According to recent epidemiological data, schizophrenia affects 4 of every 1000 individuals around the world (Saha et al., 2005), and it can be considered the third leading cause of disability (Hyman, 2008). Schizophrenia is broadly characterized by three core symptoms: positive symptoms (hallucinations, delusions, grandiosity, paranoia, and suspiciousness); negative symptoms (blunted affect, social avoidance, poor rapport, lack of motivation, lack of spontaneity, and emotional withdrawal); and cognitive dysfunction (Tandon et al., 2009). Cognitive impairment is evident in around 85% of these patients (Keefe et al., 2003), and while working and declarative memory are strongly disrupted in schizophrenia (Mohs, 1995, Bilder et al., 2000 and Weickert and Goldberg, 2005), other cognitive domains may also be impaired, including attention, executive function, language/fluency, processing speed, and social cognition (Heinrichs and Zakzanis, 1998, Hutton et al., 1998, Conklin et al., 2000, Buchanan et al., 2005 and Braw et al., 2008; Figure 10.4). The cognitive dysfunction observed in patients with schizophrenia has long been considered to be the result of altered cortical-cerebellar-thalamic-cortical circuit activity (Andreasen et al., 1998). Interestingly, cognitive deficits are present early in the course of schizophrenia, before psychosis (Lencz et al., 2006 and Gonzalez-Blanch et al., 2008), and in patients without medication (Mohamed et al., 1999). At present, neurocognitive deficits found in schizophrenia are considered to constitute an endophenotype because they are stable and heritable (Green et al., 2004).
Beneficial and Detrimental Effects of Antipsychotic Treatments on Cognitive Function in Schizophrenic Patients
There are several antipsychotic medications approved by the FDA to alleviate the positive symptoms of schizophrenia. FDA-approved medications are typical and atypical antipsychotics that can treat positive symptoms with similar efficacy (Leucht et al., 2009). Typical antipsychotic drugs are antagonists or partial agonists of the dopamine D2 receptor, although they do not enhance cognitive function in patients with schizophrenia (Friedman et al., 2002 and Peuskens et al., 2005). In fact, they may negatively affect cognition because of their anticholinergic activity (Minzenberg et al., 2004). However, atypical antipsychotic drugs that combine partial agonism of the dopamine D2 receptor with antagonism at the serotonin 5-HT2A receptor may have positive effects on cognitive function in schizophrenic patients (Sumiyoshi et al., 2013).
In patients with persistent negative and cognitive symptoms, an antipsychotic (usually clozapine) is frequently prescribed along with another atypical antipsychotic, although this combination therapy is not always beneficial for improving negative or cognitive symptoms (Citrome, 2011). Given that the degree of magnitude and the extent of cognitive impairment is greater in schizophrenia than in bipolar disorder, even small improvements in cognition after pharmacological treatment can be readily detected. Thus, in contrast to what has been observed in bipolar disorder, the use of atypical antipsychotics (such as risperidone or quetiapine) in schizophrenia does not seem to negatively affect cognition (Keefe et al., 2007). Conversely, some atypical antipsychotics (particularly olanzapine or risperidone) may even improve some domains such as immediate memory, executive function, vigilance, verbal fluency, or visuospatial processing (Harvey and Keefe, 2001, Bilder et al., 2002, Lindenmayer et al., 2007 and Houthoofd et al., 2008), although they do not restore cognitive function to normal levels (Peuskens et al., 2005, Keefe et al., 2007, Davidson et al., 2009 and van Veelen et al., 2010). Hence, pursuing effective therapies for all cognitive deficits that occur in schizophrenia is the main focus of research into this disease.
Adjunct Treatments for Cognitive Dysfunction in Schizophrenia
At present, no medications have been approved by the FDA to treat cognitive impairments in schizophrenia. More than 50 clinical trials of patients with schizophrenia have been carried out, but the improvements in cognitive function achieved have been modest (Citrome, 2014). Given that the approaches to treat cognitive dysfunction in schizophrenia involve different types of drugs, we pay attention here to only the most relevant of these treatments (Figure 10.4).
Glutamatergic Targets: NMDA, AMPA, and Metabotropic Glutamate Receptors
Two neurotransmitter systems are believed to be critical in the pathophysiology of schizophrenia: the glutamatergic and dopaminergic systems (Kantrowitz and Javitt, 2010). Glutamate is an excitatory neurotransmitter found in the central nervous system, and it is critical in many brain functions, including cognition (Moghgaddam, 2003). Neuroimaging and pharmacological studies of schizophrenia have provided strong evidence of glutamatergic dysfunction; interestingly, blockers of NMDA receptors (such as ketamine or phencyclidine) reproduce many of the positive and negative symptoms of schizophrenia in healthy volunteers as well as induce cognitive impairment, whereas they exacerbate these symptoms in patients with schizophrenia (Javitt and Zukin, 1991, Krystal et al., 1994 and Morgan and Curran, 2006). These findings led to the hypothesis that hypofunctional NMDA receptor signaling may explain the positive, negative, and cognitive symptoms of schizophrenia (Coyle and Tsai, 2004, Javitt, 2009 and Gao, 2012).
Studies of experimental animals have examined the involvement of the ionotropic (AMPA, NMDA, and kainate) and metabotropic glutamate receptors in cognitive function. Moreover, because these receptors are important for learning and memory processes, clinical trials testing the efficacy of some agonists of these receptors on cognition have been performed.
Ionotropic and Metabotropic Glutamate Receptors
While several ampakines (positive modulators of AMPA-type glutamate receptors) have been found to improve learning and memory in animals, they were ineffective in enhancing cognition in patients with schizophrenia when given as adjuncts to antipsychotic drugs (Goff et al., 2008a and Goff et al., 2008b). Kainate receptors also have been identified as a therapeutic target and tested by administering topiramate, an anticonvulsant, as an adjunct to atypical antipsychotics. However, adjunctive topiramate treatment produced cognitive dulling in a randomized controlled study (Muscatello et al., 2011).
In humans, NMDA glutamate receptors in the prefrontal cortex are involved in executive function, those in the visual cortex are important in detecting movement, and those in the hippocampus are critical for learning and memory. Because such sensory and cognitive deficits are found in patients with schizophrenia (Kantrowitz and Javitt, 2011), most effort has concentrated on investigating the effects of drugs that could enhance NMDA receptor activity. NMDA receptors can only be activated in the presence of glutamate and glycine. Because glycine does not readily cross the blood–brain barrier, the effects of other drugs that act at the glycine coagonist site of the NMDA receptor, such as d-serine and d-cycloserine, have been tested. Although d-cycloserine was initially reported to improve executive function in patients with schizophrenia (Heresco-Levy et al., 2005), subsequent studies reported a low efficacy of d-cycloserine in ameliorating cognitive deficits in these patients (Buchanan et al., 2007). By contrast, d-serine has been reported to improve several symptom domains (Kantrowitz et al., 2010), and it was effective when administered as an adjunct with certain antipsychotics, such as risperidone or olanzapine, but not clozapine (Tsai and Lin, 2010; Figure 10.4).
Glycine Transporter-1 Inhibitors
At present, a novel therapeutic target for the treatment of schizophrenia is the use of glycine transporter-1 inhibitors, which may help increase the availability of glycine at the synapse (Chue, 2013). Indeed, clinical studies involving treatment with glycine transporter inhibitors such as sarcosine and bitopertin were found to improve some of the core symptoms associated with schizophrenia (Hashimoto, 2010 and Javitt, 2012). Remarkably, sarcosine as an adjunctive treatment with different antipsychotics improved several symptoms in schizophrenic patients, yet not when combined with the antipsychotic clozapine (Tsai and Lin, 2010). This seems to be related to the glycine transport inhibitory activity of clozapine itself (Javitt et al., 2005). In two recent clinical trials, the glycine transporter inhibitor bitopertin was found to be well tolerated and to reduce positive and negative symptoms in patients with schizophrenia, although pro-cognitive effects were not investigated (Bugarski-Kirola et al., 2014 and Umbricht et al., 2014).
The potential therapeutic utility of metabotropic receptors also has been investigated; initially, a selective agonist for the metabolic Glu2/3 receptor was found to effectively treat positive and negative symptoms of schizophrenia (Patil et al., 2007). However, further studies did not replicate these findings, and no more clinical trials using this agonist have been carried out.
Given that acetylcholine is a critical neurotransmitter in learning and memory processes, several studies have investigated the potential benefits of using acetylcholinesterase inhibitors to improve cognitive function in schizophrenia (Buchanan et al., 2003). The use of donepezil, an acetylcholinesterase inhibitor, indirectly increases the levels of acetylcholine in the brain through reuptake blockade, as seen in case report studies, and a general improvement in attention, memory, coherent speech, and word fluency was reported in an open-label trial (MacEwan et al., 2001, Stryjer et al., 2002 and Chung et al., 2009). By contrast, in other studies donepezil was not effective in improving cognitive function in patients with schizophrenia when added to risperidone (Fagerlund et al., 2007 and Akhondzadeh et al., 2008), ziprasidone (Friedman et al., 2002), or other atypical antipsychotics (Keefe et al., 2008). Moreover, a recent prospective assessment of the benefits of donepezil on cognitive impairment in schizophrenia failed to support the use of this medication (Thakurathi et al., 2013). Inconclusive results were obtained with galantamine, another cholinesterase inhibitor. Thus, while there are indications that these drugs may be effective in treating cognitive impairments in people with schizophrenia (Schubert et al., 2006, Lee et al., 2007 and Buchanan et al., 2008), these beneficial effects on cognition were been found in all these patients (Dyer et al., 2008 and Sacco et al., 2008). In addition, other studies observed no benefits on cognition after treatment with rivastigmine, another acetylcholinesterase inhibitor (Sharma et al., 2006).
Nicotinic and Muscarinic Acetylcholine Receptors as Targets for Cognitive Enhancement in Schizophrenia
The fact that up to 88% of people with schizophrenia are smokers (Moss et al., 2009) led to the formulation of two hypotheses: (1) the self-mediation hypothesis, suggesting that patients smoke to alleviate their psychiatric symptomatology and the side effects of antipsychotics (Khantzian, 1985 and Winterer, 2010); and (2) the addition vulnerability hypothesis (Chambers et al., 2001), which proposes that schizophrenia and tobacco addiction not only share genetic factors but also brain alterations (George, 2007). Nicotine is the main psychoactive element in tobacco, and after inhalation of tobacco smoke into the lungs, nicotine is rapidly delivered in the bloodstream, reaching the brain and activating nicotinic and muscarinic receptors. In addition, nicotine affects the release of other neurotransmitters including dopamine, glutamate, and γ-aminobutyric acid. Several studies have confirmed that nicotine administration to patients with schizophrenia enhances attention, reaction time, working memory, as well as verbal and spatial memory (Levin et al., 1996, Depatie et al., 2002, Smith et al., 2002 and Harris et al., 2004; AhnAllen et al., 2008). Because patients with schizophrenia who smoke have low rates of quitting, different pharmacotherapies that act on central nicotinic receptors (nicotine replacement, bupropion, and varenicline) have been tested for smoking cessation (George and O’Malley, 2004). Interestingly, varenicline has not only proven to be effective for smoking cessation but also in improving attention, executive function, as well as verbal learning and memory (Smith et al., 2009, Hong et al., 2011 and Shim et al., 2012). Furthermore, a recent meta-analysis highlighted the positive effects of using cholinergic receptor agonists as adjunct pharmacotherapy for cognitive deficits in schizophrenia (Choi et al., 2013). There is also recent evidence that xanomeline, an M1/M4 agonist, significantly restores cognitive deficits with repeated dosing (Melancon et al., 2013).
At present, several pharmaceutical companies are carrying out clinical trials to define the utility of different agonists of nicotinic receptors for treating cognitive impairments in patients with schizophrenia and Alzheimer’s disease. Their research is mainly focused on the α7 nicotinic receptors (α7nAChR)—because these receptors are abundant in brain areas involved in attention and long-term and working memory—and testing several new nicotinic agonists. Thus, some anabaseine derivatives that are partial agonists of α7nAChR have been tested, but with different results. While some authors indicated that 3-[2,4-dimethoxybenzylidene]anabaseine improved attention and working memory in non-smokers with schizophrenia (Olincy and Freedman, 2012), others reported that it did not ameliorate cognitive deficits in patients with schizophrenia (Freedman et al., 2008). TC-5619, a full agonist of α7nAChR, was recently reported to produce some cognitive benefits in schizophrenia (Lieberman et al., 2013). Moreover, encenicline (EVP-6124) is another agonist that is well tolerated; in addition to reducing negative symptoms, it also enhances cognitive function in schizophrenic patients taking antipsychotics (Mazurov et al., 2012 and Preskorn et al., 2014; Figure 10.4).
Drugs that increase noradrenergic activity have been found to improve ADHD. Because attention functions are affected in patients with schizophrenia, several drugs that target the noradrenergic system have been tested in schizophrenia. Thus, treatment with guanfacine, a selective α2 adrenergic receptor agonist, was reported to improve not only attention (Friedman et al., 2001) but also cognition (McClure et al., 2007). However, other noradrenergic transport inhibitors that are used in ADHD, such as atomoxetine, did not enhance cognition (Friedman et al., 2008 and Kelly et al., 2009).
5-HT1A Receptor Agonists
Because low dopamine concentrations in the prefrontal cortex are considered to be one of the main biological substrates underlying several of the cognitive impairments observed in schizophrenia, drugs that may enhance dopamine neurotransmission in this brain area may improve cognition in this psychiatric disease (Sawaguchi and Goldman-Rakic, 1991 and Murphy et al., 1996). It was postulated that potential benefits could be obtained by administering atypical antipsychotics that act as D2/D5-HT2A receptor antagonists together with 5-HT1A receptor agonists that can also enhance dopamine release in the prefrontal cortex (Ichikawa et al., 2001). Interestingly, some atypical antipsychotics (e.g., clozapine, olanzapine, and ziprazidone) are also partial 5-HT1A receptor agonists what has been associated to their poor capability to improve negative and cognitive symptoms of schizophrenia (Li et al., 1998). Thus, administration of tandospirone, a 5-HT1A agonist, to patients with schizophrenia receiving stable doses of atypical antipsychotics improved executive function and verbal memory (Sumiyoshi et al., 2001). The same research group subsequently found that when administered with atypical antipsychotics, buspirone improved attention (Sumiyoshi et al., 2007).
Psychostimulants increase the release of dopamine and norepinephrine, and they are widely used to treat attention disorders (Mattay et al., 2000). In addition, some beneficial effects on processing speed, attention, executive function, working memory accuracy, and language production were reported when d-amphetamine was concomitantly administered with antipsychotics in single-dose trials (Barch and Carter, 2005 and Pietrzak et al., 2010). However, long-term treatment with psychostimulants is not recommended because psychostimulants can worsen psychosis. Nevertheless, d-amphetamine improved the reaction times of spatial working memory and in Stroop tasks in both participants with schizophrenia and controls, and it increased language production and improved working memory accuracy in those with schizophrenia (Barch and Carter, 2005).
Modafinil is a wakefulness-promoting medication that was reported to improve attention and executive functions, as well as short-term verbal and visual memory, in patients with schizophrenia (Hunter et al., 2006, Turner et al., 2004, Sevy et al., 2005 and Morein-Zamir et al., 2007; Figure 10.4). However, other studies demonstrated that modafinil had no positive effects on cognitive dysfunction in schizophrenia (Freudenreich et al., 2009, Kane et al., 2010 and Lohr et al., 2013). Although the reasons remain unclear, there are case reports in the literature indicating that modafinil can worsen psychosis in patients with schizophrenia (Narendran et al., 2002). Therefore, the use of this medication to improve cognition in schizophrenia is more than questionable.
Why Is It Difficult to Restore Cognition in Schizophrenia?
The fact that most drugs assessed had only modest effects or failed to restore cognitive function in patients with schizophrenia has led researchers to postulate that the cognitive impairment observed in schizophrenic patients is caused by structural brain changes (including changes in cortical structure and the loss of gray matter) (DeLisi et al., 2006), modifications that are unlikely to be reverted by pharmacological methods. In addition, it is possible that concomitant treatment with antipsychotic medications may diminish the positive effects of nootropics on cognitive impairment in patients with schizophrenia. A significant blockade of dopamine D2 receptor is typically necessary to achieve a clinical response in schizophrenic patients (Laruelle et al., 1998), a fact that may alter neural plasticity. In addition, atypical antipsychotics can act through 5-HT2A receptors and affect the serotonergic system, which is known to play a critical role in the regulation of other neurotransmitter systems. In addition, it is possible that the use of antipsychotics impairs the pro-cognitive effects of other drugs, or that these drugs might increase the side effects of atypical antipsychotics. Finally, the appropriate dose of the nootropic drug may differ in schizophrenic patients taking antipsychotic medication. Thus, doses of procholinergic medications that are typically used in Alzheimer’s disease, in which an extensive loss of cholinergic neurons occur, are probably not appropriate to treat schizophrenic patients who do not suffer from comparable cholinergic functional impairment.