1. IntroductionSchizophrenia (Sch) is a severe mental disorder that affects approximately 0.5–1% of the population [1]. It includes positive, negative and cognitive symptoms and can lead to significant functional disorders and pronounced social maladaptation of patients [2]. There are several neurochemical hypotheses for the development of Sch: dopaminergic [3], kynurenic [4], glutamatergic [5] and others [6]. The leading hypothesis is dopaminergic, which has formed the basis of the approaches to Sch therapy. Antipsychotics (APs) are the first-line drugs for Sch treatment [7]. However, the issue of achieving a balance between the effectiveness and safety of APs remains open [8]. Other neurochemical hypotheses for the development of Sch continue to be explored as they may provide clues to discover a disease-modifying therapy for mental disorders [9].The response to APs of the first and new generations (Figure 1) [9] is variable, and it is still difficult to predict whether the therapy will be effective or not [10].About 20–30% of patients with Sch do not have an adequate response ≥2 in terms of dose and duration of AP treatment [12]. This is the clinical definition of treatment-resistant Sch (TRS). As is known, TRS is a serious condition with associated clinical, social and medical expenses and consequences [13]. The definition of TRS has been revised several times. The first definition of TRS was proposed by Kane et al. [14]; this definition is based on the lack of response to Aps, using the example of clozapine. Most new definitions of TRS include failure to respond to at least two consecutive APs courses. In most cases, one of the two APs must be atypical, and have an adequate dose and duration of treatment (≥6 weeks). An adequate dose of an AP in the most recent report is defined as a daily dose equivalent to chlorpromazine ≥ 400 mg [15,16,17]. The absence of a therapeutic response to APs was indicated as a relative change in the evaluation scales (≥20% decrease in the scale of positive and negative symptoms of Sch) [17]. Thus, most patients with TRS may never achieve functional recovery [18], which leads to an increased burden of illness for the patient, family and the Healthcare System [19] (Figure 2).Two types of TRS are known: (1) a type of resistance to APs that is already present at the onset of the disease; (2) the second type of resistance to APs, which develops later during the progression of Sch and/or after a period of successful therapeutic response to APs [20,21]. Treatment methods of Sch that include both typical (the first generation) and atypical (new generations) APs act primarily as brain dopaminergic receptor antagonists. Although these APs are highly effective in treating positive symptoms, their efficacy is limited in patients with persistent negative symptoms or cognitive impairment in patients with Sch [22]. Therefore, the development of a disease-modifying therapy for Sch [23], resistant to APs, is relevant. Associative genetic studies and genome-wide associative studies have identified over a hundred candidate genes as molecular biomarkers of TRS risk with modest effect [24,25,26]. Interestingly, some of these candidate genes have proteins involved in glutamatergic transmission, especially with the N-methyl-D-aspartate receptors (NMDARs) [27]. So, NMDARs are ligand-dependent ionotropic glutamate receptors, consisting of four subunits [28]. Three families of NMDAR subunits are known: GluN1, GluN2 (subtypes GluN2A, GluN2B, GluN2C and GluN2D) and GluN3 (subtypes GluN3A and GluN3B). At the same time, NMDAR is formed by two GluN1 subunits and either two GluN2 subunits, or a combination of GluN2 and GluN3 subunits, which form a channel (pore) [29]. GluN1 subunits have a glycine co-agonist or D-Serine (D-Ser) recognition sites, while GluN2 subunits have glutamate co-agonist recognition sites. In addition, NMDARs are at rest blocked by Mg2+ ions, which close the Ca2+ channel; NMDAR opens when three things happen simultaneously: (1) glutamate binds to its site on NMDAR; (2) glycine or D-Ser bind to their sites on NMDAR; and (3) depolarization of the neuron membrane occurs. At the same time, depolarization of the cell membrane removes Mg2+ ions from the channel (pore), and the binding of co-agonists Glyc and glutamate provides a voltage-dependent influx of Na+ and Ca2+ ions and outflow of K+ ions, causing postsynaptic effects of glutamate neurotransmission (Figure 3) [30]. NMDARs are located predominantly postsynaptically, but can also be located extrasynaptically. Activation of synaptic NMDARs usually promotes the survival of synapses and neurons, while excessive activation of extrasynaptic NMDARs by excess glutamate (“Glutamate shock”) can have a neurotoxic effect and cause neuronal death [31]. D-Aspartate (D-Asp) is a direct NMDAR agonist that excites both metabotropic glutamate receptors and dopaminergic neurons in the brain [32]. In addition, D-Asp is indirectly involved in the initiation and progression of neurodegenerative processes [33] and plays an important role in the neuroplasticity, physiology and morphology of neuronal dendrites, along with regulation of gray matter volume and brain activity [34,35]. D-Ser and D-Asp are D-amino acids [36], and like most amino acids, they have a chiral carbon center, which allows the formation of two stereoisomers. These stereoisomers are mirror images of each other. Similar amino acids have both a left-handed (L) and a right-handed (D) enantiomer (Figure 4) [36].L-amino acids are used in the human body as building blocks of proteins and intermediate products in biochemical processes [37]. Various studies in animal models and humans have demonstrated that D-amino acids, in particular D-Ser and D-Asp (Table 1) [38], are able to modulate various NMDAR-dependent processes, including synaptic plasticity, brain development, cognition and aging brain [39]. Dysfunctional NMDAR activity is associated with the etiology and pathophysiology of a wide range of psychiatric and neurological disorders, including Sch [40]. For example, according to one of the main hypotheses of Sch, glutamate activity in NMDARs is insufficient due to disturbances in the formation of glutamate NMDA synapses during brain development, while this hypothesis not only does not reject, but also confirms, the dopamine hypothesis of Sch [41].

This explains the growing number of studies on the role of D-Ser and D-Asp in the pathogenesis of Sch, TRS and disease-modifying therapy for TRS.

4. DiscussionSch is one of the most common mental disorders that affects the working population in many countries; although, incidence rates range from 0.2% in some African countries (Central African Republic, Somalia) to 0.5% in the USA, Australia and New Zealand [111]. Although some of the differences in these epidemiological rates may be due to different approaches and timing of the diagnosis of this mental disorder, differences in the prevalence of Sch can also be explained by studies that demonstrate that the lack of certain nutrients in the diet can contribute to the development of Sch as an additional externally modifiable risk factor [112,113]. Notably, some authors have shown that deficiencies in essential vitamins, minerals and polyunsaturated fatty acids are often reported in the population, but rarely in patients with Sch [114,115,116]. Other authors demonstrate that the daily supplementation of essential nutrients is often effective in reducing Sch symptoms and may be considered an adjunctive (disease-modifying) therapy strategy for TRS. Free-form amino acids are one of the most effective and safest nutrients available to support mental health, not only are they the building blocks of proteins that provide structure to the CNS, but they are also critical to the proper functioning of the CNS, as some amino acids are key to maintaining adequate levels of neurotransmitters (including dopamine, norepinephrine, serotonin, etc.), as demonstrated in this review using D-Asp and D-Ser). Although most Sch patients consume adequate amounts of protein, they may still be deficient in amino acids, the causes of this phenomenon are usually associated with impaired digestion and intestinal microbiota [117,118], when how much protein the patient consumes with food is of less importance, since his body does not can effectively break down exogenous protein into individual amino acids and their deficiency occurs. When this happens, recommending more complex proteins is not the answer to amino acid deficiencies. It is known that the consumption of free-form amino acids does not require additional digestion as amino acids are readily available and absorbed directly into the systemic circulation; this provides easy access to the amino acids necessary for the functioning of the CNS. For many Sch patients, amino acid supplementation may be one of the most consistently effective disease-modifying therapies, improving the expected therapeutic effect on APs.

Amino acid supplements can also reduce the positive and negative symptoms of Sch because they are either converted to neurotransmitters or have effects similar to neurotransmitters in the CNS, as demonstrated by D-Ser and D-Asp. The mechanisms underlying the therapeutic effects of D-Asp and D-Ser are variable and continue to be studied. However, their modulating effect on glutamatergic and dopaminergic neurotransmission is beyond doubt. At the same time, D-Ser as a component of TRS disease-modifying therapy has been more studied than D-Asp. However, studies in animal models of Sch, TRS and ultra-TRS (UTRS) patients demonstrate better prognosis (better outcomes in catamnesis) and a lower risk of developing ADRs when exogenous D-Asp and D-Ser are given as dietary supplements. In addition, diet therapy, long forgotten because it is not of interest to pharmaceutical companies, is also important in providing nutritional support to patients with TRS. In a number of countries, there is huge resistance to the use of supplements as a disease-modifying therapy for Sch and TRS, in particular from psychiatrists, mainly due to their lack of knowledge on this issue. Most psychiatrists prefer to use prescription APs and other medications (e.g., antidepressants, mood stabilizers, etc.) that have passed randomized controlled trials and are registered by the FDA.

However, the use of first and new-generation APs does not solve the problem of TRS in more than 30% of cases and sometimes leads to the development of serious ADRs, especially in chronic psychopharmacotherapy [9]. Thus, if psychiatrists avoid such TRS disease-modifying therapy due to a lack of knowledge or willingness to use new Sch treatments that are not supported by pharmaceutical companies and not yet approved by the FDA, they may jeopardize patient recovery due to their own laziness or selfishness [118]. Timely and correct medical diagnosis of TRS and a clear understanding of all possible therapeutic strategies should always be the prerogative of the practicing psychiatrist in the treatment of mental disorders. At the same time, it takes some time for clinicians to become familiar with all available TRS disease-modifying therapy options, including nutritional support (particularly exogenous D-Ser and D-Asp) and dietary advice that includes foods rich in these amino acids [85] (Table 5). However, this is an important task of modern psychiatry, which is undesirable to ignore.

The authors believe that psychiatrists who treat patients with Sch should be aware of available nutritional support methods, at appropriate doses, and possible ADRs. Such an approach is important in providing alternative and adjuvant (disease-modifying) therapy to their patients. At the same time, any form of treatment, including the administration of exogenous D-Asp and D-Ser and foods rich in these amino acids, should be monitored, and doses and duration of treatment should be adjusted individually for each patient as necessary to achieve optimal results.

So, our summarized results of fundamental and clinical studies of D-Asp and D-Ser demonstrated that low blood levels of these amino acids can be considered additional metabolic biomarkers of TRS, so their study may be useful in patients at risk of developing TRS. At the same time, low serum levels of D-Asp and/or D-Ser may indicate that this group of patients with Sch requires dietary adjustment (diet therapy) and/or additional administration of supplements containing these amino acids (Figure 7). Undoubtedly, large randomized intervention studies are needed to study in detail the effect of various doses of D-Asp and D-Ser (low, medium, high and very high) in patients with risk of Sch, TRS and UTRS, but even now it can be recognized that these amino acids have a positive effect on positive and negative symptoms of Sch and cognitive impairments.