Next Article in Journal
Melatonin Suppresses Oral Squamous Cell Carcinomas Migration and Invasion through Blocking FGF19/FGFR 4 Signaling Pathway
Next Article in Special Issue
A Potential Interface between the Kynurenine Pathway and Autonomic Imbalance in Schizophrenia
Previous Article in Journal
A Human Pan-Cancer System Analysis of Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 3 (PLOD3)
Previous Article in Special Issue
Pharmaco-Magnetic Resonance as a Tool for Monitoring the Medication-Related Effects in the Brain May Provide Potential Biomarkers for Psychotic Disorders
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 22
Issue 18
10.3390/ijms22189905
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments

by
Antón L. Martínez
1,†,
José Brea
1,†,
Sara Rico
1,
María Teresa de los Frailes
2 and
María Isabel Loza
1,*
1
BioFarma Research Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
2
Experimental Sciences Faculty, Universidad Francisco de Vitoria, 28223 Pozuelo de Alarcón, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2021, 22(18), 9905; https://doi.org/10.3390/ijms22189905
Submission received: 24 June 2021 / Revised: 8 September 2021 / Accepted: 10 September 2021 / Published: 14 September 2021
(This article belongs to the Special Issue Molecular Mechanisms of Schizophrenia and Novel Targets)
Versions Notes

Abstract

:
Schizophrenia is a major mental illness characterized by positive and negative symptoms, and by cognitive deficit. Although cognitive impairment is disabling for patients, it has been largely neglected in the treatment of schizophrenia. There are several reasons for this lack of treatments for cognitive deficit, but the complexity of its etiology—in which neuroanatomic, biochemical and genetic factors concur—has contributed to the lack of effective treatments. In the last few years, there have been several attempts to develop novel drugs for the treatment of cognitive impairment in schizophrenia. Despite these efforts, little progress has been made. The latest findings point to the importance of developing personalized treatments for schizophrenia which enhance neuroplasticity, and of combining pharmacological treatments with non-pharmacological measures.

1. Introduction

Schizophrenia is a major mental illness characterized by psychosis, apathy, social withdrawal and cognitive impairment [1]. The symptoms of schizophrenia have been placed into three categories: positive symptoms such as delusions and hallucinations [2]; negative symptoms such as affective flattening, alogia and diminished emotional expression; and cognitive deficit [3]. Although schizophrenia was considered an early dementia in the 19th century, the cognitive symptoms of schizophrenia have been largely neglected in the treatment of the disease [4]. However, in the last few years, there has been a growing interest in the study of cognitive impairment [5]. The reasons for this are that cognitive impairment is one of the first symptoms to manifest in schizophrenia, it is disabling for schizophrenic patients, and it contributes to their functional impairment [6]. Cognitive deficit cannot be treated with current antipsychotic drugs, which can only effectively treat positive symptoms of the disease [7]. Therefore, cognitive impairment in schizophrenia is still a clear unmet clinical need.
Cognitive deficit comprises an impairment in several cognitive domains, such as processing speed, attention, working memory, verbal and visual learning, problem solving and social cognition [8]. This impairment is found even in the first episode of schizophrenia [9].
Cognitive deficit is a process involving genomic, neurobiological and neuroanatomic factors that interact with each other in a complex way. The aim of this review is to go over the etiology of neurocognitive impairment in schizophrenia and the status of current research on the treatments for this symptom of schizophrenia.

2. Etiology of Neurocognitive Impairment

2.1. Neuroanatomic Findings

Several image studies have described that cognitive deficit in schizophrenia is associated with cortical thickness [10,11,12]. Interestingly, this effect is more pronounced in women than in men, where there may not even be a significant decrease in cortical thickness [13]. Indeed, cognitive deficit is related to other changes in brain structure and function, such as a greater ventricular volume [14], a reduction in cerebellar volume [13], a decrease in the function of basal ganglia [15] and a loss of dendritic spines in pyramidal neurons of the dorsolateral prefrontal cortex (DLPFC) [16]. These changes could be related to the observed disruption in cortico-cerebellar-thalamic-cortical circuits in patients suffering from schizophrenia [17], and to the reduction in the metabolic rate of the prefrontal cortex [18].
Similar neuroanatomic changes have also been observed in animal models of schizophrenia [19] and, interestingly, in patients suffering from encephalitis caused by herpes virus [20].
Changes in brain neuroanatomy used to be attributed to disorders in neurodevelopment [21,22], but it is now assumed that these disorders do not explain the whole process and it is believed that cognitive impairment might be due to the cumulative effect of neurodevelopmental abnormalities, changes in neuronal maturation and alterations in neuroplasticity [23].

2.2. Biochemical Findings

Cognitive deficit in schizophrenia has been related to an increase in inflammatory cytokines, to an imbalance in hormones such as cortisol and prolactin, in neurotrophic factors such as BDNF and in neurotransmitters such as GABA and glutamate [24].

2.2.1. Inflammatory Cytokines

It has been observed that an increase in blood levels of C-reactive protein (CRP) is related to a lower cognitive performance, especially in verbal management, visual and working memory, processing speed, problem solving, executive function speed and in attention according to the meta-analysis by Bora et al. [5]. Interestingly, reductions in CRP levels are associated with an improvement in cognitive function [25].
Although the evidence is weaker than for CRP, an increase in other inflammatory cytokines such as IL-1ß and IL-6 has been also observed in schizophrenic patients with cognitive deficit [26,27]. These findings are in accordance with several studies that relate inflammation and neurodegeneration [28].

2.2.2. Hormones

Cognitive deficit in schizophrenic patients has been linked to imbalances in serum levels of cortisol and prolactin.
Cortisol is a hormone that participates in the response to stress and inflammation. Moreover, cortisol easily crosses the blood–brain barrier, binding glucocorticoid receptors in prefrontal cortex, hippocampus and amygdala [29]. Higher cortisol levels are associated with lower hippocampal volume and lower BDNF expression [30,31]. Additionally, higher levels of cortisol and greater blunting of the cortisol awakening response (CAR) are related to poorer performance in cognitive tasks [32,33]. However, the influence of cortisol levels on neuroanatomic findings and in cognitive performance may depend on the sex of the patients and the clinical diagnosis of the patient [34].
Prolactin levels have also been linked to cognitive impairment. However, the study of prolactin levels in schizophrenic patients is difficult because typical antipsychotics, as D2 receptor antagonists, increase prolactin concentrations in blood because they block D2 receptors in the tuberoinfundibular pathway [35]. It has been observed that in antipsychotic-naive schizophrenia patients, higher levels of prolactin are related to poorer cognitive performance [36]. The reasons for this poorer performance are not clear, but it was observed that there is a decrease in grey matter volume in patients with hyperprolactinemia [37], and that prolactin levels are related to higher inflammatory markers [38].

2.2.3. Neurotrophic Factors

BDNF is a neuropeptide that enhances brain remodeling and synaptic plasticity. It was observed that reduced levels of BDNF are related to lower cognitive capacities in patients with schizophrenia [39,40]. This reduction in BDNF levels has also been observed in other pathologies related to cognitive deficit. Vasconcelos et al. observed that this reduction in BDNF is related to an increase in oxidative stress in schizophrenic patients, as the administration of alpha-lipoic acid, a drug that counteracts free radicals, increases BDNF and improves cognitive capacities in animal models of schizophrenia [41]. Indeed, clozapine, an antipsychotic drug that improves negative symptoms and cognitive capacities in schizophrenic patients, increases brain BDNF levels [42]. The influence of variants of BDNF in cognitive deficit has also been studied; one example is BDNF Val66Met, which is related to a worse cognitive function [43,44]. However, there is a great deal of variability between different studies because of the heterogeneity among ethnic groups.

2.2.4. Neurotransmitters

Cognitive deficit in schizophrenia has been linked to imbalances in neurotransmitters such as glutamate, GABA, dopamine, acetylcholine and histamine [45]. Glutamate and GABA play a major and well-known role in cognitive deficit in schizophrenia. An imbalance in both neurotransmitters was observed in DLPFC [46]. This area is associated with working memory—that is, the ability to manipulate information to guide behavior or thought [47]. The performance of working memory tasks implies the activation of the area showing an increase in gamma oscillatory activity (30–80 Hz) of glutamatergic pyramidal neurons, whose synchrony is regulated by GABA and glutamate [48]. In patients with schizophrenia-related cognitive deficit, there is no increase in gamma oscillatory activity in response to working memory demands [49].
It has been described that in patients suffering from schizophrenia-induced cognitive deficit there is a reduction in the glutamatergic stimulation of NMDA receptors in pyramidal neurons [50]. The activation of NMDA receptors depends upon the binding of co-agonists such as D-serine and glycine [51]. In schizophrenia-induced cognitive deficit there is a higher blockage of glycine sites in NMDA receptors due to higher levels of kynurenic acid in dorsal prefrontal cortex [52]. Inflammatory cytokines have also been reported to increase kynurenic acid levels, linking the observed increase in inflammatory cytokines with imbalances in glutamate signaling in schizophrenia subjects [53]. This is in agreement with the fact that most animal models of schizophrenia implicate the administration of drugs that block NMDA receptors to the animals, such as MK-801 (dizocilpine), ketamine or PCP (phencyclidine) [54].
However, the reduced sensitivity of NMDA receptors in pyramidal neurons in schizophrenia patients does not implicate a reduction in glutamate in DLPFC [55]. In fact, it has been described that glutaminase, the enzyme that participates in glutamate synthesis, is highly overexpressed in schizophrenia subjects [56]. Furthermore, there is an increase in the expression of metabotropic glutamate receptors in DLPFC of schizophrenia patients [57]. Those receptors exert a presynaptic regulation of glutamatergic signaling [58].
These imbalances in glutamatergic signaling are accompanied by changes in GABAergic inputs to pyramidal neurons, which are also crucial for pyramidal neurons’ synchronicity [59]. It was observed that in schizophrenia subjects there is a reduction in the expression of the 67 kDa isoform of glutamate decarboxylase (GAD67) [60]. This enzyme synthetizes GABA, and its deficit suggests a reduction in GABAergic signaling in DLPFC. This is consistent with the observed reduction in parvalbumin (PV) in DLPFC [61]. PV is a marker of GABAergic interneurons on DLPFC that buffers calcium facilitating GABA release [62], which modulates the activity of pyramidal neurons [63]. The reduction in PV suggests that there is a reduction in GABA-mediated synapsis.
There is also a reduction in other subpopulations of GABAergic neurons, such as somatostatin (SST)-expressing GABAergic neurons. A global reduction in SST expression in DLPFC in schizophrenia patients has been reported [64].
Although not fully described, changes in other neurotransmitters such as acetylcholine, histamine or dopamine have been reported in schizophrenia-induced cognitive deficit patients [46]. It has been suggested that there is a relationship between a decrease in striatal dopamine and the observed disruption in cortico-cerebellar-thalamic-cortical circuits in cognitive deficits in schizophrenia [65,66].
Recently, it has been demonstrated that the acetylcholinesterase blocker galantamine improves cognitive deficit in schizophrenia, suggesting that a reduction in acetylcholine signaling may play a role in cognitive deficit [67]. It has also been observed that, in schizophrenic patients, there is lower M1 receptor binding in the hippocampus, which results in impaired learning [68].
The role of histamine in cognitive deficit in schizophrenic patients is unclear, but Jin et al. described an increase in the expression of histamine H3 receptors in prefrontal cortex neurons of schizophrenic patients. These data suggest that the H3 receptor may play a role in cognitive decline in those patients [69].

2.3. Genetic Findings

Schizophrenia is a multifactorial disease whose etiology involves the interaction between environmental and genetic factors (see [70] for a review). Several genes related to cognitive deficit in schizophrenia have been identified.
Most of them encode proteins that participate in neurotransmission, such as the glutamate receptor-encoding GRIN2B and GRIN2A genes, the serotonin receptor-encoding HTR2A gene or the COMT gene [70]. COMT encodes catechol-O-methyltransferase, the enzyme that degrades catecholamines such as noradrenaline and dopamine [71]. Val158Met COMT polymorphism has been related to social cognitive deficits [72], resulting from a reduction in dopaminergic neurotransmission [73]. Nevertheless, more research is needed to identify the exact role of COMT polymorphisms in schizophrenia. Another gene involved in cognitive deficit in schizophrenia is AKT1, which encodes a serine threonine kinase activated by dopamine type 2 receptor agonists [74]. It also plays a crucial role in the neuregulin signaling pathway, and is related with social recognition [75].
Another subset of genes involved in schizophrenia are those related to brain development, for example DTNBP1, encoding dysbindin. This protein is involved in hippocampal formation [76], highlighting its role in cognitive processes critical to schizophrenia [77]. In recent years, several studies have associated the presence of single-nucleotide polymorphisms (SNPs) with cognitive deficit in schizophrenia [78,79]. Another gene related to neurodevelopment is DISC1, which participates in the acquisition of neuronal phenotypic features including axonal growth and dendritic spine formation, and in neuronal intracellular transport [80]. It was observed that some variants of the DISC1 gene are associated with alterations in the expression of genes that participate in brain development, leading to intellectual disabilities [81].

3. Treatment of Cognitive Deficit in Schizophrenia

The treatment of schizophrenia currently relies on antipsychotics. There are two different subgroups of antipsychotics: typical and atypical [82]. Typical antipsychotics such as haloperidol or chlorpromazine are D2 receptor antagonists [83]. They are effective against positive symptoms, but they are less effective and even ineffective against negative symptoms and cognitive deficit [83]. Atypical antipsychotics like clozapine, olanzapine and risperidone block both D2 and 5-HT2A receptors, modulating both glutamatergic and dopaminergic neurotransmission in prefrontal cortex [84].
Several meta-analyses have reflected that atypical antipsychotics elicited a slight improvement in some cognitive functions, while none of them were found to have a positive profile in all cognitive functions [85,86]. In the most recent study, Baldez et al. analyzed 54 randomized double-blinded studies to create a ranking of the effect of antipsychotics on neuropsychological tests [87]. They found that olanzapine was ranked first in motor performance and visuoconstruction, amisulpride came first in attention and verbal memory, ziprasidone in working memory, sertindole in processing speed and perphenazine in executive functions, while lurasidone occupied the first position in a composite score. They also observed that clozapine and typical antipsychotics occupied the last positions [87].
De la Fuente-Revenga et al. reported that chronic treatments with atypical antipsychotics such as clozapine could induce the transcription of the HDAC2 gene, with a detrimental effect on cognitive functions in cortical neurons [88]. This effect seems to be mediated by 5-HT2A receptors [89], suggesting that compensatory mechanisms may confer atypical antipsychotics both positive and negative effects on cognitive function, with a high variability between individuals. Therefore, because the efficacy of antipsychotics in treating cognitive deficit is very poor, several strategies have been developed to address the cognitive symptoms of schizophrenia (Table 1).

3.1. Antioxidant Compounds

A multitude of drugs with antioxidant effects have been tested. In clinical trials, they appeared to be effective in alleviating cognitive deficit in schizophrenia, although most trials included a low number of patients [127].
Some antioxidant compounds have been reported to induce the transcription of genes encoding neurogenesis-related proteins [128]. Thus, alpha-lipoic acid increases BDNF expression in animal models of schizophrenia, with an improvement in memory impairment [41]. In a small clinical trial, it was observed that dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) counteracted cortical thickness observed in schizophrenic patients [90]. Another effect of antioxidant compounds is the enhancement of the nitrergic activity in the central nervous system [41]. Nitric oxide has been demonstrated to be effective in activating NMDA receptors in animal models of schizophrenia [129], but its efficacy has not yet been confirmed in clinical trials [130].
Another antioxidant compound, N-acetylcysteine, has been described as slightly beneficial for cognitive deficit in schizophrenic patients, improving cognitive speed [91]. This may be due to its role as precursor of glutamate, enhancing glutamatergic transmission in DLPFC and complementing its antioxidant effect [131,132].
Tetracyclines are a group of antibiotic drugs with an antioxidant effect that have been suggested to be beneficial for cognitive deficit in schizophrenia [133]. In clinical trials, minocycline has demonstrated a beneficial effect in alleviating cognitive deficit in schizophrenia, improving information processing speed [92,93].
In summary, it has been observed that drugs with an antioxidant effect may help to relieve cognitive deficit in schizophrenia by a combination of neurogenic, neuroprotective and nitrergic mechanisms, but their role in the pharmacotherapy of schizophrenic patients has not yet been properly established.

3.2. Modulation of Serotonergic Neurotransmission

As described above, atypical antipsychotic drugs interact with serotonin 5-HT2A receptors, with both positive and negative effects on cognitive function. The negative effects of chronic antipsychotic treatments on cognitive function mediated by 5-HT2A receptors could be avoided employing HDAC2 inhibitors [134].
In addition to the role of 5-HT2A receptors in the treatment of cognitive deficit in schizophrenic patients, the role of other serotonin receptors has also been studied. Some atypical antipsychotic drugs, such as quetiapine or aripiprazole, stimulate 5-HT1A receptors [135,136], providing an inhibitory feedback control of serotonin release in several areas of the brain [137]. This effect is related with an improvement in some cognitive functions such as verbal memory in schizophrenic patients, as seen with the 5-HT1A agonist tandospirone [138]. Nevertheless, activation of 5-HT1A receptors is also associated with hallucinations and nightmares, suggesting that 5-HT1A receptor agonists may exacerbate positive symptoms of schizophrenia [139].
Antagonists of 5-HT3 receptors, such as the anti-emetic drug ondansetron, were shown to be mildly effective against cognitive deficits in schizophrenia in clinical trials, although these trials were conducted with very few patients [95]. Tropisetron, another 5-HT3 receptor antagonist, improved cognition in schizophrenic patients [96]. Tropisetron is also an agonist of α7 nicotinic acetylcholine receptors, demonstrating that the synergy between acetylcholine receptor agonism and 5-HT3 receptor antagonism is beneficial for the treatment of cognitive deficit in schizophrenia [140].
The 5-HT6 receptor is another serotonin receptor involved in cognitive function (see [141] for a review). It was demonstrated that AVN-492, as an antagonist of 5-HT6 receptors, counteracted cognitive impairment in animal models of schizophrenia [142]. Nevertheless, findings in clinical trials with schizophrenic patients were contradictory. Only some of them showed a scarce beneficial effect of the 5-HT6 antagonist AVN-211 in cognitive function [97,98]. This may be due to the fact that most of the compounds assayed as cognitive enhancers were not specific 5-HT6 receptor antagonists, suggesting the existence of synergistic interactions with other receptors.
The 5-HT7 receptor has also been proposed as a target for novel drugs improving cognitive enhancement (see [143] for a review). It has been suggested that the activation of the 5-HT7 receptor reduces neuronal excitability, and it has been proposed that 5-HT7 antagonists could exert a beneficial effect in cognition and memory [144]. In animal models of schizophrenia, it has been demonstrated that the inhibition of 5-HT7 receptors exerts a synergistic effect with the inhibition of other receptors such as sigma receptors or 5-HT1 receptors, both by combining them with an atypical antipsychotic or by using a multitarget strategy [145,146,147].
Although there is not much information about 5-HT5A receptor function, it has been demonstrated that its inhibition exerts a procognitive effect in animal models of schizophrenia [148,149]. A recent work by Yamazaki et al. demonstrated that this effect is due to the activation of dopaminergic and GABAergic neurons in the prefrontal cortex as a result of the inhibition of the serotonin receptor [150].
Some antidepressants are also modulators of serotonergic neurotransmission, as serotonin reuptake inhibitors. However, recent evidence indicates that their effect may be related to an enhancement of neuroplasticity [151].

3.3. Regulation of GABAergic Neurotransmission

As described above, there is a reduction in the GABAergic transmission in DLPFC in schizophrenic patients, leading to a desynchronization of the depolarization of pyramidal neurons. Nevertheless, benzodiazepines, as non-selective agonists of GABA receptors, exert a deleterious effect in cognitive function in schizophrenic patients—specifically in attention and working memory [99]. This may be due to the fact that stimulation of GABA receptors exerts contradictory actions in neurons. The stimulation of synaptic GABAA receptors induces a phasic inhibition of the neuron, and the stimulation of extrasynaptic GABAA receptors induces a tonic inhibition of the neuron [7]. Attempts to develop selective modulators of GABAA receptors did not yield compounds with a procognitive effect [152].
On the other hand, one GABAB receptor agonist, baclofen, showed an improvement of cognitive function in an animal model of schizophrenia [153]. However, this result contradicts those published in other studies [7].
Another strategy to regulate GABAergic neurotransmission is the employment of GABA prodrugs such as BL-1020, an ester between the atypical antipsychotic perphenazine and GABA [154]. The use of this prodrug demonstrated a beneficial effect on cognitive function in animal models of schizophrenia and in phase 2 clinical trials [100,155]. Unfortunately, the results of phase 3 assays were negative [101].

3.4. Potentiation of Histaminergic Neurotransmission

An increase in the expression of histamine H3 receptors in the prefrontal cortex has been observed in schizophrenic patients. In fact, it has been observed that H3 receptor antagonists exerted a procognitive role in preclinical cognitive models [156]. However, in a phase 2 clinical trial, the H3 receptor antagonist ABT-288 failed to demonstrate any benefit in comparison to placebo in schizophrenic patients [102]. Recent research has described a procognitive effect of samelisant, an inverse agonist of H3 receptors, in animal models of schizophrenia [157]. Nevertheless, more studies are required.

3.5. Potentiation of Cholinergic Neurotransmission

Smoking has long been observed to be more common in schizophrenic patients than in the general population [158]. It has been proposed that this could be due to the fact that nicotine improves cognition in schizophrenic patients [159,160]. Indeed, it has been widely described that α7 nicotinic acetylcholine receptor activators have a beneficial procognitive effect both in animal models of schizophrenia [161,162] and in patients, although modulation of nicotinic receptors in humans entails a high risk of adverse events [163]. The reason for the beneficial effect of α7 nicotinic acetylcholine receptor activators on cognitive deficit is complex. On the one hand, they enhance theta activity and synaptic plasticity in hippocampal neurons, potentiating memory [164]. On the other hand, a nicotinic acetylcholine receptor agonist was shown to enhance the release of dopamine, glutamate and acetylcholine in the cerebral cortex and in the nucleus accumbens, which are reduced in schizophrenic patients with cognitive deficit [165].
One of the assayed α7 nicotinic acetylcholine receptor activators is varenicline, which is widely used for smoking cessation [166]. Although a beneficial effect was observed in animal models [167,168], there is no evidence from clinical trials of its efficacy in alleviating cognitive deficit in schizophrenic patients [103]. Other compounds activating α7 nicotinic acetylcholine receptors such as bradanicline, nelonicline and encenicline did not show a beneficial effect in clinical trials [104,105,106].
A positive effect, namely, the alleviation of cognitive deficit in in vivo models of schizophrenia, was also described resulting from activation of muscarinic acetylcholine receptors (specifically M1 and M4 receptors) present in the central nervous system [169,170]. Xanomeline, as an M1 and M4 receptor agonist, showed a beneficial effect in cognitive deficit in a clinical assay with 20 subjects [107]. Recently, it was shown that this drug induced beneficial effects in neuronal connectivity in animal models of schizophrenia [171].
The potentiation of cholinergic neurotransmission has not only been achieved by the direct activation of acetylcholine receptors. Another strategy to treat cognitive deficit in schizophrenia is the use of acetylcholinesterase inhibitors such as galantamine or donepezil, which prevent the degradation of acetylcholine in the synaptic cleft [172,173]. Galantamine has been assayed both in animal models of schizophrenia and in clinical trials in combination with memantine, an antagonist of NMDA glutamate receptors with procognitive effects [174]. Unfortunately, although the combination of both drugs seemed to be beneficial for cognitive improvement in animal models of schizophrenia [174], no robust benefits were observed in clinical trials with schizophrenic patients [108,175].

3.6. Potentiation of Glutamatergic Neurotransmission

As described above, schizophrenic patients with cognitive deficit show a reduction in NMDA receptor stimulation in DLPFC with imbalances in glutamate synthesis. Thus, several strategies have been proposed to tackle glutamatergic neurotransmission in order to relieve cognitive deficit in schizophrenic patients. One of them is the direct activation of NMDA receptors by employing CIQ isomers [(R) and (S)-(3-chlorophenyl) (6,7-dimethoxy-1-((4-methoxyphe-noxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)meth-anone] [176], but because most animal models of schizophrenia employ NMDA antagonists to induce schizophrenia-like symptoms, it is not clear how translational those findings are. In animal models of schizophrenia it was observed that NMDA receptor antagonists such as memantine exert a beneficial effect for cognitive deficit [177], but this effect was not observed in clinical trials [109].
Another strategy to activate NMDA receptors is the enhancement of the function of co-agonists of the receptor such as glycine or serine. Inhibitors of glycine transporter-1 (GlyT1) have been widely studied as a treatment of cognitive deficit in schizophrenia because they elevate synaptic glycine levels [178]. However, studies assessing the clinical efficacy of the GlyT1 inhibitors have been contradictory: bitopertin failed to show a robust benefit in alleviating cognitive deficit [110], while BI 425809 showed a slight improvement in cognitive functions [111]. The different effect could be due to the small number of patients included in clinical trials, to the heterogeneity of clinical scales to assess cognitive deficit or to the short follow-up time in clinical trials [110,111,179]. On the other hand, cycloserine has been assayed as an activator of NMDA receptors, but the evidence of a positive effect on cognitive deficit in schizophrenia is not strong [180].
The activation of glutamate metabotropic receptors has been studied as a novel mechanism to improve cognitive deficit in schizophrenia because the activation of metabotropic receptors reduces the release of glutamate in cortical neurons, which, as exposed above, is paradoxically augmented in schizophrenia [181]. Results in mice are contradictory because a clear benefit was observed in some studies, while other studies failed to show a benefit of activating metabotropic receptors on cognitive deficit [182,183]. This lack of efficacy was also observed in clinical trials with LY2140023 [112]. Regardless, animal studies suggest that there are several strategies that appear to improve the effect of activating metabotropic receptors, such as administering them in adolescence, before the onset of schizophrenia symptoms [184,185]. Some studies have also shown a synergistic effect between the activation of glutamate metabotropic receptors and M4 acetylcholine receptors [186]. Shen et al. described that the activation of M4 receptors enhanced brain neuroplasticity [187], suggesting that the activation of metabotropic glutamate receptors requires an increase in neuronal plasticity to exert a beneficial effect on cognitive deficit.
The modulation of AMPA receptors has also been studied as an approach to enhance cognition in schizophrenic patients because the interplay between NMDA and AMPA receptors is critical for neuroplasticity [188]. The activation of AMPA receptors participates in cognitive processes such as learning and memory; however, AMPA agonists tend to induce AMPA receptor desensitization [189]. To avoid this effect, ampakines (allosteric potentiators of AMPA receptors) have been proposed to alleviate cognitive deficit, having been shown to improve cognitive functions in animal models of schizophrenia [190]. In clinical trials, the ampakine CX-516 has been shown to improve memory and attention in patients treated with clozapine [113], although it showed no clear beneficial effects in monotherapy [114].

3.7. Potentiation of Dopaminergic Neurotransmission

As described above, cognitive deficit in schizophrenia is related to a decrease in dopaminergic neurotransmission in DLPFC. Most dopamine receptors in DLPFC neurons are D1 receptors, which co-localize in dendritic spines with hyperpolarization-activated cyclic nucleotide-gated potassium channels (KCNQ1), whose dysfunction seem to be related to schizophrenia [191]. Because the relationship between dopaminergic neurotransmission and cognition follows an inverted U-shaped curve, both D1 agonists and antagonists have been assayed in animal models of schizophrenia as cognitive enhancers [192,193]. As dopaminergic neurotransmission refines the synaptic signals that reach the dendrites, the effect of dopaminergic drugs depends on the baseline levels of dopamine in the prefrontal cortex [194]. In the last few years, there has been a significant effort to develop D1 receptor positive allosteric modulators (PAMs) for cognitive deficit in schizophrenia (for a review see [195]). In phase 1 clinical trials, D1 receptor PAMs have been shown to be safe and tolerable [196]. However, one phase 2 clinical trial evaluating the procognitive efficacy of the D1 receptor PAM ASP4345 was stopped because the primary endpoint of the assay was not reached [197].
D3 receptor antagonism has been proposed as a mechanism for novel drugs against cognitive deficit in schizophrenia. The D3 receptor plays a crucial role in the regulation of dopamine release. Blockage of the D3 receptor enhances dopaminergic neurotransmission, with a beneficial effect on cognitive deficit [198]. On the other hand, the D3 receptor interacts with the nicotinic α7 receptor, boosting neuroplasticity (see [199] for a review). D3 and D2 receptor homology is very high, making it very difficult to develop drugs to selectively inhibit D3 receptors [200]. However, it has been proposed that the procognitive effects of several atypical antipsychotics may be due to their effects on D3 receptors (see [201] for a review).
Another strategy to increase the dopaminergic neurotransmission in DLPFC is the employment of the dopamine reuptake inhibitor modafinil. Modafinil has long been employed as a cognitive enhancer in both healthy individuals and in patients with neurodegenerative diseases and psychiatric pathologies [202]. Although it has been classified as a dopamine reuptake inhibitor, modafinil also modulates norepinephrine and serotonin transport, enhances glutamatergic neurotransmission and blocks GABAergic signaling [203]. It was suggested that modafinil improved cognitive functions in animal models of schizophrenia [204], but a recent systematic review by Ortiz-Orendain et al. concludes that the evidence for the efficacy of modafinil in alleviating cognitive deficit in schizophrenic patients is weak [116].

3.8. Antidepressant Drugs

Antidepressant drugs have been tested for the treatment of cognitive deficit in animal models of schizophrenia. Some of them, such as reboxetine or escitalopram, have been shown to be beneficial, especially in combination with different atypical antipsychotic drugs [205,206,207]. However, a meta-analysis highlighted that there was a high variability between assays, leading to the conclusion that there were no clinically relevant effects on cognition in schizophrenic patients [117]. These results take on new meaning in light of the recent study by Casarotto et al., in which the authors demonstrated that the mechanism of action of both typical and long-acting antidepressants is to enhance neuronal plasticity by binding to the TrkB BDNF receptor [151].

3.9. Inhibition of Phosphodiesterases

Phosphodiesterase inhibition is a promising mechanism of action for improving cognitive function in schizophrenia because cAMP and cGMP are second messengers of many receptors whose hypofunctions are involved in cognitive deficit in schizophrenia, such as dopamine or glutamate [208]. Preventing the degradation of cAMP and cGMP is expected to potentiate central neurotransmitters’ activity. From the eleven members of the phosphodiesterase family, phosphodiesterases 1, 2, 4, 5, 9, 10 and 11 are widely expressed in central nervous system (see [209] and [210] for a review). We will focus on phosphodiesterases 1, 4 and 10, as they are the most studied in schizophrenia-induced cognitive deficit.
Phosphodiesterase 1 (PDE1) is an enzyme related to oxidative stress that colocalizes with dopamine receptors [211]. Its inhibition in animal models of schizophrenia appeared to be useful in alleviating cognitive deficit as an adjuvant of antipsychotic therapies with anti-inflammatory effect [212,213].
Phosphodiesterase 4 (PDE4) is one of the most widely studied phosphodiesterases in schizophrenia. It interacts with DISC1 which, as exposed above, is involved in neurogenesis and whose malfunction is related to schizophrenia [214]. Roflumilast, an inhibitor of phosphodiesterase 4, and has been tested for the alleviation of cognitive deficit in schizophrenic patients, showing little improvement in either electrophysiological abnormalities or cognitive impairments elicited by schizophrenia [118,215]. Studies with more patients are needed in order to draw meaningful conclusions about the efficacy of roflumilast in schizophrenia-induced cognitive deficit.
Phosphodiesterase 10 (PDE10) has been described as a promising target for the treatment of many neurodegenerative and psychiatric diseases (see [216] for a review). Its blockage in animal models of schizophrenia using rodents and apes induces a beneficial effect in cognitive deficit [217,218]. TAK-063, a PDE10 inhibitor, has reached clinical trials, and although it was shown to be safe in phase 1 [219], it did not show a significant improvement in cognitive abilities in phase 2 studies with schizophrenic patients [119].

3.10. Steroids

Both cortical and sexual hormones are linked to schizophrenia. Chronic activation of the hypothalamic–pituitary–adrenal (HPA) axis has been suggested to play a role in the pathogenesis of schizophrenia [220]. As described above, both increased cortisol levels and blunted cortisol awakening response have been associated with a worse cognitive functioning in patients with schizophrenia. However, few assays have been performed to evaluate the efficacy of drugs counteracting the deleterious effect of cortical hormones on cognitive deficit in schizophrenic patients. The neuroprotective steroid dehydroepiandrosterone exerts a clear beneficial effect on cognitive function in animal models of schizophrenia [221], even though this effect is not always observed in clinical trials with schizophrenic patients, with only slight increases in attention and movement and visual skills [120,121]. It has been suggested that its beneficial effect may be achieved only in the early stages of the disease [222].
The role of sexual hormones, especially estrogens and progesterone, in the pathogenesis of schizophrenia is better known. Estrogens participate in neuronal development and regulation and exert a neuroprotective role [223]. It has been described that estrogen replacement therapy as an adjunctive to antipsychotics may exert a slight beneficial effect in cognitive functions in some schizophrenic patients [224]. However, estrogen replacement therapy increases the risk of uterine and breast cancer [225]. Raloxifene is a drug with estrogen-agonistic properties in the brain and estrogen-antagonistic properties in breast and uterus, reducing the risk of uterine and breast cancer. The effect of raloxifene in cognitive deficit is inconsistent, as it has been shown to have a beneficial effect in some trials [122,123], while no benefit was seen in others [124]. These differences could be explained by the heterogeneity of the patients included in each assay, because the effect of raloxifene may depend on the severity of schizophrenia and whether the patients are post- or premenopausal women.
Pregnenolone is a precursor of progesterone and other steroid hormones that has also been tested as a drug for cognitive impairment in schizophrenic patients due to its beneficial effect as a neurogenesis enhancer, anti-apoptotic agent, HPA axis modulator, enhancer of myelination and regulator of GABAergic and glutamatergic neurotransmission [226]. As with raloxifene, the effects of pregnenolone are inconsistent between different trials, with a benefit seen in several trials [121], while no benefit of pregnenolone was produced in others [125,126]. The reason for these differences between trials may be due to different baseline serum pregnenolone levels. High serum pregnenolone is correlated with lower improvements in cognitive function.

4. Conclusions and Future Perspectives

Despite the large amount of work done investigating the etiologies and treatments of cognitive deficit in schizophrenia, little progress has been made. There are several reasons for this slow development. One of them is the low translationality of the animal models of schizophrenia. Most rely on giving mice a drug such as MK-801 or scopolamine that induces schizophrenia-like symptoms. Schizophrenia is more complex than that and, as explained in the Introduction, neuroanatomical abnormalities, biochemical imbalances and genetic alterations concur in its etiology. To overcome this drawback, novel models of schizophrenia must be developed, including new animal models such as genetically modified mice [227] and in vitro models using immortalized neuronal cells relevant to schizophrenia [228], which could be helpful for early drug discovery.
Another reason for the high attrition rate is the holistic complexity of schizophrenia. Schizophrenia is a syndrome characterized by a series of symptoms and signs, and the alterations behind them vary between patients. In addition, even the physiological status of each patient influences these symptoms and signs. Therefore, a more personalized treatment should be prescribed for schizophrenic patients. The determination of biomarkers and the advances in pharmacogenomics could make it possible to identify the most appropriate treatments for each patient [229].
Lack of adherence to the treatment in patients with schizophrenia also hampers the discovery of novel efficient drugs for cognitive deficit in schizophrenia because it introduces biases in the measurement of drug efficacy. To overcome this drawback, a more personalized therapy with motivational interviews to emphasize the benefits of the treatment and to identify the problems associated with the therapy could improve patient adherence to treatment [230].
Several successful treatments used for cognitive deficit in schizophrenia exert their action by enhancing neuroplasticity. This suggests that the combination of those pharmacological treatments with non-pharmacological therapies such as cognitive training could represent an advancement in the treatment of cognitive deficit in schizophrenic patients.

Author Contributions

Writing—original draft preparation, A.L.M. and S.R.; writing—review and editing, J.B., M.T.d.l.F. and M.I.L.; conceptualization, J.B., M.T.d.l.F. and M.I.L.; supervision, M.I.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Mueser, K.T.; McGurk, S.R. Schizophrenia. Lancet 2004, 363, 2063–2072. [Google Scholar] [CrossRef]
  2. Carrà, G.; Crocamo, C.; Angermeyer, M.; Brugha, T.; Toumi, M.; Bebbington, P. Positive and negative symptoms in schizophrenia: A longitudinal analysis using latent variable structural equation modelling. Schizophr. Res. 2019, 204, 58–64. [Google Scholar] [CrossRef]
  3. Chang, C.-Y.; Luo, D.-Z.; Pei, J.-C.; Kuo, M.-C.; Hsieh, Y.-C.; Lai, W.-S. Not Just a Bystander: The Emerging Role of Astrocytes and Research Tools in Studying Cognitive Dysfunctions in Schizophrenia. Int. J. Mol. Sci. 2021, 22, 5343. [Google Scholar] [CrossRef]
  4. Dollfus, S.; Lyne, J. Negative symptoms: History of the concept and their position in diagnosis of schizophrenia. Schizophr. Res. 2017, 186, 3–7. [Google Scholar] [CrossRef] [PubMed]
  5. Bora, E. Peripheral inflammatory and neurotrophic biomarkers of cognitive impairment in schizophrenia: A meta-Analysis. Psychol. Med. 2019, 49, 1971–1979. [Google Scholar] [CrossRef]
  6. Mesholam-Gately, R.I.; Giuliano, A.J.; Goff, K.P.; Faraone, S.V.; Seidman, L.J. Neurocognition in First-Episode Schizophrenia: A Meta-Analytic Review. Neuropsychology 2009, 23, 315–336. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Xu, M.-Y.; Wong, A.H.C. GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia. Acta Pharmacol. Sin. 2018, 39, 733–753. [Google Scholar] [CrossRef] [Green Version]
  8. Bezdicek, O.; Michalec, J.; Kališová, L.; Kufa, T.; Děchtěrenko, F.; Chlebovcová, M.; Havlík, F.; Green, M.F.; Nuechterlein, K.H. Profile of cognitive deficits in schizophrenia and factor structure of the Czech MATRICS Consensus Cognitive Battery. Schizophr. Res. 2020, 218, 85–92. [Google Scholar] [CrossRef]
  9. Hoff, A.L.; Riordan, H.; O’Donnell, D.W.; Morris, L.; DeLisi, L.E. Neuropsychological functioning of first-episode schizophreniform patients. Am. J. Psychiatry 1992, 149, 898–903. [Google Scholar] [CrossRef]
  10. Xie, T.; Zhang, X.; Tang, X.; Zhang, H.; Yu, M.; Gong, G.; Wang, X.; Evans, A.; Zhang, Z.; He, Y. Mapping convergent and divergent cortical thinning patterns in patients with deficit and nondeficit schizophrenia. Schizophr. Bull. 2019, 45, 211–221. [Google Scholar] [CrossRef] [PubMed]
  11. Haijma, S.V.; Van Haren, N.; Cahn, W.; Koolschijn, P.C.M.P.; Hulshoff Pol, H.E.; Kahn, R.S. Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects. Schizophr. Bull. 2013, 39, 1129–1138. [Google Scholar] [CrossRef]
  12. Planchuelo-Gómez, Á.; Lubeiro, A.; Núñez-Novo, P.; Gomez-Pilar, J.; de Luis-García, R.; del Valle, P.; Martín-Santiago, Ó.; Pérez-Escudero, A.; Molina, V. Identificacion of MRI-based psychosis subtypes: Replication and refinement. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2020, 100, 109907. [Google Scholar] [CrossRef]
  13. Gould, I.C.; Shepherd, A.M.; Laurens, K.R.; Cairns, M.J.; Carr, V.J.; Green, M.J. Multivariate neuroanatomical classification of cognitive subtypes in schizophrenia: A support vector machine learning approach. NeuroImage Clin. 2014, 6, 229–236. [Google Scholar] [CrossRef] [Green Version]
  14. Brugger, S.P.; Howes, O.D. Heterogeneity and Homogeneity of Regional Brain Structure in Schizophrenia: A Meta-analysis. JAMA Psychiatry 2017, 74, 1104–1111. [Google Scholar] [CrossRef] [PubMed]
  15. Alústiza, I.; Radua, J.; Albajes-Eizagirre, A.; Domínguez, M.; Aubá, E.; Ortuño, F. Meta-Analysis of Functional Neuroimaging and Cognitive Control Studies in Schizophrenia: Preliminary Elucidation of a Core Dysfunctional Timing Network. Front. Psychol. 2016, 7, 1–12. [Google Scholar] [CrossRef] [Green Version]
  16. Elsworth, J.D.; Morrow, B.A.; Hajszan, T.; Leranth, C.; Roth, R.H. Phencyclidine-induced Loss of Asymmetric Spine Synapses in Rodent Prefrontal Cortex is Reversed by Acute and Chronic Treatment with Olanzapine. Neuropsychopharmacology 2011, 36, 2054–2061. [Google Scholar] [CrossRef] [Green Version]
  17. Ji, J.L.; Diehl, C.; Schleifer, C.; Tamminga, C.A.; Keshavan, M.S.; Sweeney, J.A.; Clementz, B.A.; Hill, S.K.; Pearlson, G.; Yang, G.; et al. Schizophrenia Exhibits Bi-directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits. Cereb. Cortex 2019, 29, 4463–4487. [Google Scholar] [CrossRef]
  18. Huang, M.L.; Khoh, T.T.; Lu, S.J.; Pan, F.; Chen, J.K.; Hu, J.B.; Hu, S.H.; Xu, W.J.; Zhou, W.H.; Wei, N.; et al. Relationships between dorsolateral prefrontal cortex metabolic change and cognitive impairment in first-episode neuroleptic-naive schizophrenia patients. Medicine 2017, 96. [Google Scholar] [CrossRef] [PubMed]
  19. Ellegood, J.; Markx, S.; Lerch, J.P.; Steadman, P.E.; Genç, C.; Provenzano, F.; Kushner, S.A.; Henkelman, R.M.; Karayiorgou, M.; Gogos, J.A. Neuroanatomical phenotypes in a mouse model of the 22q11.2 microdeletion. Mol. Psychiatry 2014, 19, 99–107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Schretlen, D.J.; Vannorsdall, T.D.; Winicki, J.M.; Mushtaq, Y.; Hikida, T.; Sawa, A.; Yolken, R.H.; Dickerson, F.B.; Cascella, N.G. Neuroanatomic and cognitive abnormalities related to herpes simplex virus type 1 in schizophrenia. Schizophr. Res. 2010, 118, 224–231. [Google Scholar] [CrossRef] [PubMed]
  21. Weinberger, D.R. The neurodevelopmental origins of schizophrenia in the penumbra of genomic medicine. World Psychiatry 2017, 16, 225–226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Murray, R.M.; Lewis, S.W. Is schizophrenia a neurodevelopmental disorder? BMJ 1987, 295, 681–682. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Tripathi, A.; Kar, S.K.; Shukla, R. Cognitive deficits in schizophrenia: Understanding the biological correlates and remediation strategies. Clin. Psychopharmacol. Neurosci. 2018, 16, 7–17. [Google Scholar] [CrossRef] [Green Version]
  24. Snyder, M.A.; Gao, W.J. NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Front. Cell. Neurosci. 2013, 7, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Fathian, F.; Loberg, E.M.; Gjestad, R.; Steen, V.M.; Kroken, R.A.; Jorgensen, H.A.; Johnsen, E. Associations between C-reactive protein levels and cognition during the first 6 months after acute psychosis. Acta Neuropsychiatr. 2019, 31, 36–45. [Google Scholar] [CrossRef]
  26. Fillman, S.G.; Weickert, T.W.; Lenroot, R.K.; Catts, S.V.; Bruggemann, J.M.; Catts, V.S.; Weickert, C.S. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume. Mol. Psychiatry 2016, 21, 1090–1098. [Google Scholar] [CrossRef]
  27. Ribeiro-Santos, R.; de Campos-Carli, S.M.; Ferretjans, R.; Teixeira-Carvalho, A.; Martins-Filho, O.A.; Teixeira, A.L.; Salgado, J.V. The association of cognitive performance and IL-6 levels in schizophrenia is influenced by age and antipsychotic treatment. Nord. J. Psychiatry 2020, 74, 187–193. [Google Scholar] [CrossRef]
  28. Baune, B.T.; Ponath, G.; Rothermundt, M.; Riess, O.; Funke, H.; Berger, K. Association between genetic variants of IL-1β, IL-6 and TNF-α cytokines and cognitive performance in the elderly general population of the MEMO-study. Psychoneuroendocrinology 2008, 33, 68–76. [Google Scholar] [CrossRef]
  29. Lupien, S.J.; Juster, R.P.; Raymond, C.; Marin, M.F. The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity. Front. Neuroendocrinol. 2018, 49, 91–105. [Google Scholar] [CrossRef]
  30. Mondelli, V.; Cattaneo, A.; Murri, M.B.; Papadopoulos, A.S.; Aitchison, K.J. Stress and inflammation reduce BDNF expression in first- episode psychosis: A pathway to smaller hippocampal volume. J. Clin. Psychiatry 2011, 72, 1677–1684. [Google Scholar] [CrossRef] [PubMed]
  31. Mondelli, V.; Pariante, C.M.; Navari, S.; Aas, M.; D’Albenzio, A.; Di Forti, M.; Handley, R.; Hepgul, N.; Marques, T.R.; Taylor, H.; et al. Higher cortisol levels are associated with smaller left hippocampal volume in first-episode psychosis. Schizophr. Res. 2010, 119, 75–78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Aas, M.; Dazzan, P.; Mondelli, V.; Toulopoulou, T.; Reichenberg, A.; Di Forti, M.; Fisher, H.L.; Handley, R.; Hepgul, N.; Marques, T.; et al. Abnormal cortisol awakening response predicts worse cognitive function in patients with first-episode psychosis. Psychol. Med. 2011, 41, 463–476. [Google Scholar] [CrossRef] [Green Version]
  33. Havelka, D.; Prikrylova-Kucerova, H.; Prikryl, R.; Ceskova, E. Cognitive impairment and cortisol levels in first-episode schizophrenia patients. Stress 2016, 19, 383–389. [Google Scholar] [CrossRef] [PubMed]
  34. Labad, J. The role of cortisol and prolactin in the pathogenesis and clinical expression of psychotic disorders. Psychoneuroendocrinology 2019, 102, 24–36. [Google Scholar] [CrossRef] [PubMed]
  35. Goodnick, P.J.; Santana, O.; Rodriguez, L. Antipsychotics: Impact on prolactin levels. Expert Opin. Pharmacother. 2002, 3, 1381–1391. [Google Scholar] [CrossRef] [PubMed]
  36. Montalvo, I.; Gutiérrez-Zotes, A.; Creus, M.; Monseny, R.; Ortega, L.; Franch, J.; Lawrie, S.M.; Reynolds, R.M.; Vilella, E.; Labad, J. Increased prolactin levels are associated with impaired processing speed in subjects with early psychosis. PLoS ONE 2014, 9. [Google Scholar] [CrossRef] [Green Version]
  37. Yao, S.; Song, J.; Gao, J.; Lin, P.; Yang, M.; Zahid, K.R.; Yan, Y.; Cao, C.; Ma, P.; Zhang, H.; et al. Cognitive function and serum hormone levels are associated with gray matter volume decline in female patients with prolactinomas. Front. Neurol. 2018, 8, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. García-Rizo, C.; Vázquez-Bourgon, J.; Labad, J.; Ortiz García de la Foz, V.; Gómez-Revuelta, M.; Juncal Ruiz, M.; Crespo-Facorro, B. Prolactin, metabolic and immune parameters in naïve subjects with a first episode of psychosis. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2021, 110, 110332. [Google Scholar] [CrossRef] [PubMed]
  39. Hori, H.; Yoshimura, R.; Katsuki, A.; Atake, K.; Igata, R.; Konishi, Y.; Nakamura, J. Relationships between Serum Brain-Derived Neurotrophic Factor, Plasma Catecholamine Metabolites, Cytokines, Cognitive Function and Clinical Symptoms in Japanese Patients with Chronic Schizophrenia Treated with Atypical Antipsychotic Monotherapy. World J. Biol. Psychiatry 2017, 18, 401–408. [Google Scholar] [CrossRef]
  40. Yang, Y.; Liu, Y.; Wang, G.; Hei, G.; Wang, X.; Li, R.; Li, L.; Wu, R.; Zhao, J. Brain-derived neurotrophic factor is associated with cognitive impairments in first-episode and chronic schizophrenia. Psychiatry Res. 2019, 273, 528–536. [Google Scholar] [CrossRef]
  41. Vasconcelos, G.S.; Ximenes, N.C.; de Sousa, C.N.S.; Oliveira, T.; de Lima, L.L.L.; de Lucena, D.F.; Gama, C.S.; Macêdo, D.; Vasconcelos, S.M.M. Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms. Schizophr. Res. 2015, 165, 163–170. [Google Scholar] [CrossRef]
  42. Ertuĝrul, A.; Özdemir, H.; Vural, A.; Dalkara, T.; Meltzer, H.Y.; Saka, E. The influence of N-desmethylclozapine and clozapine on recognition memory and BDNF expression in hippocampus. Brain Res. Bull. 2011, 84, 144–150. [Google Scholar] [CrossRef] [PubMed]
  43. Zhang, X.Y.; Chen, D.C.; Xiu, M.H.; Haile, C.N.; Luo, X.; Xu, K.; Zhang, H.P.; Zuo, L.; Zhang, Z.; Zhang, X.; et al. Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum. Genet. 2012, 131, 1187–1195. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Ho, B.-C.; Milev, P.; O’Leary, D.S.; Librant, A.; Andreasen, N.C.; Wassink, T.H. Cognitive and Magnetic Resonance Imaging Brain Morphometric Correlates of Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism in Patients with Schizophrenia and Healthy Volunteers. Arch. Gen. Psychiatry 2006, 63, 731. [Google Scholar] [CrossRef] [Green Version]
  45. Huang, M.; Panos, J.J.; Kwon, S.; Oyamada, Y.; Rajagopal, L.; Meltzer, H.Y. Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: Role of relative serotonin (5-HT) 2A and da D2 antagonism and 5-HT1A partial agonism. J. Neurochem. 2014, 128, 938–949. [Google Scholar] [CrossRef]
  46. Schoonover, K.E.; Dienel, S.J.; Lewis, D.A. Prefrontal cortical alterations of glutamate and GABA neurotransmission in schizophrenia: Insights for rational biomarker development. Biomark. Neuropsychiatry 2020, 3, 100015. [Google Scholar] [CrossRef]
  47. Fang, X.; Wang, Y.; Cheng, L.; Zhang, Y.; Zhou, Y.; Wu, S.; Huang, H.; Zou, J.; Chen, C.; Chen, J.; et al. Prefrontal dysconnectivity links to working memory deficit in first-episode schizophrenia. Brain Imaging Behav. 2018, 12, 335–344. [Google Scholar] [CrossRef]
  48. Chiu, P.W.; Lui, S.S.Y.; Hung, K.S.Y.; Chan, R.C.K.; Chan, Q.; Sham, P.C.; Cheung, E.F.C.; Mak, H.K.F. In vivo gamma-aminobutyric acid and glutamate levels in people with first-episode schizophrenia: A proton magnetic resonance spectroscopy study. Schizophr. Res. 2018, 193, 295–303. [Google Scholar] [CrossRef]
  49. Cho, R.Y.; Konecky, R.O.; Carter, C.S. Impairments in frontal cortical γ synchrony and cognitive control in schizophrenia. Proc. Natl. Acad. Sci. USA 2006, 103, 19878–19883. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Weickert, C.S.; Fung, S.J.; Catts, V.S.; Schofield, P.R.; Allen, K.M.; Moore, L.T.; Newell, K.A.; Pellen, D.; Huang, X.F.; Catts, S.V.; et al. Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol. Psychiatry 2013, 18, 1185–1192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Billard, J.-M. Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging. Front. Mol. Biosci. 2018, 5, 1–110. [Google Scholar] [CrossRef] [PubMed]
  52. Sathyasaikumar, K.V.; Stachowski, E.K.; Wonodi, I.; Roberts, R.C.; Rassoulpour, A.; McMahon, R.P.; Schwarcz, R. Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals with Schizophrenia. Schizophr. Bull. 2011, 37, 1147–1156. [Google Scholar] [CrossRef] [Green Version]
  53. Kindler, J.; Lim, C.K.; Weickert, C.S.; Boerrigter, D.; Galletly, C.; Liu, D.; Jacobs, K.R.; Balzan, R.; Bruggemann, J.; O’Donnell, M.; et al. Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia. Mol. Psychiatry 2020, 25, 2860–2872. [Google Scholar] [CrossRef] [Green Version]
  54. Jones, C.A.; Watson, D.J.G.; Fone, K.C.F. Animal models of schizophrenia. Br. J. Pharmacol. 2011, 164, 1162–1194. [Google Scholar] [CrossRef]
  55. Kaminski, J.; Mascarell-Maricic, L.; Fukuda, Y.; Katthagen, T.; Heinz, A.; Schlagenhauf, F. Glutamate in the Dorsolateral Prefrontal Cortex in Patients with Schizophrenia: A Meta-analysis of 1H-Magnetic Resonance Spectroscopy Studies. Biol. Psychiatry 2021, 89, 270–277. [Google Scholar] [CrossRef]
  56. Gluck, M.R.; Thomas, R.G.; Davis, K.L.; Haroutunian, V. Implications for Altered Glutamate and GABA Metabolism in the Dorsolateral Prefrontal Cortex of Aged Schizophrenic Patients. Am. J. Psychiatry 2002, 159, 1165–1173. [Google Scholar] [CrossRef]
  57. Volk, D.W.; Eggan, S.M.; Lewis, D.A. Alterations in Metabotropic Glutamate Receptor 1α and Regulator of G Protein Signaling 4 in the Prefrontal Cortex in Schizophrenia. Am. J. Psychiatry 2010, 167, 1489–1498. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Upreti, C.; Zhang, X.; Alford, S.; Stanton, P.K. Role of presynaptic metabotropic glutamate receptors in the induction of long-term synaptic plasticity of vesicular release. Neuropharmacology 2013, 66, 31–39. [Google Scholar] [CrossRef] [Green Version]
  59. Whittington, M.A.; Cunningham, M.O.; LeBeau, F.E.N.; Racca, C.; Traub, R.D. Multiple origins of the cortical gamma rhythm. Dev. Neurobiol. 2011, 71, 92–106. [Google Scholar] [CrossRef] [PubMed]
  60. Volk, D.W.; Austin, M.C.; Pierri, J.N.; Sampson, A.R.; Lewis, D.A. Decreased Glutamic Acid Decarboxylase67 Messenger RNA Expression in a Subset of Prefrontal Cortical γ-Aminobutyric Acid Neurons in Subjects with Schizophrenia. Arch. Gen. Psychiatry 2000, 57, 237. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Enwright, J.F.; Sanapala, S.; Foglio, A.; Berry, R.; Fish, K.N.; Lewis, D.A. Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia. Neuropsychopharmacology 2016, 41, 2206–2214. [Google Scholar] [CrossRef] [Green Version]
  62. Liu, Y.; Yang, X.J.; Xia, H.; Tang, C.-M.; Yang, K. GABA releases from parvalbumin-expressing and unspecific GABAergic neurons onto CA1 pyramidal cells are differentially modulated by presynaptic GABAB receptors in mouse hippocampus. Biochem. Biophys. Res. Commun. 2019, 520, 449–452. [Google Scholar] [CrossRef] [PubMed]
  63. Lewis, D.A. The chandelier neuron in schizophrenia. Dev. Neurobiol. 2011, 71, 118–127. [Google Scholar] [CrossRef]
  64. Morris, H.M.; Hashimoto, T.; Lewis, D.A. Alterations in Somatostatin mRNA Expression in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia or Schizoaffective Disorder. Cereb. Cortex 2008, 18, 1575–1587. [Google Scholar] [CrossRef] [Green Version]
  65. Avram, M.; Brandl, F.; Cabello, J.; Leucht, C.; Scherr, M.; Mustafa, M.; Leucht, S.; Ziegler, S.; Sorg, C. Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms. Brain 2019, 142, 1813–1826. [Google Scholar] [CrossRef] [PubMed]
  66. Avram, M.; Brandl, F.; Knolle, F.; Cabello, J.; Leucht, C.; Scherr, M.; Mustafa, M.; Koutsouleris, N.; Leucht, S.; Ziegler, S.; et al. Aberrant striatal dopamine links topographically with cortico-thalamic dysconnectivity in schizophrenia. Brain 2020, 143, 3495–3505. [Google Scholar] [CrossRef] [PubMed]
  67. Koola, M.M.; Looney, S.W.; Hong, H.; Pillai, A.; Hou, W. Meta-analysis of randomized controlled trials of galantamine in schizophrenia: Significant cognitive enhancement. Psychiatry Res. 2020, 291. [Google Scholar] [CrossRef]
  68. Bakker, G.; Vingerhoets, C.; Bloemen, O.J.N.; Sahakian, B.J.; Booij, J.; Caan, M.W.A.; van Amelsvoort, T.A.M.J. The muscarinic M1 receptor modulates associative learning and memory in psychotic disorders. NeuroImage Clin. 2020, 27, 102278. [Google Scholar] [CrossRef]
  69. Jin, C.Y.; Anichtchik, O.; Panula, P. Altered histamine H 3 receptor radioligand binding in post-mortem brain samples from subjects with psychiatric diseases. Br. J. Pharmacol. 2009, 157, 118–129. [Google Scholar] [CrossRef] [Green Version]
  70. Zai, G.; Robbins, T.W.; Sahakian, B.J.; Kennedy, J.L. A review of molecular genetic studies of neurocognitive deficits in schizophrenia. Neurosci. Biobehav. Rev. 2017, 72, 50–67. [Google Scholar] [CrossRef] [PubMed]
  71. Apud, J.A.; Weinberger, D.R. Treatment of cognitive deficits associated with schizophrenia: Potential role of catechol-O-methyltransferase inhibitors. CNS Drugs 2007, 21, 535–557. [Google Scholar] [CrossRef] [PubMed]
  72. Burton, C.Z.; Vella, L.; Kelsoe, J.R.; Bilder, R.M.; Twamley, E.W. Catechol-O-methyltransferase genotype and response to Compensatory Cognitive Training in outpatients with schizophrenia. Psychiatr. Genet. 2015, 25, 131–134. [Google Scholar] [CrossRef]
  73. Malhotra, A.K.; Kestler, L.J.; Mazzanti, C.; Bates, J.A.; Goldberg, T.; Goldman, D. A Functional Polymorphism in the COMT Gene and Performance on a Test of Prefrontal Cognition. Am. J. Psychiatry 2002, 159, 652–654. [Google Scholar] [CrossRef] [PubMed]
  74. Pinheiro, A.P.; Keefe, R.S.E.; Skelly, T.; Olarte, M.; Leviel, K.; Lange, L.A.; Lange, E.M.; Stroup, T.S.; Lieberman, J.; Sullivan, P.F. AKT1 and neurocognition in schizophrenia. Aust. N. Z. J. Psychiatry 2007, 41, 169–177. [Google Scholar] [CrossRef]
  75. Huang, C.H.; Pei, J.C.; Luo, D.Z.; Chen, C.; Chen, Y.W.; Lai, W.S. Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia. Front. Behav. Neurosci. 2015, 8, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Tang, T.T.T.; Yang, F.; Chen, B.S.; Lu, Y.; Ji, Y.; Roche, K.W.; Lu, B. Dysbindin regulates hippocampal LTP by controlling NMDA receptor surface expression. Proc. Natl. Acad. Sci. USA 2009, 106, 21395–21400. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Al-Shammari, A.R.; Bhardwaj, S.K.; Musaelyan, K.; Srivastava, L.K.; Szele, F.G. Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone. npj Schizophr. 2018, 4, 15. [Google Scholar] [CrossRef]
  78. Yang, Y.; Zhang, L.; Guo, D.; Zhang, L.; Yu, H.; Liu, Q.; Su, X.; Shao, M.; Song, M.; Zhang, Y.; et al. Association of DTNBP1 With Schizophrenia: Findings from Two Independent Samples of Han Chinese Population. Front. Psychiatry 2020, 11, 1–9. [Google Scholar] [CrossRef]
  79. Zhang, J.P.; Burdick, K.E.; Lencz, T.; Malhotra, A.K. Meta-analysis of genetic variation in DTNBP1 and general cognitive ability. Biol. Psychiatry 2010, 68, 1126–1133. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Tropea, D.; Hardingham, N.; Millar, K.; Fox, K. Mechanisms underlying the role of DISC1 in synaptic plasticity. J. Physiol. 2018, 596, 2747–2771. [Google Scholar] [CrossRef] [Green Version]
  81. Teng, S.; Thomson, P.A.; McCarthy, S.; Kramer, M.; Muller, S.; Lihm, J.; Morris, S.; Soares, D.C.; Hennah, W.; Harris, S.; et al. Rare disruptive variants in the DISC1 Interactome and Regulome: Association with cognitive ability and schizophrenia. Mol. Psychiatry 2018, 23, 1270–1277. [Google Scholar] [CrossRef] [Green Version]
  82. Meltzer, H.Y. Update on typical and atypical antipsychotic drugs. Annu. Rev. Med. 2013, 64, 393–406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Meltzer, H.Y.; Matsubara, S.; Lee, J.C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 1989, 251, 238–246. [Google Scholar] [PubMed]
  84. Gray, J.A.; Roth, B.L. Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia. Schizophr. Bull. 2007, 33, 1100–1119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Nielsen, R.E.; Levander, S.; Kjaersdam Telléus, G.; Jensen, S.O.W.; Østergaard Christensen, T.; Leucht, S. Second-generation antipsychotic effect on cognition in patients with schizophrenia—A meta-analysis of randomized clinical trials. Acta Psychiatr. Scand. 2015, 131, 185–196. [Google Scholar] [CrossRef] [PubMed]
  86. Désaméricq, G.; Schurhoff, F.; Meary, A.; Szöke, A.; Macquin-Mavier, I.; Bachoud-Lévi, A.C.; Maison, P. Long-term neurocognitive effects of antipsychotics in schizophrenia: A network meta-analysis. Eur. J. Clin. Pharmacol. 2014, 70, 127–134. [Google Scholar] [CrossRef] [PubMed]
  87. Baldez, D.P.; Biazus, T.B.; Rabelo-da-Ponte, F.D.; Nogaro, G.P.; Martins, D.S.; Kunz, M.; Czepielewski, L.S. The effect of antipsychotics on the cognitive performance of individuals with psychotic disorders: Network meta-analyses of randomized controlled trials. Neurosci. Biobehav. Rev. 2021, 126, 265–275. [Google Scholar] [CrossRef]
  88. De la Fuente Revenga, M.; Ibi, D.; Saunders, J.M.; Cuddy, T.; Ijaz, M.K.; Toneatti, R.; Kurita, M.; Holloway, T.; Shen, L.; Seto, J.; et al. HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice. Neuroscience 2018, 388, 102–117. [Google Scholar] [CrossRef]
  89. Ibi, D.; de la Fuente Revenga, M.; Kezunovic, N.; Muguruza, C.; Saunders, J.M.; Gaitonde, S.A.; Moreno, J.L.; Ijaz, M.K.; Santosh, V.; Kozlenkov, A.; et al. Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects. Nat. Neurosci. 2017, 20, 1247–1259. [Google Scholar] [CrossRef]
  90. Pawełczyk, T.; Piątkowska-Janko, E.; Bogorodzki, P.; Gębski, P.; Grancow-Grabka, M.; Trafalska, E.; Żurner, N.; Pawełczyk, A. Omega-3 fatty acid supplementation may prevent loss of gray matter thickness in the left parieto-occipital cortex in first episode schizophrenia: A secondary outcome analysis of the OFFER randomized controlled study. Schizophr. Res. 2018, 195, 168–175. [Google Scholar] [CrossRef]
  91. Conus, P.; Seidman, L.J.; Fournier, M.; Xin, L.; Cleusix, M.; Baumann, P.S.; Ferrari, C.; Cousins, A.; Alameda, L.; Gholam-Rezaee, M.; et al. N-acetylcysteine in a double-blind randomized placebo-controlled trial: Toward biomarker-guided treatment in early psychosis. Schizophr. Bull. 2018, 44, 317–327. [Google Scholar] [CrossRef] [Green Version]
  92. Zhang, L.; Zheng, H.; Wu, R.; Kosten, T.R.; Zhang, X.-Y.; Zhao, J. The effect of minocycline on amelioration of cognitive deficits and pro-inflammatory cytokines levels in patients with schizophrenia. Schizophr. Res. 2019, 212, 92–98. [Google Scholar] [CrossRef]
  93. Liu, F.; Guo, X.; Wu, R.; Ou, J.; Zheng, Y.; Zhang, B.; Xie, L.; Zhang, L.; Yang, L.; Yang, S.; et al. Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: A double blind, randomized, controlled trial. Schizophr. Res. 2014, 153, 169–176. [Google Scholar] [CrossRef] [PubMed]
  94. Sumiyoshi, T.; Matsui, M.; Yamashita, I.; Nohara, S.; Uehara, T.; Kurachi, M.; Meltzer, H.Y. Effect of adjunctive treatment with serotonin-1A agonist tandospirone on memory functions in schizophrenia. J. Clin. Psychopharmacol. 2000, 20, 386–388. [Google Scholar] [CrossRef] [PubMed]
  95. Zheng, W.; Cai, D.-B.; Zhang, Q.-E.; He, J.; Zhong, L.-Y.; Sim, K.; Ungvari, G.S.; Ning, Y.-P.; Xiang, Y.-T. Adjunctive ondansetron for schizophrenia: A systematic review and meta-analysis of randomized controlled trials. J. Psychiatr. Res. 2019, 113, 27–33. [Google Scholar] [CrossRef]
  96. Xia, L.; Liu, L.; Hong, X.; Wang, D.; Wei, G.; Wang, J.; Zhou, H.; Xu, H.; Tian, Y.; Dai, Q.; et al. One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia. Neuropsychopharmacology 2020, 45, 1362–1368. [Google Scholar] [CrossRef]
  97. Morozova, M.A.; Lepilkina, T.A.; Rupchev, G.E.; Beniashvily, A.G.; Burminskiy, D.S.; Potanin, S.S.; Bondarenko, E.V.; Kazey, V.I.; Lavrovsky, Y.; Ivachtchenko, A.V. Add-on clinical effects of selective antagonist of 5HT6 receptors AVN-211 (CD-008-0173) in patients with schizophrenia stabilized on antipsychotic treatment: Pilot study. CNS Spectr. 2014, 19, 316–323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Morozova, M.; Burminskiy, D.; Rupchev, G.; Lepilkina, T.; Potanin, S.; Beniashvili, A.; Lavrovsky, Y.; Vostokova, N.; Ivaschenko, A. 5-HT6 Receptor Antagonist as an Adjunct Treatment Targeting Residual Symptoms in Patients with Schizophrenia. J. Clin. Psychopharmacol. 2017, 37, 169–175. [Google Scholar] [CrossRef]
  99. Fond, G.; Berna, F.; Boyer, L.; Godin, O.; Brunel, L.; Andrianarisoa, M.; Aouizerate, B.; Capdevielle, D.; Chereau, I.; Danion, J.M.; et al. Benzodiazepine long-term administration is associated with impaired attention/working memory in schizophrenia: Results from the national multicentre FACE-SZ data set. Eur. Arch. Psychiatry Clin. Neurosci. 2018, 268, 17–26. [Google Scholar] [CrossRef]
  100. Geffen, Y.; Keefe, R.; Rabinowitz, J.; Anand, R.; Davidson, M. BL-1020, a New γ-Aminobutyric Acid–Enhanced Antipsychotic. J. Clin. Psychiatry 2012, 73, e1168–e1174. [Google Scholar] [CrossRef] [PubMed]
  101. Phase IIb-III Study of BL-1020 Small Molecule for Schizophrenia (CLARITY). Available online: https://clinicaltrials.gov/ct2/show/results/NCT01363349?term=bl-1020&draw=2&rank=3 (accessed on 18 March 2021).
  102. Haig, G.M.; Bain, E.; Robieson, W.; Othman, A.A.; Baker, J.; Lenz, R.A. A randomized trial of the efficacy and safety of the H3 antagonist ABT-288 in cognitive impairment associated with schizophrenia. Schizophr. Bull. 2014, 40, 1433–1442. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Tanzer, T.; Shah, S.; Benson, C.; De Monte, V.; Gore-Jones, V.; Rossell, S.L.; Dark, F.; Kisely, S.; Siskind, D.; Melo, C.D. Varenicline for cognitive impairment in people with schizophrenia: Systematic review and meta-analysis. Psychopharmacology 2020, 237, 11–19. [Google Scholar] [CrossRef]
  104. Brannan, S. Two global phase III trials of encenicline for cognitive impairment in chronic schizophrenia patients: Red flags and lessons learned. Schizophr. Bull. 2019, 45, S141–S142. [Google Scholar] [CrossRef]
  105. Haig, G.M.; Wang, D.; Zhao, J.; Othman, A.A.; Bain, E.E. Efficacy and Safety of the α7-Nicotinic Acetylcholine Receptor Agonist ABT-126 in the Treatment of Cognitive Impairment Associated with Schizophrenia. J. Clin. Psychiatry 2018, 79. [Google Scholar] [CrossRef]
  106. Walling, D.; Marder, S.R.; Kane, J.; Fleischhacker, W.W.; Keefe, R.S.E.; Hosford, D.A.; Dvergsten, C.; Segreti, A.C.; Beaver, J.S.; Toler, S.M.; et al. Phase 2 Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) in Negative and Cognitive Symptoms of Schizophrenia. Schizophr. Bull. 2016, 42, 335–343. [Google Scholar] [CrossRef] [Green Version]
  107. Shekhar, A.; Potter, W.Z.; Lightfoot, J.; Lienemann, J.; Dubé, S.; Mallinckrodt, C.; Bymaster, F.P.; McKinzie, D.L.; Felder, C.C. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am. J. Psychiatry 2008, 165, 1033–1039. [Google Scholar] [CrossRef]
  108. Singh, J.; Kour, K.; Jayaram, M.B. Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database Syst. Rev. 2012, 1, CD007967. [Google Scholar] [CrossRef] [PubMed]
  109. Di Iorio, G.; Baroni, G.; Lorusso, M.; Montemitro, C.; Spano, M.C.; di Giannantonio, M. Efficacy of Memantine in Schizophrenic Patients: A Systematic Review. J. Amino Acids 2017, 2017, 7021071. [Google Scholar] [CrossRef] [Green Version]
  110. Kantrowitz, J.T.; Nolan, K.A.; Epstein, M.L.; Lehrfeld, N.; Shope, C.; Petkova, E.; Javitt, D.C. Neurophysiological Effects of Bitopertin in Schizophrenia. J. Clin. Psychopharmacol. 2017, 37, 447–451. [Google Scholar] [CrossRef]
  111. Fleischhacker, W.W.; Podhorna, J.; Gröschl, M.; Hake, S.; Zhao, Y.; Huang, S.; Keefe, R.S.E.; Desch, M.; Brenner, R.; Walling, D.P.; et al. Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: A double-blind, randomised, placebo-controlled phase 2 study. Lancet Psychiatry 2021, 8, 191–201. [Google Scholar] [CrossRef]
  112. Downing, A.M.; Kinon, B.J.; Millen, B.A.; Zhang, L.; Liu, L.; Morozova, M.A.; Brenner, R.; Rayle, T.J.; Nisenbaum, L.; Zhao, F.; et al. A double-blind, placebo-controlled comparator study of LY2140023 monohydrate in patients with schizophrenia. BMC Psychiatry 2014, 14, 351. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Goff, D.C.; Leahy, L.; Berman, I.; Posever, T.; Herz, L.; Leon, A.C.; Johnson, S.A.; Lynch, G. A Placebo-Controlled Pilot Study of the Ampakine CX516 Added to Clozapine in Schizophrenia. J. Clin. Psychopharmacol. 2001, 21, 484–487. [Google Scholar] [CrossRef] [PubMed]
  114. Marenco, S.; Egan, M.F.; Goldberg, T.E.; Knable, M.B.; McClure, R.K.; Winterer, G.; Weinberger, D.R. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: A case series. Schizophr. Res. 2002, 57, 221–226. [Google Scholar] [CrossRef]
  115. Astellas Pharma Global Development. A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-group Study to Assess the Safety and Efficacy of ASP4345 as Add-on Treatment for Cognitive Impairment in Subjects with Schizophrenia on Stable Doses of Antipsychotic Medication. Available online: https://astellasclinicalstudyresults.com/study.aspx?ID=404 (accessed on 9 August 2021).
  116. Ortiz-Orendain, J.; Covarrubias-Castillo, S.A.; Vazquez-Alvarez, A.O.; Castiello-de Obeso, S.; Arias Quiñones, G.E.; Seegers, M.; Colunga-Lozano, L.E. Modafinil for people with schizophrenia or related disorders. Cochrane Database Syst. Rev. 2019, 12, CD008661. [Google Scholar] [CrossRef]
  117. Vernon, J.A.; Grudnikoff, E.; Seidman, A.J.; Frazier, T.W.; Vemulapalli, M.S.; Pareek, P.; Goldberg, T.E.; Kane, J.M.; Correll, C.U. Antidepressants for cognitive impairment in schizophrenia—A systematic review and meta-analysis. Schizophr. Res. 2014, 159, 385–394. [Google Scholar] [CrossRef] [Green Version]
  118. Gilleen, J.; Farah, Y.; Davison, C.; Kerins, S.; Valdearenas, L.; Uz, T.; Lahu, G.; Tsai, M.; Ogrinc, F.; Reichenberg, A.; et al. An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients. Psychopharmacology 2018. [Google Scholar] [CrossRef] [Green Version]
  119. Macek, T.A.; McCue, M.; Dong, X.; Hanson, E.; Goldsmith, P.; Affinito, J.; Mahableshwarkar, A.R. A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia. Schizophr. Res. 2019, 204, 289–294. [Google Scholar] [CrossRef]
  120. Ritsner, M.S.; Gibel, A.; Ratner, Y.; Tsinovoy, G.; Strous, R.D. Improvement of Sustained Attention and Visual and Movement Skills, but Not Clinical Symptoms, after Dehydroepiandrosterone Augmentation in Schizophrenia. J. Clin. Psychopharmacol. 2006, 26, 495–499. [Google Scholar] [CrossRef]
  121. Ritsner, M.S.; Gibel, A.; Shleifer, T.; Boguslavsky, I.; Zayed, A.; Maayan, R.; Weizman, A.; Lerner, V. Pregnenolone and Dehydroepiandrosterone as an Adjunctive Treatment in Schizophrenia and Schizoaffective Disorder. J. Clin. Psychiatry 2010, 71, 1351–1362. [Google Scholar] [CrossRef]
  122. Weickert, T.W.; Weinberg, D.; Lenroot, R.; Catts, S.V.; Wells, R.; Vercammen, A.; O’Donnell, M.; Galletly, C.; Liu, D.; Balzan, R.; et al. Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol. Psychiatry 2015, 20, 685–694. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Gurvich, C.; Hudaib, A.; Gavrilidis, E.; Worsley, R.; Thomas, N.; Kulkarni, J. Raloxifene as a treatment for cognition in women with schizophrenia: The influence of menopause status. Psychoneuroendocrinology 2019, 100, 113–119. [Google Scholar] [CrossRef]
  124. Weiser, M.; Levi, L.; Burshtein, S.; Hagin, M.; Matei, V.P.; Podea, D.; Micluția, I.; Tiugan, A.; Păcală, B.; Grecu, I.G.; et al. Raloxifene Plus Antipsychotics Versus Placebo Plus Antipsychotics in Severely Ill Decompensated Postmenopausal Women with Schizophrenia or Schizoaffective Disorder. J. Clin. Psychiatry 2017, 78, e758–e765. [Google Scholar] [CrossRef] [PubMed]
  125. Marx, C.E.; Keefe, R.S.E.; Buchanan, R.W.; Hamer, R.M.; Kilts, J.D.; Bradford, D.W.; Strauss, J.L.; Naylor, J.C.; Payne, V.M.; Lieberman, J.A.; et al. Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia. Neuropsychopharmacology 2009, 34, 1885–1903. [Google Scholar] [CrossRef]
  126. Marx, C.E.; Lee, J.; Subramaniam, M.; Rapisarda, A.; Bautista, D.C.T.; Chan, E.; Kilts, J.D.; Buchanan, R.W.; Wai, E.P.; Verma, S.; et al. Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. Psychopharmacology 2014, 231, 3647–3662. [Google Scholar] [CrossRef] [PubMed]
  127. Magalhães, P.V.S.; Dean, O.; Andreazza, A.C.; Berk, M.; Kapczinski, F. Antioxidant treatments for schizophrenia. Cochrane Database Syst. Rev. 2016, 2, CD008919. [Google Scholar] [CrossRef] [Green Version]
  128. Ni, Y.-F.; Zhang, W.; Bao, X.-F.; Wang, W.; Song, L.; Jiang, B. GM1 ganglioside reverses the cognitive deficits induced by MK801 in mice. Behav. Pharmacol. 2016, 27, 451–459. [Google Scholar] [CrossRef]
  129. Pitsikas, N. The role of nitric oxide donors in schizophrenia: Basic studies and clinical applications. Eur. J. Pharmacol. 2015, 766, 106–113. [Google Scholar] [CrossRef] [PubMed]
  130. Merritt, K.; Catalan, A.; Cowley, S.; Demjaha, A.; Taylor, M.; McGuire, P.; Cooper, R.; Morrison, P. Glyceryl trinitrate in first-episode psychosis unmedicated with antipsychotics: A randomised controlled pilot study. J. Psychopharmacol. 2020, 34, 839–847. [Google Scholar] [CrossRef]
  131. Yolland, C.O.B.; Phillipou, A.; Castle, D.J.; Neill, E.; Hughes, M.E.; Galletly, C.; Smith, Z.M.; Francis, P.S.; Dean, O.M.; Sarris, J.; et al. Improvement of cognitive function in schizophrenia with N-acetylcysteine: A theoretical review. Nutr. Neurosci. 2020, 23, 139–148. [Google Scholar] [CrossRef]
  132. Rapado-Castro, M.; Dodd, S.; Bush, A.I.; Malhi, G.S.; Skvarc, D.R.; On, Z.X.; Berk, M.; Dean, O.M. Cognitive effects of adjunctive N -acetyl cysteine in psychosis. Psychol. Med. 2017, 47, 866–876. [Google Scholar] [CrossRef]
  133. Ben-Azu, B.; Omogbiya, I.A.; Aderibigbe, A.O.; Umukoro, S.; Ajayi, A.M.; Iwalewa, E.O. Doxycycline prevents and reverses schizophrenic-like behaviors induced by ketamine in mice via modulation of oxidative, nitrergic and cholinergic pathways. Brain Res. Bull. 2018, 139, 114–124. [Google Scholar] [CrossRef]
  134. Kurita, M.; Holloway, T.; González-Maeso, J. HDAC2 as a new target to improve schizophrenia treatment. Expert Rev. Neurother. 2013, 13, 1–3. [Google Scholar] [CrossRef] [Green Version]
  135. Hai, D.; Shi, S.; Luo, H. The therapeutic effect of quetiapine on cognitive impairment associated with 5-HT1A presynaptic receptor involved schizophrenia. J. Integr. Neurosci. 2019, 18, 245. [Google Scholar] [CrossRef]
  136. Casey, A.B.; Canal, C.E. Classics in Chemical Neuroscience: Aripiprazole. ACS Chem. Neurosci. 2017, 8, 1135–1146. [Google Scholar] [CrossRef]
  137. Meller, E.; Goldstein, M.; Bohmaker, K. Receptor reserve for 5-hydroxytryptamine1A-mediated inhibition of serotonin synthesis: Possible relationship to anxiolytic properties of 5-hydroxytryptamine1A agonists. Mol. Pharmacol. 1990, 37, 231–237. [Google Scholar] [PubMed]
  138. Sumiyoshi, T.; Matsui, M.; Nohara, S.; Yamashita, I.; Kurachi, M.; Sumiyoshi, C.; Jayathilake, K.; Meltzer, H.Y. Enhancement of Cognitive Performance in Schizophrenia by Addition of Tandospirone to Neuroleptic Treatment. Am. J. Psychiatry 2001, 158, 1722–1725. [Google Scholar] [CrossRef] [PubMed]
  139. Rënyi, L.; Evenden, J.L.; Fowler, C.J.; Jerning, E.; Kelder, D.; Lake-Bakaar, D.; Larsson, L.G.; Mohell, N.; Sällemark, M.; Ross, S.B. The pharmacological profile of (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a selective 5-hydroxytryptamine(1A) receptor agonist. J. Pharmacol. Exp. Ther. 2001, 299, 883–893. [Google Scholar] [PubMed]
  140. Poddar, I.; Callahan, P.M.; Hernandez, C.M.; Yang, X.; Bartlett, M.G.; Terry, A.V. Tropisetron enhances recognition memory in rats chronically treated with risperidone or quetiapine. Biochem. Pharmacol. 2018, 151, 180–187. [Google Scholar] [CrossRef]
  141. Nikiforuk, A. The procognitive effects of 5-HT6 receptor ligands in animal models of schizophrenia. Rev. Neurosci. 2014, 25. [Google Scholar] [CrossRef]
  142. Ivachtchenko, A.V.; Okun, I.; Aladinskiy, V.; Ivanenkov, Y.; Koryakova, A.; Karapetyan, R.; Mitkin, O.; Salimov, R.; Ivashchenko, A.; Bezprozvanny, I. AVN-492, A Novel Highly Selective 5-HT6R Antagonist: Preclinical Evaluation. J. Alzheimer’s Dis. 2017, 58, 1043–1063. [Google Scholar] [CrossRef]
  143. Zareifopoulos, N.; Papatheodoropoulos, C. Effects of 5-HT-7 receptor ligands on memory and cognition. Neurobiol. Learn. Mem. 2016, 136, 204–209. [Google Scholar] [CrossRef] [PubMed]
  144. Ohmura, Y.; Yoshida, T.; Konno, K.; Minami, M.; Watanabe, M.; Yoshioka, M. Serotonin 5-HT 7 Receptor in the Ventral Hippocampus Modulates the Retrieval of Fear Memory and Stress-Induced Defecation. Int. J. Neuropsychopharmacol. 2015, 19, pyv131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Wang, L.; Zhang, Y.; Wang, C.; Zhang, X.; Wang, Z.; Liang, X.; Alachkar, A.; Civelli, O. A Natural Product with High Affinity to Sigma and 5-HT7 Receptors as Novel Therapeutic Drug for Negative and Cognitive Symptoms of Schizophrenia. Neurochem. Res. 2019, 44, 2536–2545. [Google Scholar] [CrossRef]
  146. Nikiforuk, A.; Kos, T.; Fijał, K.; Hołuj, M.; Rafa, D.; Popik, P. Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats. PLoS ONE 2013, 8, e66695. [Google Scholar] [CrossRef] [Green Version]
  147. Rajagopal, L.; Massey, B.W.; Michael, E.; Meltzer, H.Y. Serotonin (5-HT)1A receptor agonism and 5-HT7 receptor antagonism ameliorate the subchronic phencyclidine-induced deficit in executive functioning in mice. Psychopharmacology 2016, 233, 649–660. [Google Scholar] [CrossRef]
  148. Nikiforuk, A.; Hołuj, M.; Kos, T.; Popik, P. The effects of a 5-HT 5A receptor antagonist in a ketamine-based rat model of cognitive dysfunction and the negative symptoms of schizophrenia. Neuropharmacology 2016, 105, 351–360. [Google Scholar] [CrossRef] [PubMed]
  149. Yamazaki, M.; Harada, K.; Yamamoto, N.; Yarimizu, J.; Okabe, M.; Shimada, T.; Ni, K.; Matsuoka, N. ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia. Eur. Neuropsychopharmacol. 2014, 24, 1698–1708. [Google Scholar] [CrossRef] [Green Version]
  150. Yamazaki, M.; Yamamoto, N.; Yarimizu, J.; Okabe, M.; Moriyama, A.; Furutani, M.; Marcus, M.M.; Svensson, T.H.; Harada, K. Functional mechanism of ASP5736, a selective serotonin 5-HT5A receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia. Eur. Neuropsychopharmacol. 2018, 28, 620–629. [Google Scholar] [CrossRef]
  151. Casarotto, P.C.; Girych, M.; Fred, S.M.; Kovaleva, V.; Moliner, R.; Enkavi, G.; Biojone, C.; Cannarozzo, C.; Sahu, M.P.; Kaurinkoski, K.; et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell 2021, 184, 1299–1313.e19. [Google Scholar] [CrossRef]
  152. Timić Stamenić, T.; Joksimović, S.; Biawat, P.; Stanković, T.; Marković, B.; Cook, J.M.; Savić, M.M. Negative modulation of α 5 GABA A receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion. J. Psychopharmacol. 2015, 29, 1013–1024. [Google Scholar] [CrossRef] [Green Version]
  153. Arai, S.; Takuma, K.; Mizoguchi, H.; Ibi, D.; Nagai, T.; Kamei, H.; Kim, H.-C.; Yamada, K. GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice. Eur. J. Pharmacol. 2009, 602, 101–104. [Google Scholar] [CrossRef] [PubMed]
  154. Nudelman, A.; Gil-Ad, I.; Shpaisman, N.; Terasenko, I.; Ron, H.; Savitsky, K.; Geffen, Y.; Weizman, A.; Rephaeli, A. A Mutual Prodrug Ester of GABA and Perphenazine Exhibits Antischizophrenic Efficacy with Diminished Extrapyramidal Effects. J. Med. Chem. 2008, 51, 2858–2862. [Google Scholar] [CrossRef]
  155. Geffen, Y.; Nudelman, A.; Gil-Ad, I.; Rephaeli, A.; Huang, M.; Savitsky, K.; Klapper, L.; Winkler, I.; Meltzer, H.Y.; Weizman, A. BL-1020: A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia. Eur. Neuropsychopharmacol. 2009, 19, 1–13. [Google Scholar] [CrossRef] [PubMed]
  156. Sadek, B.; Saad, A.; Sadeq, A.; Jalal, F.; Stark, H. Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases. Behav. Brain Res. 2016, 312, 415–430. [Google Scholar] [CrossRef] [PubMed]
  157. Nirogi, R.; Grandhi, V.R.; Medapati, R.B.; Ganuga, N.; Benade, V.; Gandipudi, S.; Manoharan, A.; Abraham, R.; Jayarajan, P.; Bhyrapuneni, G.; et al. Histamine 3 receptor inverse agonist Samelisant (SUVN-G3031): Pharmacological characterization of an investigational agent for the treatment of cognitive disorders. J. Psychopharmacol. 2021, 35, 713–729. [Google Scholar] [CrossRef]
  158. Sagud, M.; Mihaljevic, A.; Pivac, N. Smoking in schizophrenia: Recent findings about an old problem. Curr. Opin. Psychiatry 2019, 32, 402–408. [Google Scholar] [CrossRef]
  159. Boggs, D.L.; Carlson, J.; Cortes-Briones, J.; Krystal, J.H.; D’Souza, D.C. Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia. Curr. Pharm. Des. 2014, 20, 5077–5092. [Google Scholar] [CrossRef] [Green Version]
  160. AhnAllen, C.G.; Bidwell, L.C.; Tidey, J.W. Cognitive effects of very low nicotine content cigarettes, with and without nicotine replacement, in smokers with schizophrenia and controls. Nicotine Tob. Res. Off. J. Soc. Res. Nicotine Tob. 2015, 17, 510–514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  161. Verma, M.K.; Goel, R.N.; Bokare, A.M.; Dandekar, M.P.; Koul, S.; Desai, S.; Tota, S.; Singh, N.; Nigade, P.B.; Patil, V.B.; et al. LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization. Eur. J. Pharmacol. 2021, 891, 173685. [Google Scholar] [CrossRef]
  162. Bristow, L.J.; Easton, A.E.; Li, Y.-W.; Sivarao, D.V.; Lidge, R.; Jones, K.M.; Post-Munson, D.; Daly, C.; Lodge, N.J.; Gallagher, L.; et al. The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia. PLoS ONE 2016, 11, e0159996. [Google Scholar] [CrossRef]
  163. Beinat, C.; Banister, S.D.; Herrera, M.; Law, V.; Kassiou, M. The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia. CNS Drugs 2015, 29, 529–542. [Google Scholar] [CrossRef]
  164. Stoiljkovic, M.; Kelley, C.; Nagy, D.; Leventhal, L.; Hajós, M. Selective activation of α7 nicotinic acetylcholine receptors augments hippocampal oscillations. Neuropharmacology 2016, 110, 102–108. [Google Scholar] [CrossRef]
  165. Huang, M.; Felix, A.R.; Flood, D.G.; Bhuvaneswaran, C.; Hilt, D.; Koenig, G.; Meltzer, H.Y. The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens. Psychopharmacology 2014, 231, 4541–4551. [Google Scholar] [CrossRef]
  166. Smith, R.C.; Amiaz, R.; Si, T.-M.; Maayan, L.; Jin, H.; Boules, S.; Sershen, H.; Li, C.; Ren, J.; Liu, Y.; et al. Varenicline Effects on Smoking, Cognition, and Psychiatric Symptoms in Schizophrenia: A Double-Blind Randomized Trial. PLoS ONE 2016, 11, e0143490. [Google Scholar] [CrossRef] [Green Version]
  167. Potasiewicz, A.; Golebiowska, J.; Popik, P.; Nikiforuk, A. Procognitive effects of varenicline in the animal model of schizophrenia depend on α4β2- and α 7-nicotinic acetylcholine receptors. J. Psychopharmacol. 2018, 33, 269881118812097. [Google Scholar] [CrossRef]
  168. Terry, A.V.J.; Plagenhoef, M.; Callahan, P.M. Effects of the nicotinic agonist varenicline on the performance of tasks of cognition in aged and middle-aged rhesus and pigtail monkeys. Psychopharmacology 2016, 233, 761–771. [Google Scholar] [CrossRef] [Green Version]
  169. Rook, J.M.; Bertron, J.L.; Cho, H.P.; Garcia-Barrantes, P.M.; Moran, S.P.; Maksymetz, J.T.; Nance, K.D.; Dickerson, J.W.; Remke, D.H.; Chang, S.; et al. A Novel M(1) PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity. ACS Chem. Neurosci. 2018, 9, 2274–2285. [Google Scholar] [CrossRef] [PubMed]
  170. Popiolek, M.; Mandelblat-Cerf, Y.; Young, D.; Garst-Orozco, J.; Lotarski, S.M.; Stark, E.; Kramer, M.; Butler, C.R.; Kozak, R. In Vivo Modulation of Hippocampal Excitability by M4 Muscarinic Acetylcholine Receptor Activator: Implications for Treatment of Alzheimer’s Disease and Schizophrenic Patients. ACS Chem. Neurosci. 2019, 10, 1091–1098. [Google Scholar] [CrossRef]
  171. Montani, C.; Canella, C.; Schwarz, A.J.; Li, J.; Gilmour, G.; Galbusera, A.; Wafford, K.; Gutierrez-Barragan, D.; McCarthy, A.; Shaw, D.; et al. The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain. Neuropsychopharmacology 2021, 46, 1194–1206. [Google Scholar] [CrossRef]
  172. Conley, R.R.; Boggs, D.L.; Kelly, D.L.; McMahon, R.P.; Dickinson, D.; Feldman, S.; Ball, M.P.; Buchanan, R.W. The Effects of Galantamine on Psychopathology in Chronic Stable Schizophrenia. Clin. Neuropharmacol. 2009, 32, 69–74. [Google Scholar] [CrossRef] [Green Version]
  173. Zhu, W.; Zhang, Z.; Qi, J.; Liu, F.; Chen, J.; Zhao, J.; Guo, X. Adjunctive treatment for cognitive impairment in patients with chronic schizophrenia: A double-blind, placebo-controlled study. Neuropsychiatr. Dis. Treat. 2014, 10, 1317–1323. [Google Scholar] [CrossRef] [Green Version]
  174. Koola, M.M.; Buchanan, R.W.; Pillai, A.; Aitchison, K.J.; Weinberger, D.R.; Aaronson, S.T.; Dickerson, F.B. Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia. Schizophr. Res. 2014, 157, 84–89. [Google Scholar] [CrossRef] [Green Version]
  175. Koola, M.M. Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia. Mol. Neuropsychiatry 2018, 4, 134–148. [Google Scholar] [CrossRef]
  176. Gawai, P.; Upadhyay, R.; Gakare, S.G.; Sarode, L.; Dravid, S.M.; Ugale, R.R. Antipsychotic-like profile of CIQ isomers in animal models of schizophrenia. Behav. Pharmacol. 2020, 31, 524–534. [Google Scholar] [CrossRef]
  177. Okada, M.; Fukuyama, K.; Kawano, Y.; Shiroyama, T.; Ueda, Y. Memantine protects thalamocortical hyper-glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc. Pharmacol. Res. Perspect. 2019, 7, e00457. [Google Scholar] [CrossRef] [Green Version]
  178. Javitt, D.C. Glycine transport inhibitors for the treatment of schizophrenia: Symptom and disease modification. Curr. Opin. Drug Discov. Develop. 2009, 12, 468–478. [Google Scholar]
  179. Fone, K.C.F.; Watson, D.J.G.; Billiras, R.I.; Sicard, D.I.; Dekeyne, A.; Rivet, J.-M.; Gobert, A.; Millan, M.J. Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management. Mol. Neurobiol. 2020, 57, 2144–2166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  180. Goff, D.C. D-cycloserine in Schizophrenia: New Strategies for Improving Clinical Outcomes by Enhancing Plasticity. Curr. Neuropharmacol. 2017, 15, 21–34. [Google Scholar] [CrossRef]
  181. Mateo, Z.; Porter, J.T. Group II metabotropic glutamate receptors inhibit glutamate release at thalamocortical synapses in the developing somatosensory cortex. Neuroscience 2007, 146, 1062–1072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  182. Lins, B.R.; Howland, J.G. Effects of the metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on rats tested with the paired associates learning task in touchscreen-equipped operant conditioning chambers. Behav. Brain Res. 2016, 301, 152–160. [Google Scholar] [CrossRef]
  183. Sokolenko, E.; Hudson, M.R.; Nithianantharajah, J.; Jones, N.C. The mGluR(2/3) agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice. J. Psychopharmacol. 2019, 33, 1588–1599. [Google Scholar] [CrossRef]
  184. Clifton, N.E.; Morisot, N.; Girardon, S.; Millan, M.J.; Loiseau, F. Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: Adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine. Psychopharmacology 2013, 225, 579–594. [Google Scholar] [CrossRef] [PubMed]
  185. Xing, B.; Han, G.; Wang, M.-J.; Snyder, M.A.; Gao, W.-J. Juvenile treatment with mGluR2/3 agonist prevents schizophrenia-like phenotypes in adult by acting through GSK3β. Neuropharmacology 2018, 137, 359–371. [Google Scholar] [CrossRef]
  186. Cieślik, P.; Radulska, A.; Pelikant-Małecka, I.; Płoska, A.; Kalinowski, L.; Wierońska, J.M. Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice. Int. J. Mol. Sci. 2019, 20, 2781. [Google Scholar] [CrossRef] [Green Version]
  187. Shen, W.; Plotkin, J.L.; Francardo, V.; Ko, W.K.D.; Xie, Z.; Li, Q.; Fieblinger, T.; Wess, J.; Neubig, R.R.; Lindsley, C.W.; et al. M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia. Neuron 2015, 88, 762–773. [Google Scholar] [CrossRef] [Green Version]
  188. Chater, T.E.; Goda, Y. The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity. Front. Cell. Neurosci. 2014, 8. [Google Scholar] [CrossRef]
  189. Chen, S.; Zhao, Y.; Wang, Y.; Shekhar, M.; Tajkhorshid, E.; Gouaux, E. Activation and Desensitization Mechanism of AMPA Receptor-TARP Complex by Cryo-EM. Cell 2017, 170, 1234–1246.e14. [Google Scholar] [CrossRef] [Green Version]
  190. Zheng, Y.; Balabhadrapatruni, S.; Masumura, C.; Darlington, L.C.; Smith, P.F. Effects of the Putative Cognitive-Enhancing Ampakine, CX717, on Attention and Object Recognition Memory. Curr. Alzheimer Res. 2011, 8, 876–882. [Google Scholar] [CrossRef]
  191. Bruce, H.A.; Kochunov, P.; Paciga, S.A.; Hyde, C.L.; Chen, X.; Xie, Z.; Zhang, B.; Xi, H.S.; O’Donnell, P.; Whelan, C.; et al. Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia. Genes Brain Behav. 2017, 16, 515–521. [Google Scholar] [CrossRef] [Green Version]
  192. Kozak, R.; Kiss, T.; Dlugolenski, K.; Johnson, D.E.; Gorczyca, R.R.; Kuszpit, K.; Harvey, B.D.; Stolyar, P.; Sukoff Rizzo, S.J.; Hoffmann, W.E.; et al. Characterization of PF-6142, a Novel, Non-Catecholamine Dopamine Receptor D1 Agonist, in Murine and Nonhuman Primate Models of Dopaminergic Activation. Front. Pharmacol. 2020, 11, 1005. [Google Scholar] [CrossRef]
  193. Tanyeri, P.; Buyukokuroglu, M.E.; Mutlu, O.; Ulak, G.; Akar, F.Y.; Celikyurt, I.K.; Erden, B.F. Effects of ziprasidone, SCH23390 and SB277011 on spatial memory in the Morris water maze test in naive and MK-801 treated mice. Pharmacol. Biochem. Behav. 2015, 138, 142–147. [Google Scholar] [CrossRef] [PubMed]
  194. Zahrt, J.; Taylor, J.R.; Mathew, R.G.; Arnsten, A.F.T. Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J. Neurosci. 1997, 17, 8528–8535. [Google Scholar] [CrossRef] [Green Version]
  195. Svensson, K.A.; Hao, J.; Bruns, R.F. Chapter Nine—Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders. In Neuropsychotherapeutics; Witkin, J.M., Ed.; Academic Press: Cambridge, MA, USA, 2019; Volume 86, pp. 273–305. ISBN 1054-3589. [Google Scholar]
  196. Wilbraham, D.; Biglan, K.M.; Svensson, K.A.; Tsai, M.; Kielbasa, W. Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects. Clin. Pharmacol. Drug Dev. 2021, 10, 393–403. [Google Scholar] [CrossRef]
  197. Hatzipantelis, C.J.; Langiu, M.; Vandekolk, T.H.; Pierce, T.L.; Nithianantharajah, J.; Stewart, G.D.; Langmead, C.J. Translation-Focused Approaches to GPCR Drug Discovery for Cognitive Impairments Associated with Schizophrenia. ACS Pharmacol. Transl. Sci. 2020, 3, 1042–1062. [Google Scholar] [CrossRef]
  198. Huang, M.; Kwon, S.; Oyamada, Y.; Rajagopal, L.; Miyauchi, M.; Meltzer, H.Y. Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement. Pharmacol. Biochem. Behav. 2015, 138, 49–57. [Google Scholar] [CrossRef]
  199. Mutti, V.; Fiorentini, C.; Missale, C.; Bono, F. Dopamine D3 receptor heteromerization: Implications for neuroplasticity and neuroprotection. Biomolecules 2020, 10, 1016. [Google Scholar] [CrossRef]
  200. Manvich, D.F.; Petko, A.K.; Branco, R.C.; Foster, S.L.; Porter-Stransky, K.A.; Stout, K.A.; Newman, A.H.; Miller, G.W.; Paladini, C.A.; Weinshenker, D. Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens. Neuropsychopharmacology 2019, 44, 1445–1455. [Google Scholar] [CrossRef] [PubMed]
  201. Torrisi, S.A.; Laudani, S.; Contarini, G.; De Luca, A.; Geraci, F.; Managò, F.; Papaleo, F.; Salomone, S.; Drago, F.; Leggio, G.M. Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments. Pharmaceuticals 2020, 13, 365. [Google Scholar] [CrossRef]
  202. Minzenberg, M.J.; Carter, C.S. Modafinil: A Review of Neurochemical Actions and Effects on Cognition. Neuropsychopharmacology 2008, 33, 1477–1502. [Google Scholar] [CrossRef] [PubMed]
  203. Murillo-Rodríguez, E.; Barciela Veras, A.; Barbosa Rocha, N.; Budde, H.; Machado, S. An Overview of the Clinical Uses, Pharmacology, and Safety of Modafinil. ACS Chem. Neurosci. 2018, 9, 151–158. [Google Scholar] [CrossRef]
  204. Dawson, N.; Thompson, R.J.; McVie, A.; Thomson, D.M.; Morris, B.J.; Pratt, J.A. Modafinil reverses phencyclidine-induced deficits in cognitive flexibility, cerebral metabolism, and functional brain connectivity. Schizophr. Bull. 2012, 38, 457–474. [Google Scholar] [CrossRef] [PubMed]
  205. Rogóż, Z.; Kamińska, K. The effect of combined treatment with escitalopram and risperidone on the MK-801-induced changes in the object recognition test in mice. Pharmacol. Rep. 2016, 68, 116–120. [Google Scholar] [CrossRef]
  206. Bruno, A.; Zoccali, R.; Bellinghieri, P.M.; Pandolfo, G.; De Fazio, P.; Spina, E.; Muscatello, M.R.A. Reboxetine adjuvant therapy in patients with schizophrenia showing a suboptimal response to clozapine: A 12-week, open-label, pilot study. J. Clin. Psychopharmacol. 2014, 34, 620–623. [Google Scholar] [CrossRef]
  207. Bymaster, F.P.; Perry, K.W.; Tollefson, G.D. Combination Therapy for Treatment of Psychoses. Patent WO1998011897, 26 March 1998. [Google Scholar]
  208. Al-Nema, M.Y.; Gaurav, A. Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia. Curr. Top. Med. Chem. 2020, 20, 2404–2421. [Google Scholar] [CrossRef]
  209. Duinen, M.; Reneerkens, O.; Lambrecht, L.; Sambeth, A.; Rutten, B.; Os, J.; Blokland, A.; Prickaerts, J. Treatment of Cognitive Impairment in Schizophrenia: Potential Value of Phosphodiesterase Inhibitors in Prefrontal Dysfunction. Curr. Pharm. Des. 2015, 21, 3813–3828. [Google Scholar] [CrossRef]
  210. Snyder, G.L.; Vanover, K.E. PDE Inhibitors for the Treatment of Schizophrenia. Adv. Neurobiol. 2017, 17, 385–409. [Google Scholar] [CrossRef]
  211. Enomoto, T.; Tatara, A.; Goda, M.; Nishizato, Y.; Nishigori, K.; Kitamura, A.; Kamada, M.; Taga, S.; Hashimoto, T.; Ikeda, K.; et al. A novel phosphodiesterase 1 inhibitor DSR-141562 exhibits efficacies in animal models for positive, negative, and cognitive symptoms associated with schizophrenia. J. Pharmacol. Exp. Ther. 2019, 371, 692–702. [Google Scholar] [CrossRef] [PubMed]
  212. Ahmed, H.I.; Abdel-Sattar, S.A.; Zaky, H.S. Vinpocetine halts ketamine-induced schizophrenia-like deficits in rats: Impact on BDNF and GSK-3β/β-catenin pathway. Naunyn. Schmiedebergs. Arch. Pharmacol. 2018, 391, 1327–1338. [Google Scholar] [CrossRef] [PubMed]
  213. O’Brien, J.J.; O’Callaghan, J.P.; Miller, D.B.; Chalgeri, S.; Wennogle, L.P.; Davis, R.E.; Snyder, G.L.; Hendrick, J.P. Inhibition of calcium-calmodulin-dependent phosphodiesterase (PDE1) suppresses inflammatory responses. Mol. Cell. Neurosci. 2020, 102, 103449. [Google Scholar] [CrossRef] [PubMed]
  214. Millar, K.J.; Mackie, S.; Clapcote, S.J.; Murdoch, H.; Pickard, B.S.; Christie, S.; Muir, W.J.; Blackwood, D.H.; Roder, J.C.; Houslay, M.D.; et al. Disrupted in schizophrenia 1 and phosphodiesterase 4B: Towards an understanding of psychiatric illness. J. Physiol. 2007, 584, 401–405. [Google Scholar] [CrossRef]
  215. Gilleen, J.; Nottage, J.; Yakub, F.; Kerins, S.; Valdearenas, L.; Uz, T.; Lahu, G.; Tsai, M.; Ogrinc, F.; Williams, S.C.; et al. The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial. J. Psychopharmacol. 2021, 35, 15–22. [Google Scholar] [CrossRef]
  216. Zagorska, A.; Partyka, A.; Bucki, A.; Gawalskax, A.; Czopek, A.; Pawlowski, M. Phosphodiesterase 10 Inhibitors—Novel Perspectives for Psychiatric and Neurodegenerative Drug Discovery. Curr. Med. Chem. 2018, 25, 3455–3481. [Google Scholar] [CrossRef] [PubMed]
  217. Smith, S.M.; Uslaner, J.M.; Cox, C.D.; Huszar, S.L.; Cannon, C.E.; Vardigan, J.D.; Eddins, D.; Toolan, D.M.; Kandebo, M.; Yao, L.; et al. The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. Neuropharmacology 2013, 64, 215–223. [Google Scholar] [CrossRef] [PubMed]
  218. Takakuwa, M.; Watanabe, Y.; Saijo, T.; Murata, M.; Anabuki, J.; Tezuka, T.; Sato, S.; Kojima, K.; Hashimoto, K. Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor MT-3014 in rats. Pharmacol. Biochem. Behav. 2020, 196, 172972. [Google Scholar] [CrossRef] [PubMed]
  219. Yurgelun-Todd, D.A.; Renshaw, P.F.; Goldsmith, P.; Uz, T.; Macek, T.A. A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects. Psychopharmacology 2020, 237, 317–328. [Google Scholar] [CrossRef] [Green Version]
  220. Bradley, A.J.; Dinan, T.G. A systematic review of hypothalamic-pituitary-adrenal axis function in schizophrenia: Implications for mortality. J. Psychopharmacol. 2010, 24, 91–118. [Google Scholar] [CrossRef] [PubMed]
  221. Pitsikas, N.; Zoupa, E.; Gravanis, A. The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts cognitive deficits induced by the D1/D2 dopaminergic receptor agonist apomorphine in rats. Psychopharmacology 2021, 238, 227–237. [Google Scholar] [CrossRef]
  222. Soria, V.; González-Rodríguez, A.; Huerta-Ramos, E.; Usall, J.; Cobo, J.; Bioque, M.; Barbero, J.D.; García-Rizo, C.; Tost, M.; Monreal, J.A.; et al. Targeting hypothalamic-pituitary-adrenal axis hormones and sex steroids for improving cognition in major mood disorders and schizophrenia: A systematic review and narrative synthesis. Psychoneuroendocrinology 2018, 93, 8–19. [Google Scholar] [CrossRef]
  223. Chakrabarti, M.; Haque, A.; Banik, N.L.; Nagarkatti, P.; Nagarkatti, M.; Ray, S.K. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration. Brain Res. Bull. 2014, 109, 22–31. [Google Scholar] [CrossRef] [Green Version]
  224. Bergemann, N.; Parzer, P.; Jaggy, S.; Auler, B.; Mundt, C.; Maier-Braunleder, S. Estrogen and Comprehension of Metaphoric Speech in Women Suffering from Schizophrenia: Results of a Double-Blind, Placebo-Controlled Trial. Schizophr. Bull. 2008, 34, 1172–1181. [Google Scholar] [CrossRef]
  225. Lobo, R.A. Hormone-replacement therapy: Current thinking. Nat. Rev. Endocrinol. 2017, 13, 220–231. [Google Scholar] [CrossRef]
  226. Marx, C.E.; Bradford, D.W.; Hamer, R.M.; Naylor, J.C.; Allen, T.B.; Lieberman, J.A.; Strauss, J.L.; Kilts, J.D. Pregnenolone as a novel therapeutic candidate in schizophrenia: Emerging preclinical and clinical evidence. Neuroscience 2011, 191, 78–90. [Google Scholar] [CrossRef] [PubMed]
  227. Winship, I.R.; Dursun, S.M.; Baker, G.B.; Balista, P.A.; Kandratavicius, L.; Maia-de-Oliveira, J.P.; Hallak, J.; Howland, J.G. An Overview of Animal Models Related to Schizophrenia. Can. J. Psychiatry 2019, 64, 5–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  228. Bray, N.J.; Kapur, S.; Price, J. Investigating schizophrenia in a “dish”: Possibilities, potential and limitations. World Psychiatry 2012, 11, 153–155. [Google Scholar] [CrossRef] [PubMed]
  229. Perkovic, M.; Erjavec, G.; Strac, D.; Uzun, S.; Kozumplik, O.; Pivac, N. Theranostic Biomarkers for Schizophrenia. Int. J. Mol. Sci. 2017, 18, 733. [Google Scholar] [CrossRef]
  230. Dobber, J.; Latour, C.; de Haan, L.; Scholte op Reimer, W.; Peters, R.; Barkhof, E.; van Meijel, B. Medication adherence in patients with schizophrenia: A qualitative study of the patient process in motivational interviewing. BMC Psychiatry 2018, 18, 135. [Google Scholar] [CrossRef] [Green Version]
Table
Table 1. Summary of the drugs mentioned in the review assayed in clinical trials with their mechanisms of action, the quality of the evidence and the observed effect.
Table 1. Summary of the drugs mentioned in the review assayed in clinical trials with their mechanisms of action, the quality of the evidence and the observed effect.
Mechanism of ActionDrugQuality of EvidenceEffect ObservedReference
AntioxidantPUFAsRandomized trialCounteraction of cortical thickness[90]
N-acetylcysteineRandomized double-blind trialImprovement in cognitive speed[91]
MinocyclineRandomized double-blind trialsImprovement in information processing speed[92,93]
5-HT1A agonismTandospironeRandomized double-blind trialImprovement in executive function and verbal memory[94]
5-HT3 antagonismOndansetronMeta-analysisSlight improvement in some functions (visual memory)[95]
5-HT3 antagonism + α7 nicotinic agonismTropisetronRandomized double-blind trialImprovement in memory[96]
5-HT6 antagonismAVN-211Randomized double-blind trialContradictory effects on cognitive domains[97,98]
Non-selective GABA receptor agonistsBenzodiazepinesObservational studyAttention and working memory impairment[99]
GABA prodrugBL-1020Randomized double-blind trial (Phase 2)Improvement in a composite score[100]
Randomized double-blind trial (Phase 2b-3)No benefits[101]
H3 receptor antagonistABT-288Randomized double-blind trial (Phase 2)No benefits[102]
α7 nicotinic receptor agonistVareniclineMeta-analysisNo benefits[103]
EnceniclineRandomized double-blind trials (Phase 3)No benefits[104]
NeloniclineRandomized double-blind trial (Phase 2b)No benefits[105]
BradaniclineRandomized double-blind trial (Phase 2)No benefits[106]
M1 and M4 muscarinic receptors agonistXanomelineRandomized double-blind trial (pilot study)Slight improvement in verbal learning and memory function[107]
Acetylcholinesterase inhibitorGalantamineMeta-analysisNo clear improvement in memory, executive functioning, attention or reaction time[108]
NMDA receptor antagonistMemantineSystematic review of open label or double-blind trialsNo benefits[109]
Inhibitors of glycine transportersBitopertinRandomized double-blind trialNo benefits[110]
BI425809Randomized double-blind trial (Phase 2)Slight increase in a composite score[111]
Activator of glutamate metabotropic receptorsLY2140023Randomized double-blind trialNo benefit[112]
Allosteric activator of AMPA receptorsCX-516Randomized single-blind trialImprovement in attention and memory (combined with clozapine)[113]
Randomized double-blind trial (4 patients)No benefit[114]
D1 receptor positive allosteric modulator (PAM)ASP4345Randomized double-blind trial (Phase 2)No benefit[115]
Dopamine reuptake inhibitorModafinilSystematic reviewNo benefit[116]
AntidepressantsAntidepressants belonging to various classesMeta-analysisNo clear benefits of the combination of antidepressants and antipsychotics[117]
Phosphodiesterase 4 inhibitorRoflumilastRandomized double-blind trialVerbal memory improvement[118]
Phosphodiesterase 10 inhibitorTAK-063Randomized double-blind trial (Phase 2)No benefit[119]
Neuroprotective steroidDehydroepiandrosteroneRandomized double-blind trialSlight improvement in attention and visual and movement skills[120]
Neuroprotective steroidDehydroepiandrosteroneRandomized double-blind trialNo benefit[121]
Estrogen agonist in brainRaloxifeneRandomized double-blind trialsImprovement in verbal memory and other cognitive domains[122,123]
RaloxifeneRandomized double-blind trialNo benefit[124]
Progesterone precursorPregnenoloneRandomized double-blind trialImprovement in memory and working attention[121]
Randomized double-blind trialsNo benefit[125,126]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Martínez, A.L.; Brea, J.; Rico, S.; de los Frailes, M.T.; Loza, M.I. Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments. Int. J. Mol. Sci. 2021, 22, 9905. https://doi.org/10.3390/ijms22189905

AMA Style

Martínez AL, Brea J, Rico S, de los Frailes MT, Loza MI. Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments. International Journal of Molecular Sciences. 2021; 22(18):9905. https://doi.org/10.3390/ijms22189905

Chicago/Turabian Style

Martínez, Antón L., José Brea, Sara Rico, María Teresa de los Frailes, and María Isabel Loza. 2021. "Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments" International Journal of Molecular Sciences 22, no. 18: 9905. https://doi.org/10.3390/ijms22189905

APA Style

Martínez, A. L., Brea, J., Rico, S., de los Frailes, M. T., & Loza, M. I. (2021). Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments. International Journal of Molecular Sciences, 22(18), 9905. https://doi.org/10.3390/ijms22189905

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop