläinen et al., 2012). Furthermore, "negative symptoms" (eg, low motivation and social withdrawal) and cognitive deficits (poor memory and concentration) persist despite antipsychotic treatment, causing much of the long-term disability associated with schizophrenia (Green, Kern, Braff, & Mintz, 2000). Therefore, to facilitate full recovery, new treatments are needed in the earliest stages of illness to reduce residual positive symptoms, and treat negative symptoms and cognitive deficits.
Nutritional deficiencies are recognized as a risk-factor for various psychiatric disorders (Sarris, Logan, et al., 2015). People with schizophrenia generally have low-quality diets (Dipasquale et al., 2013) and a spectrum of nutritional deficiencies, even from illness onset (Firth, Carney, et al., 2017). Furthermore, reduced levels of vitamins and polyunsaturated fatty-acids (PUFAS) are associated with various adverse outcomes in FEP; including greater symptom severity, reduced neural integrity and neurocognitive impairments (Firth, Carney, et al., 2017;Graham et al., 2015;Shivakumar et al., 2015).
Certain food-derived nutrients have been shown to provide effective adjunctive treatment for patients with long-term schizophrenia. For instance, a double-blind randomized controlled trial (RCT) in 2008 showed that 2000 mg per day of the amino-acid "n-acetylcysteine" (NAC) significantly reduced negative symptoms in patients with established illness (Berk et al., 2008). This finding was replicated by an independent research group in 2013 (Farokhnia et al., 2013). Additionally, our previous meta-analysis found that adjunctive treatment with highdose B-vitamins significantly reduced total psychiatric symptoms among 297 long-term patients in 7 different studies .
The potential beneficial effects of B-vitamins in schizophrenia has recently been confirmed by Roffman et al. (2017), who reported reductions in total and negative symptom scores from adjunctive treatment with 15 mg daily of "l-methylfolate" (vitamin B9), along with significantly improved brain structure and connectivity after 12 weeks of treatment.
Although focused on long-term schizophrenia, we previously found that vitamins had larger effects in patients with shorter illness duration, and those requiring lower doses of antipsychotic medications ; indicating that the benefits of vitamin supplementation may be more pronounced in early stages of psychosis. Additionally, inflammation and oxidative stress are highest in early illness (Flatow, Buckley, & Miller, 2013;Miller, Buckley, Seabolt, Mellor, & Kirkpatrick, 2011), and may drive the neurocognitive abnormalities which arise during this time (Mondelli et al., 2011).
Thus, FEP may be the ideal timeframe for administering antioxidant/ anti-inflammatory nutrients as adjunctive treatments to counteract adverse neurobiological processes implicated in schizophrenia; thus reducing the likelihood of enduring symptoms and cognitive dysfunction (Chaudhry et al., 2012;Meyer, Schwarz, & Müller, 2011).
Despite the promising indications for various nutrients in FEP, the evidence for using nutrients as an adjunctive treatment for improving outcomes in this patient group has yet to be systematically evaluated. Therefore, we aimed to identify all existing RCTs of adjunctive nutrientbased treatments in FEP, and systematically evaluate the evidence in this area. Specifically, we aimed to (1) determine the efficacy of nutrient-based adjunctive treatments for improving patient outcomes, (2) explore the underpinning mechanisms of action by examining effects on brain volume and other biomarkers in FEP and (3) report on tolerability/adverse sideeffects of nutrient treatments.

| METHODS
This systematic review and meta-analysis followed the PRISMA statement for transparent and comprehensive reporting of methodology and results (Moher, Liberati, Tetzlaff, & Altman, 2009). and keyword algorithm is shown in Appendix S1, Supporting Information.

| Search and screening process
All eligible studies: (1) used samples in which >75% of participants had a first episode of "psychosis," classified according to International Classification of Diseases (ICD)/Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. Studies which did not use the term "first-episode psychosis" were only eligible where all participants were identified as being within the first 3 years of treatment for psychotic disorders.
(2) Examined effects of any nutrients including vitamins, minerals, aminoacids, fatty-acids (or any miscellaneous food-based supplement), whilst herbal medicines were excluded. (3) Were controlled or open-label human clinical trials which measured quantitative change in any physical, psychological or neurobiological outcome following nutrient-based treatment.

| Data extraction
The following data from each study were extracted by 2 independent authors (J.F. and S.R.): 1. Study details: sample size and clinical characteristics, trial design, nutrient and dosage used and length of treatment.
2. Therapeutic target and mechanism: the primary outcome and hypothesized operative pathway of nutrient supplementation was determined from the study aims/methods sections.
3. Effects of adjunctive nutrients: quantitative outcomes of nutrient supplementation on physical, psychological or neurobiological outcome measures, along with reported comparisons with any control conditions. 4. Tolerability and adverse events: information on trial retention, nutrient adherence and any adverse events or side-effects which occurred during the trials.
5. Study quality: assessed using the Cochrane Collaboration's "Risk of Bias tool" (Higgins et al., 2011), to examine 6 aspects of trial methodology, including; randomization sequence generation, allocation concealment, blinding of participants and researchers, blinding of outcome assessments, incomplete outcome data and selective outcome reporting.
The extracted data was then synthesized for each class of nutrient examined; thus assessing the efficacy and mechanistic findings from studies examining: (1) omega-3 PUFAs, (2) amino acids, (3) vitamins/mineral supplementation, as adjunctive treatments in FEP. Safety/tolerability data across all classes of nutrients were synthesized separately.  (Conus et al., 2017). Therefore, 11 studies, reporting data from 8 RCTs with 451 participants, were included in this review. All interventions examined the effects of nutrients in FEP as an adjunctive to usual treatment alone (with placebo). No studies examined different types of nutrient interventions, or compared nutrients to other forms of adjunctive therapies. Full details and findings for each study are presented in Table 1. Risk of bias summaries are presented in Appendix S2.

| Omega-3 supplementation
Six studies with a total sample of 173 participants (from 3 double-blind RCTs with unanimously low risk of bias) examined omega-3 PUFAS in FEP, particularly with regards to eicosapentaenoic acid (EPA) (Berger et al., 2007;Berger et al., 2008;Emsley et al., 2014;Pawelczyk et al., 2016;Pawelczyk et al., 2017;Wood et al., 2010). All studies hypothesized that EPA supplementation would improve symptomatic outcomes due to the beneficial effects this neuroprotective PUFA has on various brain processes which are disrupted in FEP, including neuroinflammation, oxidative stress, neurotransmission and synaptic plasticity.
Initially, Berger et al. (2007) found that patients receiving first antipsychotic treatment were more likely to achieve symptomatic remission within 6 weeks when supplemented with 2 g EPA daily, rather than placebo (P = .036). There were no differences in remission after 12 weeks, although participants given EPA required 20% lower doses of antipsychotics. Two neuroimaging sub-studies of these participants (n = 15, n = 24) found changes neuroprotective metabolites in the treatment groups. These studies showed omega-3 supplementation improved hippocampal neuronal health (Wood et al., 2010) and significantly increased brain markers which reduce oxidative stress and neural damage, such as glutathione (Berger et al., 2008). Furthermore, both improved hippocampal neuronal health and increased glutathione were correlated with reduced negative symptoms (P = .041 and .045, respectively). to initial antipsychotic treatment, over a period of 26 weeks in 71 patients with FEP. This showed that adjunctive treatment with EPA/DHA omega-3 improved total symptoms, functioning and depression significantly more than placebo (olive oil). A sub-study of the same sample investigated how changes in blood markers of oxidative stress moderated omega-3 treatment outcomes (Pawelczyk et al., 2017). This found omega-3 increased total plasma antioxidant capacity (P < .001) and reduced oxidative marker

| Antioxidant vitamins
Three studies have used adjunctive vitamins in newly diagnosed, antipsychotic-naïve FEP patients. All hypothesized beneficial effects would occur from the antioxidant properties of the vitamins used. alone. However, the study found no effect of vitamin C on metabolic outcomes, with equivalent weight-gain and lipid dysregulation occurring from olanzapine treatment in both groups. Eranti et al. (1998) administered vitamin E (3200 IU/d) in an open-label study, in order to counteract haloperidol-induced oxidative stress and thus reduce extrapyramidal symptoms. However, vitamin E had no significant effect on either symptoms or antipsychotic side-effects.

| Side-effects and adverse events
Across all 3 RCTs of PUFA in FEP (Berger et al., 2007;Emsley et al., 2014;Pawelczyk et al., 2016), there were no reports of adverse events attributable to omega-3 treatment. Furthermore, feasibility data indicated high tolerability, as retention was consistently high and adherence was >80%. Both of the trials of taurine (O'Donnell et al., 2016) and NAC (Conus et al., 2017) also reported that there were no adverse side-effects from either of these amino acids in FEP. Similarly, adjunctive treatment with antioxidant vitamins (C and E) did not result in any adverse events or side-effects (Dakhale et al., 2005;Eranti et al., 1998). Thus, across all studies to date, there is no indication of adjunctive nutrients causing negative side-effects or increasing adverse events in FEP.

| DISCUSSION
This review aimed to assess the efficacy, tolerability and biological mechanisms of action for nutrient-based compounds trialled as adjunctive treatments for FEP to date. Across the 11 studies (with a total of 451 participants) that were identified, there are some encouraging findings for certain nutrient-based adjunctive treatments in FEP.
Omega-3 is the most widely studied nutrient in FEP to date.
Although 2 trials found no benefits for people with FEP (Berger et al., 2007;Emsley et al., 2014), one study using an extended course of supplementation (24 weeks, compared to 12 weeks in Berger et al., 2007) observed significant improvements in both symptoms and real-world functioning (Pawelczyk et al., 2016). Additionally, the 3 mechanistic sub-studies from these trials consistently found significant reductions in central markers of neuronal oxidative damage (Berger et al., 2008;Wood et al., 2010) and peripheral markers of lipid peroxidation/oxidative stress (Pawelczyk et al., 2017). Furthermore, there appears to be a relationship between these brain and biomarker improvements with reduced negative symptoms (Berger et al., 2008;Pawelczyk et al., 2017;Wood et al., 2010). Thus, more research is required to assess the longer-term benefits of omega-3 supplementation in FEP, and to determine if certain patient subgroups (ie, those most affected by negative symptoms and oxidative stress and inflammation) may be more responsive to such treatments (Rapaport et al., 2016).
Two further trials found that the dietary antioxidants NAC and vitamin C were also effective for improving markers of central and peripheral stress in FEP (Conus et al., 2017;Dakhale et al., 2005). However, larger studies are required to examine how these reductions in oxidative stress may relate to clinical improvements. This is a promising avenue for future research, given that RCTs of other anti-inflammatory (non-nutrient) agents have also demonstrated efficacy as adjunctive treatments in schizophrenia and FEP (Solmi et al., 2017;Sommer et al., 2013), specifically for reducing negative symptoms and cognitive deficits, which is a major unmet need in FEP (Meyer et al., 2011).
However, the positive findings of the high-quality and modestly sized taurine trial (O'Donnell et al., 2016) (Kaplan, Rucklidge, Romijn, & Dolph, 2015;Oulhaj, Jernerén, Refsum, Smith, & de Jager, 2016;Rucklidge, Johnstone, & Kaplan, 2013). There is increasing interest in using multi-nutrients to target mechanistic pathways implicated in neuropsychiatric conditions (Dean et al., 2015;Oulhaj et al., 2016;Sarris, Stough, et al., 2015;Sarris, Logan, et al., 2015). Although this approach has yet to be trialled in schizophrenia, a combined nutrient formula which simultaneously reduces damaging oxidative processes, while restoring deficiencies (if apparent) in folate and vitamin D could provide effective adjunctive treatment for psychotic disorders; particularly during FEP, as oxidative stress is greatest at this point (Flatow et al., 2013). Furthermore, younger patients may be more responsive to nutrient treatments .
Across all of our included studies, there was no indication of any harmful side-effects, harmful interactions with antipsychotic medications or increased adverse events from the nutrients trialled in FEP.
This suggests that continued research into the benefits of nutrientbased adjunctive treatments for FEP is worthwhile and ethical.
However, beyond nutrient supplementation, it is important to also consider the dietary nutrition intake of people with FEP. To date, the bulk of the research on dietary factors in schizophrenia has focused on reducing over-consumption of obesogenic foods, and preventing the associated weight gain (Teasdale, Ward, Rosenbaum, Samaras, & Stubbs, 2016). Future studies are required to examine how inadequate nutrient intake influences outcomes of FEP, as this could feasibly contribute towards poor recovery rates observed in this population (Teasdale, Ward, Rosenbaum, Watkins, et al., 2016). For instance, depriving the brain of neuroprotective nutrients may exacerbate psychiatric symptoms (Goff et al., 2004) whereas consuming nutritionally devoid high-fat foods increases systematic inflammation and oxidative stress (Devaraj, Wang-Polagruto, Polagruto, Keen, & Jialal, 2008;Lundman et al., 2007). Further, an RCT in patients with major depression has recently shown significant reductions in psychiatric symptoms from corrective dietary intervention (Jacka et al., 2017). Clearly, additional supplementation trials and dietary interventions are warranted to establish how nutrition-based treatments can attenuate the cardiometabolic dysfunction and poor psychosocial recovery associated with antipsychotic treatment; in order to improve physical, psychiatric and neurobiological outcomes from earliest stages of this illness.