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Glycine Transporter Inhibitors and Act at a Binding Site of the NMDA Recep- Tor Back to the Future of Psychopharmacology Archives of Psychiatry Research 2020;56:83-86 DOI:10.20471/may.2020.56.01.08 Received January 21, 2020, accepted March 23, 2020 Glycine transporter inhibitors and act at a binding site of the NMDA recep- tor. Glycine, with glutamate, is indispensable Current treatment of schizophrenia offers for activation of NMDA receptors. Conse- a wide variety of psychopharmaceuticals that quently, blocking the glycine transporter in- are licensed as first-line treatments for this creases the synaptic availability of glycine and disorder. However, if we consider their dom- thus improves NMDA neurotransmission. inant mechanism of action, choice eventually Furthermore, this enhances GABA neu- narrows, in some instances considerably. In rotransmission in the cortex, which in turn light of the facts that one third of patients do leads to a reduction in glutamatergic neuro- not respond to standard treatment and that transmission. Reduced glutamate release in current treatment options do not affect all the ventral tegmental area does not lead to schizophrenia symptom dimensions, it is not excessive stimulation of the mesolimbic do- hard to conclude that there is an unsatisfied pamine pathway. The terminal goal of GlyT1 need which should drive the development of inhibition is the abrogation of impaired new treatment modalities focusing on other NMDA receptor functionality. Exactly in this neurotransmitter systems beside dopamine way GlyT1 inhibition could potentially con- and serotonin [1]. tribute to the reduction of cognitive and neg- ative symptoms of schizophrenia with the There have been recent discoveries in reduction of positive symptoms. GlyT1 in- terms of convergent and convincing evi- hibitors are also called selective glycine reup- dence from pharmacological, autoimmune, take inhibitors or SGRI, in analogy to drugs and genetic studies which have confirmed that inhibit the reuptake of other neurotrans- that impaired glutamatergic N-methyl-D-as- mitters, such as serotonin reuptake inhibitors partate (NMDA) receptor function can pro- which acts upon the serotonin transporter duce psychotic symptoms and that it is in- (SSRI) [1,2]. volved in the pathogenesis of schizophrenia. Glycine transporters 1 (GlyT1) play a key role Several GlyT1 inhibitors are currently in in terminating the activity of glycine, which is the clinical testing phase, including bitopertin, released into synapses from glial cells to bind whose chemical structure is shown in Figure 1. We would highlight a clinical trial program 84 called “SearchLyte,” as one of the significant disease and therefore potentially respond to studies related to bitopertin, which consisted interventions targeting underlying biological of six Phase III studies. Three studies target- factors, while secondary negative symptoms ed the ability to treat patients with persistent arise from factors caused by social isolation negative symptoms. The other three studies and stigma. The latter are likely to respond were designed to determine the ability of the to psychosocial intervention and may thus drug to reduce the positive symptoms of pa- be enhanced by regular social interactions, tients who did not respond to the currently including regular assessments and medical available antipsychotic. Two trials were dis- examinations as part of a clinical trial, thus continued after analysis and the remaining contributing to a markedly more prominent trials did not meet their primary end goals placebo effect. Phase III studies were con- with the exception of the NightLyte study. ducted in chronic patients who likely devel- The aforementioned study included patients oped secondary negative symptoms. Another with a suboptimal response to treatment with problem with inclusion of chronic patients prior antipsychotics and found that the ad- in phase III studies is the fact that there is dition of bitopertin at a dose of 10 mg sig- evidence of glutamate abnormalities which nificantly improved the PANSS scores. While are more pronounced in the early stages of phase III trials focused on the additional use the disease and that drugs targeting this sys- of bitopertin, a phase II / III monotherapy tem can only have an effect on patients in the trial was also conducted. It included patients early stages of the disease. These consider- with acute exacerbation and compared pa- ations suggest that future studies should fo- tients treated with bitopertin to placebo and cus on patients in the early stages of the dis- the active control group using olanzapine. ease [3,4]. A trend of improvement in overall PANSS Another prominent GlyT1 inhibitor is N- score was detected for both bitopertin (30 methylglycine, which is also known as sar- mg) and olanzapine, which was the main cosine. Sarcosine has been the subject of endpoint of the study. However, this was not numerous, although predominantly small, significantly different from placebo for either schizophrenia studies that have shown its drug. Such a result was considered a failed superiority over placebo, either alone or as study, but bitopertin showed a significant augmentative therapy. According to some improvement in PANSS assessment and an reports, sarcosine improved negative, cogni- increased willingness of treated patients for tive and depressive symptoms of schizophre- demission from hospital treatment compared nia, including symptoms such as alogia and to placebo. Such, in some aspects, somewhat blunt affect [5,6]. However, further evidence disappointing results of the bitopertin trial is needed in order to confirm these facts. The could be explained by a number of reasons, standard dose of sarcosine used in clinical for example, the first being the possibility of studies was usually 2 grams per day, although a particularly pronounced placebo response there are recommendations that titration effect. Namely, placebo reactions are of par- should be performed on a gradual basis [5,6]. ticular concern in studies of negative symp- The chemical structure of sarcosine is shown toms that may be primary or secondary. Pri- in Figure 2. Sarcosine otherwise naturally oc- mary negative symptoms are inherent to the curs in various foods and is sold without re- Archives of Psychiatry Research 2020;56:83-86 Back to the Future of Psychopharmacology 85 Figure 1. Chemical structure of bitopertin Figure 2. Chemical structure of sarcosine striction. It is extensively promoted on the in- glycinergic neurotransmission or NMDA ternet as a supplement for “brain health” and receptor-dependent excitatory glutamatergic for various mental health problems. Even in neurotransmission. However, none of the the formulation of dietary supplements there proposed clinical applications can integrate is reasonable evidence that it has a true phar- the expected neuropharmacological effects macological effect [7]. of selective inhibitors of glycine reuptake, Several other GlyT1 inhibitors are also leading to the conclusion that the dual action in the preclinical study phase, such as SSR of glycine in the nervous system may explain 504734, SSR 241586, JNJ17305600, and PF- why none of these approaches have yielded 03463275 (2). clinically ready drugs [2, 8-12]. It is important to note that several inde- In conclusion, we cheer on and hope pendent lines of research have demonstrated for further investigations of GlyT1 inhibi- that pharmacological inhibition of glycine tors, focusing on their potential to improve reuptake may also be relevant for the treat- NMDA receptor functionality, as well as clin- ment of various other clinical conditions, ically beneficial changes in symptom expres- including depression, anxiety disorders, ob- sion. Especially in terms of negative and cog- sessive compulsive disorder, alcohol de- nitive symptomatology of schizophrenia, but pendence, epilepsy and pain. This could be also in other potential clinical applications. explained by the physiological impact of gly- Assistant Professor Vjekoslav Peitl, MD, PhD cine reuptake inhibition on either inhibitory Darko Vlahović, MD References 3. Singer P, Yee BK. Pharmacotherapy Through the 1. Stahl SM. Stahlovi temelji psihofarmakologije. Jas- Inhibition of Glycine Transporters: An Update on trebarsko: Naklada Slap; 2017. and Beyond Schizophrenia. In: Gargiulo P, Me- sones-Arroyo H, (eds). Psychiatry and Neurosci- 2. Karlović D, Peitl V, Silić A. Shizofrenije. Jastrebar- ence Update - Vol. II. Cham, Switzerland: Spring- sko: Naklada Slap; 2019. er; 2017. Glycine transporter inhibitors Archives of Psychiatry Research 2020;56:83-86 86 4. Beck K, Javitt DC, Howes OD. Targeting glutamate er-I as a novel mechanism for the treatment of de- to treat schizophrenia: lessons from recent clinical pression. Biol Psychiatry. 2013;74:734-41. studies. Psychopharmacology. 2016;233:2425-8. 9. Wu PL, Tang HS, Lane HY, Tsai CA, Tsai GE. Sar- 5. Strzelecki D, Urban-Kowalczyk M, Wysokinski cosine therapy for obsessive compulsive disorder: A. Serum levels of TNF-alpha in patients with a prospective, open-label study. J Clin Psychophar- chronic schizophrenia during treatment augmenta- macol. 2011;31:369-74. tion with sarcosine (results of the PULSAR study). 10. Socała K, Nieoczym D, Rundfeldt C, Wlaź P. Ef- Psychiatry Res. 2018;268:447-53. fects of sarcosine, a glycine transporter type 1 in- 6. Amiaz R, Kent I, Rubinstein K, Sela B, Javitt D, hibitor, in two mouse seizure models. Pharmacol Weiser M. Safety, tolerability and pharmacokinet- Rep. 2010;62:392-7. ics of open label sarcosine added on to anti-psy- 11. Centeno
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