Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial (2015)

Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial.

Objectives Hypofunction of NMDA receptor is implicated in the pathophysiology, particularly cognitive impairment, of schizophrenia. Sarcosine, a glycine transporter I (GlyT-1) inhibitor, and sodium benzoate, a d-amino acid oxidase (DAAO) inhibitor, can both enhance NMDA receptor-mediated neurotransmission. We proposed simultaneously inhibiting DAAO and GlyT-1 may be more effective than inhibition of either in improving the cognitive and global functioning of schizophrenia patients. Methods This study compared add-on sarcosine (2 g/day) plus benzoate (1 g/day) vs. sarcosine (2 g/day) for the clinical symptoms, as well as the cognitive and global functioning, of chronic schizophrenia patients in a 12-week, double-blind, randomised, placebo-controlled trial. Participants were measured with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale every 3 weeks. Seven cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Committee, were measured at weeks 0 and 12. Results Adjunctive sarcosine plus benzoate, but not sarcosine alone, improved the cognitive and global functioning of patients with schizophrenia, even when their clinical symptoms had not improved. Conclusions This finding suggests N-methyl-d-aspartate receptor-enhancement therapy can improve the cognitive function of patients with schizophrenia, further indicating this pro-cognitive effect can be primary without improvement in clinical symptoms

Adjunctive use of lisdexamfetamine

Cognitively I suffer greatly – particularly in relation to sustained attention. It’s nice to see research towards improvements in cognitive deficits and negative symptoms:

Lisdexamfetamine dimesylate as adjunctive treatment with antipsychotics for predominant negative symptoms of schizophrenia: Concurrent neurocognitive and negative symptom improvement.

Background: Both neurocognitive impairments and negative symptoms of schizophrenia (NSS) are believed related to mesocortical dopaminergic hypofunction. This analysis examined the hypothesis that the dopamine agonist, d-amphetamine prodrug, lisdexamfetamine dimesylate (LDX), would improve neurocognition along with NSS in adults with clinically stable schizophrenia maintained on atypical antipsychotics. Methods: Outpatients with schizophrenia (>2 years) and predominant NSS, on antipsychotics (>12 weeks), underwent 10-week open-label (OL) LDX augmentation (20-70mg/d). Eligible participants (any SANS-18 improvement at week 10) entered 4-week, double-blind, placebo-controlled randomized withdrawal (RW). Efficacy measures included SANS-18 (primary), Brief Assessment of Cognition in Schizophrenia-Symbol Coding Subtest (BACS-SC), Hopkins Verbal Learning Test-Revised, Immediate Recall (HVLT-R), and Letter Number Span Test (LNS). Safety evaluations included treatment-emergent adverse events (TEAEs). Results: In 92 participants receiving OL LDX, SANS-18 mean change (95% CI; weeks 0-10 OL, LOCF) was -12.9 (-15.0, -10.8) (P<.0001). Mean change (95% CI) in BACS-SC T-score was 2.0 (0.1, 3.9) (P=.0369); mean change in HVLT-R and LNS T-scores were 0.4 (-1.1, 2.0) and 1.3 (-0.4, 3.0), respectively (both P=NS). During RW, no significant differences were noted (LDX vs placebo) for these outcomes. In the OL phase, 56/92 (60.9%) reported TEAEs; 3/92 (3.3%) reported serious TEAEs. Conclusions: LDX improved NSS without worsening positive symptoms of schizophrenia. This was accompanied by small but significant improvements in BACS-SC. Confirmation with larger placebo-controlled trials, various doses, and additional cognitive measures is warranted given the significant unmet need for treating negative and cognitive symptoms in schizophrenia.

The effects in rats of lisdexamfetamine in combination with olanzapine on mesocorticolimbic dopamine efflux, striatal dopamine D2 receptor occupancy and stimulus generalization to a d-amphetamine cue.

The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine’s ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine

A focus on nAChRs

While I have the ability to focus for short periods (and jump from thing to thing well!), sustained attention and general cognitive inflexibility are things that I really struggle with, leading to further problems in sustaining goal-directed activity.  I’m trying to work on them non-pharmacologically but that is easier said than done…

I believe there are avenues worthy of further exploration:

  • In a recent trial, encenicline (an α7 nAChR partial agonist) was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia [1].
  • Preliminary findings with CDP-choline (citicoline) [Examine] in a healthy, schizophrenia-like surrogate sample are consistent with a α7 nAChR mechanism and support further trials with it as a pro-cognitive strategy [2]. Healthy adolescent males receiving 28 days of citicoline showed improved attention and psychomotor speed and reduced impulsivity [3].
  • Galantamine, a potent allosteric potentiating ligand of nAChRs, has produced neurocognitive benefits in only one study with schizophrenia patients. Buchanan et al. found that galantamine improved working memory and verbal learning over placebo in 86 schizophrenia patients while no other study has found good evidence of its procognitive benefits [4]. That said, “cholinergic agents, in particular galantamine and nicotine, appear to have the most promising cognitive enhancing effects in schizophrenia patients” [5].
  • DMXB-A:

    “3-(2,4-dimethoxy-benzylidene)-anabaseine (DMXB-A) is an a-7 nicotinic receptor partial agonist that demonstrated positive benefits on neurocognitive functions—particularly attention—in a proof of-concept study that used a randomized, double-blind, cross-over design to study 12 schizophrenia patients. However, in the phase II study, Freedman et al. found no benefits of DMXB-A over placebo on neurocognition in 31 patients with schizophrenia. They attributed the failure of the phase II trial to the possibility that strong practice effects across the study arms may have obscured any DMXB-A benefits on neurocognition.” [4]

Some recent articles:

Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats.

Alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) have generated great interest as targets of new pharmacological treatments for cognitive dysfunction in schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced α7-nAChR agents has not been extensively characterised in animal models of schizophrenia. The aim of the present study was to evaluate the efficacy of type I and II PAMs, N-(5-chloro-2,4-dimethoxyphenyl)-N’-(5-methyl-3-isoxazolyl)urea (PNU-120596) and N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI), respectively, and galantamine, an acetylcholinesterase inhibitor (AChE) that also allosterically modulates nAChRs, against ketamine-induced cognitive deficits and social withdrawal in rats. The orthosteric α7-nAChR agonist octahydro-2-methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]pyrrole (A-582941) was used as a positive control. Additionally, the antipsychotic activities of the tested compounds were assessed using the conditioned avoidance response (CAR) test. PNU-120596, CCMI, galantamine and A-582941 reversed ketamine-induced cognitive inflexibility, as assessed in the attentional set-shifting task (ASST). The tested compounds were also effective against ketamine-induced impairment in the novel object recognition task (NORT). PNU-120596, CCMI, and A-582941 ameliorated ketamine-induced social interaction deficits, whereas galantamine was ineffective. Moreover, all tested compounds selectively suppressed the CAR. The positive allosteric modulation of α7-nAChRs demonstrates preclinical efficacy not only against schizophrenia-like cognition impairments but also positive and negative symptoms. Therefore, the use of α7-nAChR PAMs as a potential treatment strategy in schizophrenia is supported.

Disruptions of executive function, including attentional deficits, are a hallmark of a number of diseases. Acetylcholine in the prefrontal cortex (PFC) regulates attentive behaviour; however the role of α7 nicotinic acetylcholine receptor (α7nAChRs) in attention is contentious. In order to probe attention we trained both wild type and α7nAChR knockout mice on a touchscreen based 5-choice serial reaction time task (5-CSRT). Following training procedures we then tested sustained attention using a probe trial experiment. To further dissect the role of specific nicotinic receptors in attention we then tested the effects of both α7nAChR and β2nAChR agonists on the performance of both wild type and knockout mice on the 5-CSRT task. At low doses, α7nAChR agonists improved attentional performance of wild-type mice, while high doses had deleterious effects on attention. α7 nAChR knockout mice displayed deficits in sustain attention that were not ameliorated by α7nAChR agonists. However, these deficits were completely reversed by the administration of a β2nAChR agonist. Furthermore, administration of a β2nAChR agonist in α7 nAChR knockout mice elicited the same biochemical response in the prefrontal cortex as the administration of α7nAChR agonists in wild type mice. Our experiments reveal an intricate relationship between distinct nicotinic receptors to regulate attentional performance and provide the basis for targeting β2nAChRs pharmacologically to decrease attentional deficits due to α7nAChR dysfunction.


Other cholinergics

  • Rivastigmine and donepezil have similarly failed to demonstrate benefits as neurocognitive enhancers in schizophrenia in several placebo-controlled trials. In a 12-week open-label trial, Chung et al. found that 28 schizophrenia patients who received up to 10 mg/day of donepezil as an adjunct to atypical antipsychotics demonstrated improvements in attention, memory, psychomotor speed, and mental set-shifting. [4].

See more here

Recognition of cognitive impairment in schizophrenia

It’s good to see some progress being made towards the recognition of cognitive impairment in schizophrenia and looking at possible treatment options:

http://www.needrecognition.com

Cognitive symptoms, which may include deficits in memory, attention, working memory, processing speed, and problem solving

  • Can be present prior to the onset of illness
  • Persist during periods of psychotic symptom remission
  • Are highly predictive of outcome and functioning

Despite the availability of effective antipsychotic therapy, cognitive impairment remains an important unmet treatment need


Patients With Schizophrenia Demonstrate Impairment in a Broad Range of Cognitive Domains vs Healthy Individuals

Cognitive domains impaired by schizophrenia

Proposed Mechanisms of Cognitive Impairment in Schizophrenia

Conversations on Cognition

Interventions:

  • Cognitive remediation
  • The MATRICS team identified drug mechanisms of interest, including cholinergic, dopaminergic, and glutamatergic approaches
  • Of the cholinergic approaches, the α7 was identified as a top target of investigation

Potential Mechanistic Targets for Treatment of Cognitive Impairment in Schizophrenia

CHOLINERGIC
  • α7 receptor
  • muscarinic M1 MAChR
DOPAMINERGIC
  • dopamine D1 receptor
GLUTAMATERGIC
  • AMPA glutamatergic receptor
  • NMDA glutamatergic receptor
  • Metabotropic glutamate receptor
  • Glycine reuptake
OTHER
  • α2 adrenergic receptor
  • GABAA R subtype

See more:

Pharmacological Treatment of Cognitive Symptoms

The Magic of Movement; the Potential of Exercise to Improve Cognition (2015)

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. (2015)

Cognitive enhancing agents in schizophrenia and bipolar disorder (2015)

Drug repurposing and emerging adjunctive treatments for schizophrenia (2015)

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review (2015)

Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms (2015)

A critical review of pro-cognitive drug targets in psychosis: convergence on myelination and inflammation

Psychopharmacological treatment of neurocognitive deficits in people with schizophrenia: a review of old and new targets.

Improving cognition via vegetable derived NO? Polyphenols?

Intravenous sodium nitroprusside (acting as a NO donor) shows impressive antipsychotic potential. I wonder if dietary nitrate supplementation (vegetables rich in nitrate include spinach, lettuce, broccoli and beetroot) can provide both antipsychotic and cognitive benefits for people with schizophrenia via improved function of the PFC?

Here’s an interesting article:

Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation.

Nitrate derived from vegetables is consumed as part of a normal diet and is reduced endogenously via nitrite to nitric oxide. It has been shown to improve endothelial function, reduce blood pressure and the oxygen cost of sub-maximal exercise, and increase regional perfusion in the brain. The current study assessed the effects of dietary nitrate on cognitive performance and prefrontal cortex cerebral blood-flow (CBF) parameters in healthy adults. In this randomised, double-blind, placebo-controlled, parallel-groups study, 40 healthy adults received either placebo or 450ml beetroot juice (~5.5mmol nitrate). Following a 90minute drink/absorption period, participants performed a selection of cognitive tasks that activate the frontal cortex for 54min. Near-Infrared Spectroscopy (NIRS) was used to monitor CBF and hemodynamics, as indexed by concentration changes in oxygenated and deoxygenated-haemoglobin, in the frontal cortex throughout. The bioconversion of nitrate to nitrite was confirmed in plasma by ozone-based chemi-luminescence. Dietary nitrate modulated the hemodynamic response to task performance, with an initial increase in CBF at the start of the task period, followed by consistent reductions during the least demanding of the three tasks utilised. Cognitive performance was improved on the serial 3s subtraction task. These results show that single doses of dietary nitrate can modulate the CBF response to task performance and potentially improve cognitive performance, and suggest one possible mechanism by which vegetable consumption may have beneficial effects on brain function.

•Dietary nitrate is reduced endogenously via nitrite to nitric oxide.
•The effects of nitrate rich beetroot juice on frontal cerebral blood-flow were tested.
•Nitrate modulated the hemodynamic response to task performance in the frontal cortex.
•Performance on one of three tasks (serial 3s subtractions) was improved.
•Plasma nitrite was increased.

“The ingestion of nitrate, including from dietary sources, is associated with a number of effects consistent with increased levels of endogenous NO synthesis, including reductions in blood pressure. This effect has been demonstrated as early as 3 h after a single dose of nitrate rich beetroot juice, with a concomitant protection of forearm endothelial function and in vitro inhibition of platelet aggregation. Dietary nitrate has also been shown to reduce the overall oxygen cost of sub-maximal exercise 2.5 h after ingestion and after three or more days of administration. Similarly, an increase in peak power and work-rate, a speeding of VO2 mean response time in healthy 60–70 year olds and delayed time to task failure during severe exercise have also been reported following the consumption of nitrate rich beetroot juice consumed daily for 4 to 15 days. Nitrate related reductions have also been demonstrated with regard to the rate of adenosine-5′-triphosphate (ATP) turnover using magnetic resonance spectroscopy, whilst improved oxygenation has been confirmed directly in the muscle during exercise using Near-Infrared Spectroscopy (NIRS).

NO plays a pivotal role in cerebral vasodilation and the neurovascular coupling of local neural activity and blood-flow. Several studies have probed the effects of dietary nitrate derived from beetroot or spinach on brain function, including three studies that have included some form of cognitive testing either as an additional measure, or as the primary focus of the project. Whilst these studies demonstrated modulation of a number of physiological parameters they did not provide evidence of cognitive improvements, possibly due to comparatively small sample sizes and other methodological factors. Two studies have also investigated the effects of dietary nitrate on cerebral blood-flow parameters. In the first of these, Presley et al. demonstrated, using arterial spin labelling magnetic resonance imaging (MRI), that a diet high in nitrate consumed for 24 h increased regional white matter perfusion in elderly humans, but with this effect restricted to areas of the frontal cortex. More recently, Aamand et al., investigated the effects of 3 days of administration of dietary nitrate (sodium nitrate) on the haemodynamic response in the visual cortex elicited by visual stimuli, as assessed by functional MRI (fMRI). They demonstrated a faster, smaller and less variable blood-oxygen-level dependent (BOLD) response following nitrate, which they interpreted as indicating an enhanced neurovascular coupling of local CBF to neuronal activity. As the BOLD response simply reflects the contrasting magnetic signals of oxygenated and deoxygenated haemoglobin (with increased activity imputed from an assumed relative decrease in deoxyhemoglobin as local activation engenders a greater influx of blood borne oxygenated -Hb), it cannot disentangle the contributions of changes in blood-flow and changes in oxygen consumption to the overall signal. The current study therefore utilised Near-Infrared Spectroscopy (NIRS), a brain imaging technique that has the advantage over fMRI BOLD in that it measures both concentration changes in deoxy-Hb and overall local CBF (changes in oxy-Hb and deoxy-Hb combined).”

  • Previous research suggests that NO exerts a number of effects that might also impact on overall cellular energy consumption in the brain. These include the inhibition of mitochondrial respiration and therefore oxygen consumption, including via inhibition of cytochrome c oxidase, and enhancement of the efficiency of oxidative phosphorylation by decreasing slipping of the proton pumps

“It is important to note that beetroot contains a plethora of other, potentially bioactive, phytochemicals including the nitrogenous betalains, a range of phenolics, including multiple flavonoids and flavonols and folates. Given the ability of similar phytochemicals to modulate peripheral endothelial function, CBF parameters and cognitive function the possibility that any effects are related to high levels of these other compounds cannot be ruled out. It is also notable that the NO3/NO2/NO pathway is reported to be most prevalent during hypoxic conditions and in the presence of reducing agents such as vitamin C and polyphenols. Having said this, recent evidence from a study directly comparing nitrate rich beetroot juice to nitrate depleted (but otherwise identical) beetroot juice suggests that the effects seen on blood pressure and the O2 cost of exercise are directly attributable to the nitrate content of the juice rather than to any other bioactive components (although synergies cannot be ruled out). Given the potential for multifarious phytochemicals to impact on CBF, an extension of the current study using these nitrate rich and depleted interventions may be able to resolve the question of the direct contribution of nitrate to the cognitive and CBF effects seen here.”

To conclude:

“…the findings here suggest that supplementation with dietary nitrate can directly modulate important physiological aspects of brain function and improve performance on a cognitive task that is intrinsically related to prefrontal cortex function. Taken alongside a previous demonstration of increased prefrontal cortex perfusion in elderly humans following consumption of a high nitrate diet for ~ 36 h, the results here suggest both a specific food component and physiological mechanisms that may contribute to epidemiological observations of relationships between the consumption of a diet rich in vegetables and polyphenols (which naturally co-occur with nitrate in vegetables) and preserved cognitive function in later life. Of particular importance, the results here were demonstrated in young humans, who can be assumed to be close to their optimum in terms of brain function, and hint at the potential benefits of a healthy, vegetable rich diet across the lifespan.

In summary, dietary nitrate, administered as beetroot juice, modulated CBF in the prefrontal cortex during the performance of cognitive tasks that activate this brain region, with this effect most consistently seen as reduced CBF during the easiest of three tasks (RVIP). Cognitive performance was improved on a further task, serial 3s subtractions. These results suggest that a single dose of dietary nitrate can modify brain function, and that this is likely to be as a result of increased NO synthesis leading to an exaggerated neurovascular response to activity or improved efficiency of cellular metabolism”

Dietary intake of cocoa flavanols is also associated with benefits for cognitive performance [1].

See also:

Novel aspects of dietary nitrate

Psychiatric Disorders and Polyphenols: Can They Be Helpful in Therapy?

GlyT1 inhibitors

GlyT1 inhibitors may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects [1]. Similarly, GlyT1 inhibition is a potential therapeutic strategy in addressing the symptom domains of autism spectrum conditions [2].

Based on an animal model (reduced Sp4 expression in mice), GlyT1 inhibition may have promise in treating attentional deficits in neuropsychiatric patients but not learning or motivational deficits [3]:

“…by using this model relevant to schizophrenia, we demonstrated that GlyT-1 inhibition (Org 24598) significantly reversed the attentional but not learning or motivational deficits of these mice. Interestingly, GlyT-1 inhibition impaired the attention of WT littermate mice without affecting their learning or motivation. These data support GlyT-1 inhibition as a potential treatment for attentional but not positive valence deficiencies (negative symptoms) related to schizophrenia as well as a U-shape dose response of optimal synaptic glycine levels for attentional performance.”

That said:

“…the inability of GlyT1-inhibition to remediate behaviors relevant to negative symptoms is surprising given that: (1) lower plasma and cerebrospinal fluid glycine level of patients with schizophrenia is linked to negative symptoms (Hashimoto et al, 2003); and (2) glycine treatment (although chronic) modestly lowers negative symptom ratings (Heresco-Levy et al, 1999; Javitt et al, 1994). However, such positive findings have not always been reproduced (Buchanan et al, 2007). In fact, Roche recently stopped trials testing a GlyT-1 inhibitor for the improvement of negative symptoms in schizophrenia, perhaps due in part to the sole reliance on clinical rating scales rather than objective translational laboratory tests as primary outcome measures. Testing negative symptoms using laboratory-based measures with relevance to those presented here may provide more relevant cross-species findings (Barnes et al, 2014; Der-Avakian et al, 2013; Young et al, 2013b) and greater sensitivity to the effects of GlyT-1 inhibitors. Constitutively reducing Sp4 expression in mice resulted in impaired attention that was remediated by GlyT-1 inhibition. The finding that this treatment did not remediate motivational deficits suggests that the attentional deficits of Sp4 mice are unlikely a result of altered motivation or learning. The lack of effect on motivation could be because of a requirement of longer treatment duration, although it improved attention acutely. Alternatively, more direct NMDAR1 activation may be required. Furthermore, the mechanism(s) underlying impaired motivation and learning resulting from reduced Sp4 expression have yet to be delineated. As SP4 regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B (Priya et al, 2014; Priya et al, 2013), further investigation of other mechanisms using these mice is warranted.

In conclusion, reduced Sp4 expression in mice largely recreates the attentional deficits observed in patients with schizophrenia as measured by the 5C-CPT (Young et al, 2013a). These data support pairing attentional assessment with evidence of reduced SP4 levels in peripheral blood mononuclear cells, as seen in first-episode patients with schizophrenia (Fuste et al, 2013). Such an approach might provide a useful personalized biomarker for predicting whether GlyT-1 inhibition may remediate attentional deficits in individual patients. However, such treatment would unlikely treat impaired positive valence related to reward anticipation. SP4 rare copy number variations and reduced protein levels are linked to several psychiatric disorders that exhibit attentional deficits including schizophrenia, bipolar disorder, and major depressive disorder (Pinacho et al, 2011; Shi et al, 2011; Tam et al, 2010; Zhou et al, 2009). Hence, identifying the mechanism(s) of how reducing Sp4 levels negatively affect attention and the neurobiology underlying GlyT-1 inhibition-induced reversal of these effects will prove vital. Importantly though, the present work using this model organism provides opportunities for personalized medicine for the treatment of attentional deficits in neuropsychiatric patients having low SP4 levels (McMahon and Insel, 2012).”

Sarcosine, a simple GlyT-1 inhibitor, has demonstrated some promising potential [4, 5]. Some worsening of symptoms has been noted at doses in excess of 2000mg [6] and a case of hypomania has been reported [7]. Antidepressant effects have also been reported [8].

Regulation of GlyTs:

BDNF, acting on TrkB receptors, inhibits glycine uptake in astrocytes by promoting GlyT internalization through a Rho-GTPase activity dependent mechanism [9]. GSK3β is important for stabilising and/or controlling the expression of functional GlyTs on the neural cell surface [10].

A soon to be published article may be of interest:

Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?

While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there are no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation [link out]

See more:

Sarcosine Therapy – A New Complementary Direction for Schizophrenia Treatment?

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia – preliminary study. (2015)

Glycinergic, NMDA and AMPA augmentation – a review

Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review. (2015)

Hopefully the following provides some direction for treating the cognitive deficits associated with schizophrenia…

Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review. (2015)

Pharmacological cognitive enhancement refers to improvement in cognitive functions after drug use in healthy individuals. This popular topic attracts attention both from the general public and the scientific community. The objective was to explore innovative mechanisms of psychostimulant’s action, whose potential effectiveness was assessed in randomized placebo-controlled trials (RCTs). A systematic review was carried out, using the words “attention”, “memory”, “learning”, “executive functions”, and “vigilance/wakefulness” combined to “cognitive enhancer” or “smart drug”. Methylphenidate, amphetamines, modafinil, nicotine, acetylcholine esterase inhibitors and antidepressants were extensively studied in previous meta-analyses and were not included in the present work. Drugs were classified according to their primary mode of action, namely catecholaminergic drugs (tolcapone, pramipexole, guanfacine), cholinergic drugs (anticholinergics), glutamatergic drugs (ampakines), histaminergic drugs, and non-specified (glucocorticoids). Overall, 50 RCTs were included in the present review. In conclusion, a number of new active drugs were found to improve some cognitive functions, in particular verbal episodic memory. However the number of RCTs was limited, and most of the studies found negative results. Future studies should assess both effectiveness and tolerance of repeated doses administration, and individual variability in dose response (including baseline characteristics and potential genetic polymorphisms). One explanation for the limited number of recent RCTs with new psychostimulants seems to be the ethical debate surrounding pharmaceutical cognitive enhancement in healthy subjects.

table 1Some findings mentioned in the article:

  • Tolcapone (200 mg single dose) is known to significantly improve executive function and verbal episodic memory performance in healthy adults (Apud et al., 2007 and Roussos et al., 2009). Tolcapone 100 mg three time a day for 1 day and 200 mg three times a day for 6 days showed no performance variation during a non conventional attentional control task (Magalona et al., 2013).
  • A 0.5 mg single dose of pramipexole has been found to induce sleepiness in healthy subjects (Micallef et al., 2009) and to impair reinforcement learning (Pizzagalli et al., 2008).
  • Guanfacine and clonidine both increased visual learning (Jakala et al., 1999). In another trial, clonidine administration (150–300 µg) was associated with subjective sedation and impaired performance (especially in attention) in 15 young adults (Tiplady et al., 2005). Clonidine impaired working memory while inducing feelings of drunkenness, but did not alter long-term formation of memories. Another study found no effect of guanfacine on executive functions and working memory in a population of healthy male adults (Muller et al., 2005). Guanfacine has also been found to influence emotional memory via modulation of the prefrontal cortex (Schulz et al., 2013).
  • Biperiden has been found to enhance episodic memory performance in healthy elderly subjects in one RCT (Wezenberg et al., 2005). Another trial found that 1–2 mg trihexyphenidyl improved verbal memory in 24 healthy elderly (Pomara et al., 2010). However, in a third trial, biperiden (4 mg) and trihexyphenidyl (5 mg) were both found to decrease memory performance (Guthrie et al., 2000)
  • Farampator (500 mg single dose) improved short-term memory, but appeared also to impair episodic memory in 16 healthy elderly volunteers (Wezenberg et al., 2007).
  • CX-516 (1-(quinoxalin-6 ylcarbonyl)piperidine) (300–900 mg, single dose) was found to improve short-term delayed memory in three RCTs (respectively 24 and 50 healthy young individuals and 18 elderly individuals (Ingvar et al., 1997, Lynch et al., 1997 and Lynch et al., 1996).
  • A single dose of 3 mg melatonin specifically enhanced recognition memory accuracy of objects encoded under stress in 27 young volunteers versus 23 placebo controls (Rimmele et al., 2009).
  • “Human studies investigating the effects of acute GC treatment on memory have reported conflicting (enhancing as well as impairing) results. A meta-analysis of 16 studies (N=563 healthy volunteers, mean age 24.23 years (SD+/−2.15)), which experimentally investigated the acute impact of cortisol treatment (hydrocortisone) on human memory, revealed that the timing of GC application in the course of a study is a relevant variable, which explains a substantial amount of the significant heterogeneity within the effect sizes ( Het et al., 2005). The used doses of hydrocortisone ranged from 5 to 100 mg (median=25 mg; DM+/−7.5). Retention interval ranged from 0 (immediate recall) up to 168 h (delayed recall). Four studies, which administered cortisol before retrieval, reported a significant decrease (average effect size of d=−0.49) in memory performance. Twelve studies, which administered cortisol before learning, found on average no effect (d=0.08), but there was heterogeneity within these effect sizes. Further analysis on these experiments indicated that studies administering cortisol in the morning found a significant memory impairment (d=−0.40), while studies conducted in the afternoon observed a small but significant memory enhancement (d=0.22) ( Het et al., 2005).”
  • A recent RCT showed that 10 mg single-dose hydrocortisone administration 45 min prior to the testing was associated with an enhancing effect on inhibitory performance in 54 healthy volunteers (Schlosser et al., 2013), a working memory impairment in another sample of 56 healthy volunteers (Terfehr et al., 2011) and to fewer specific memories on the autobiographical memory testing ( Schlosser et al., 2010). Some positive effects of 10 mg hydrocortisone on selective attention were also reported (Henckens et al., 2012)
  • Aspirin pre-treatment (600 mg, single dose) was found to improve working memory in healthy adults (Watson et al., 2009).

Perspectives

“Some potential cognitive enhancers with innovative mechanisms of action have not been tested in healthy subjects to date. GABAα5 blockers may provide a nootropic effect without the associated anxiogenic effects of general GABA inverse agonism (Koh et al., 2013 and Milic et al., 2013). Sigma agonists receptors increase acetylcholine release in both the hippocampus and the frontal cortex in rodent models (Matsuno et al., 1995) and may potentiate several NMDA-evoked responses in selected regions of the hippocampus (Hong and Werling, 2000). Piracetam and piracetam-like molecules are thought to be neuroprotective agents with potential enhancement properties, possibly due to their common 2-oxopyrrolidine structure (Gualtieri et al., 2002). Ampakine activity has been established as one of the modes of action of the racetams. However, these drugs have multiple modes of action and produce only weak AMPA receptor activation and it is unclear how significant their ampakine actions are in producing their positive effects. Animal studies suggest memory and wakefulness enhancement properties of several racetams (Barad et al., 1998, Grossman et al., 2011, Lelkes et al., 1998, Mondadori et al., 1986, Samartgis et al., 2012, Scheuer et al., 1999, Trofimov et al., 2005 and Tushmalova et al., 1995). It is noteworthy that animal experiments focused on restoring age-impaired cognitive functions (Gualtieri et al., 2002). In the end, the cyclic AMP/phosphokinase A/CREB pathway represents one of the main target for drug development to treat memory dysfunction (Tully et al., 2003). Dopamine D1/D5 receptors are coupled to activation of the cAMP/PKA/CREB pathway. Thus, D1/D5 receptor agonists may represent an effective pharmacological strategy to activate cAMP signaling to improve synaptic plasticity and memory (Otmakhova and Lisman, 1998). Cyclic nucleotide phosphodiesterases (PDEs) are enzymes, which play an important role in the abovementioned intra-cellular signal transduction pathways. There are 11 families of PDEs (PDE1–PDE11) and most of these families have more than one gene product (e.g., PDE4A, PDE4B, PDE4C, PDE4D). In addition, each gene product may have multiple splice variants (e.g., PDE4D1–PDE4D9). In total, there are more than 100 specific human PDEs. Rolipram, which belongs to the above-mentioned racetams family, is a specific PDE4 inhibitor that has been shown to enhance both hippocampal long-term potentiation, memory transient wakefulness and neuroprotection in mice (Barad et al., 1998 and Block et al., 2001) and long-term potentiation in humans (Rutten et al., 2006 and Rutten et al., 2007).”