РКИ: Влияние противовирусной терапии на когнитивную симптоматику шизофрении у больных с HSV-1

Abstract

Objective To test our hypothesis that valacyclovir, an antiherpes virus–specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1).

Methods Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response.

Results Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen’s d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve.

Conclusions Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.

Antiherpes Virus–Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial

Связь вируса простого герпеса первого типа со снижением когнитивных функций у больных шизофренией

Latent infection with neurotropic herpes viruses, such as herpes simplex virus, type 1 (HSV1), has been generally considered benign in most immunocompetent individuals except for rare cases of encephalitis. However, several recent studies have shown impaired cognitive functions among individuals with schizophrenia exposed to HSV1 compared with schizophrenia patients not exposed to HSV1. Such impairments are robust and are prominently observed in working memory, verbal memory, and executive functions. Brain regions that play a key role in the regulation of these domains have shown smaller volumes, along with correlation between these morphometric changes and cognitive impairments in schizophrenia. One study noted temporal decline in executive function and gray matter loss among HSV1-exposed first-episode antipsychotic-naïve schizophrenia patients. Furthermore, a proof-of-concept double-blind placebo-controlled trial indicated improvement in cognitive performance following supplemental anti-herpes–specific medication among HSV1 seropositive schizophrenia patients. Cross-sectional studies have also identified an association between HSV1 exposure and lesser degrees of cognitive impairment among healthy control individuals and patients with bipolar disorder. These studies fulfill several Bradford-Hill criteria, suggesting etiological links between HSV1 exposure and cognitive impairment. Exposure to other human herpes viruses such as cytomegalovirus and herpes simplex virus type 2 (HSV2) may also be associated with cognitive impairment, but the data are less consistent. These studies are reviewed critically and further lines of enquiry recommended. The results are important from a public health perspective, as HSV1 exposure is highly prevalent in many populations.

 Exposure to Herpes Simplex Virus Type 1 and Cognitive Impairments in Individuals With Schizophrenia

Оценка качества ремиссии и шкала Гамильтона

Objective: In treatment studies of depression, remission is typically defined narrowly, based on scores on symptom severity scales. Patients treated in clinical practice, however, define the concept of remission more broadly and consider functional status, coping ability, and life satisfaction as important indicators of remission status. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined how many depressed patients in ongoing treatment who scored in the remission range on the 17-item Hamilton Depression Rating scale (HDRS) did not consider themselves to be in remission from their depression. Among the HDRS remitters, we compared the demographic and clinical characteristics of patients who did and did not consider themselves to be in remission.

Method: From March 2009 to July 2010, we interviewed 274 psychiatric outpatients diagnosed with DSM-IV major depressive disorder who were in ongoing treatment. The patients completed measures of depressive and anxious symptoms, psychosocial functioning, and quality of life.

Results: Approximately one-half of the patients scoring 7 and below on the HDRS (77 of 140 patients for whom self-reported remission status was available) did not consider themselves to be in remission. The self-described remitters had significantly lower levels of depression and anxiety than the patients who did not consider themselves to be in remission (P < .001). Compared to patients who did not consider themselves to be in remission, the remitters reported significantly better quality of life (P < .001) and less functional impairment due to depression (P < .001). Remitters were significantly less likely to report dissatisfaction in their mental health (P < .01), had higher positive mental health scores (P < .001), and reported better coping ability (P < .001).

Conclusions: Some patients who meet symptom-based definitions of remission nonetheless experience low levels of symptoms or functional impairment or deficits in coping ability, thereby warranting a modification in treatment. The findings raise caution in relying exclusively on symptom-based definitions of remission to guide treatment decision-making in clinical practice.

Why Do Some Depressed Outpatients Who Are in Remission According to the Hamilton Depression Rating Scale Not Consider Themselves to Be in Remission?

Когнитивное снижение при приёме статинов: распространенность и методы коррекции

DATA SYNTHESIS: Reports of statin-associated cognitive impairment were found primarily in observational studies (eg, case reports/series). One randomized controlled trial demonstrated that simvastatin impaired some measures of cognition compared to placebo. Conversely, in the majority of randomized controlled trials and observational studies, statins were found to have either a neutral or beneficial effect on cognition. Preliminary data suggest that statins that are less lipophilic (ie, pravastatin and rosuvastatin) may be less likely to contribute to cognitive impairment due to limited penetration across the blood-brain barrier. These drugs would be a logical alternative in cases where cognitive impairment secondary to another statin is suspected.
CONCLUSIONS: Despite several reports of statin-associated cognitive impairment, this adverse effect remains a rare occurrence among the totality of the literature. If statin-associated cognitive impairment is suspected, a trial discontinuation can reveal a temporal relationship. Switching from lipophilic to hydrophilic statins may resolve cognitive impairment. The vascular benefits and putative cognitive benefits outweigh the risk of cognitive impairment associated with statin use; therefore, the current evidence does not support changing practice with respect to statin use, given this adverse effect.

 Is Statin-Associated Cognitive Impairment Clinically Relevant? A Narrative Review and Clinical Recommendations

Антихолинэстеразные свойства шалфея и влияние на когнитивные функции

Extracts of sage (Salvia officinalis/lavandulaefolia) with terpenoid constituents have previously been shown to inhibit cholinesterase and improve cognitive function. The current study combined an in vitro investigation of the cholinesterase inhibitory properties and phytochemical constituents of a S. lavandulaefolia essential oil, with a double-blind, placebo-controlled, balanced crossover study assessing the effects of a single dose on cognitive performance and mood. In this latter investigation 36 healthy participants received capsules containing either 50 µL of the essential oil or placebo on separate occasions, 7 days apart. Cognitive function was assessed using a selection of computerized memory and attention tasks and the Cognitive Demand Battery before the treatment and 1-h and 4-h post-dose. The essential oil was a potent inhibitor of human acetylcholinesterase (AChE) and consisted almost exclusively of monoterpenoids. Oral consumption lead to improved performance of secondary memory and attention tasks, most notably at the 1-h post-dose testing session, and reduced mental fatigue and increased alertness which were more pronounced 4-h post-dose. These results extend previous observations of improved cognitive performance and mood following AChE inhibitory sage extracts and suggest that the ability of well-tolerated terpenoid-containing extracts to beneficially modulate cholinergic function and cognitive performance deserves further attention.

Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults

Перспективные стратегии лечения когнитивной симптоматики шизофрении

A randomized, double-blind, placebo-controlled study demonstrated that members of a sarcosine (2 g/day) group showed greater reductions in their Positive and Negative Syndrome Scale (PANSS) total scores than members of a placebo group or D-serine (2 g/day) group, suggesting that sarcosine is superior to D-serine in that benefits both patients with long-term stable disease and also acutely ill persons with schizophrenia .

Furthermore, a randomized, double-blind study reported that sarcosine (2 g/day) alone was effective in the treatment of acutely symptomatic drugfree patients with schizophrenia.

Nonetheless, all these findings suggest that GlyT-1 inhibition could be a novel pharmacotherapeutic target for enhancing cognitive dysfunction in schizophrenia and several clinical trials are underway with very promising results.

Gaining a better understanding of the role of GlyT-1 in the treatment of cognition in schizophrenia is expected to provide new perspectives for treating this disorder. The pharmacological modulation of glycine modulatory sites on NMDA receptors by GlyT-1 inhibitors could be beneficial in the treatment of the cognitive deficits and psychosis associated with schizophrenia and other psychiatric conditions.

Galantamine, which acts as both a cholinesterase inhibitor and a nicotinic receptor modulator had the best result. The cognitive effects of galantamine may be accentuated by its nicotinic allosteric agonist action, which can improve attention and memory. Furthermore, galantamine appears to more powerfully elevate frontal cortical dopamine levels than cholinesterase inhibitors such as donepezil. This biological effect may be significant since frontal dopaminergic deficits have been proposed to underlie cognitive impairment in schizophrenia.

Importantly, significant improvement in attentional set shifting was seen. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.

Patient with schizophrenia manifest signs of a dysregulation of the NPY system. Extensive preclinical studies suggest that the neuropeptide Y (NPY) counteracts the behavioral consequences of stress and anxiety to and maintain emotional homeostasis. Thus it is involved in stress regulation and coping.

Treatment of Cognition in Schizophrenia

Когнитивная дисфункция при злоупотреблении психоактивными веществами

Novel Therapies for Cognitive Dysfunction Secondary to Substance Abuse

Влияние возраста приёма терапии эстрогеном на когнитивное снижение пожилом возрасте

Specifically, taking estrogen around the time of menopause is linked to a lowered risk of dementia for women as they enter old age, but estrogen therapy in late life is associated with a higher risk for dementia, according to a retrospective study led by Dr. Kristine Yaffe, chief of geriatric psychiatry at the San Francisco VA Medical Center.

Age During Estrogen Therapy May Impact Later Dementia

Женьшень и когнитивные функции

There is a lack of convincing evidence to show a cognitive-enhancing effect of Panax ginseng in healthy people and no high-quality evidence about its efficacy in patients with dementia, according to a report published online December 8 in the Cochrane Database of Systematic Reviews.

"Ginseng appeared to have some beneficial effects on cognition, behavior, and quality of life. However, at present, recommendations of continuing taking or stopping cannot be made due to lack of high-quality evidence," first study author JinSong Geng, of the Evidence-based Medicine Center, Medical School of Nantong University in Jiangsu, China, told Medscape Medical News.

Evidence That Ginseng Boosts Brain Function 'Not Convincing'

Циклосерин и аутизм

Researchers have launched a pilot clinical trial of a new medication aimed at relieving the sociability problems of adolescent and young adult patients with autism spectrum disorders (ASD).

The medication used, D-Cycloserine, originally was developed to treat tuberculosis, but previous studies showed, by chance, that it might change social behavior.

New Drug May Ease Social Impairment of Autism

Когнитивное снижение при шизофрении

The cholinergic system

In the 1970s, it was found that Alzheimer disease was caused primarily by the degeneration of acetylcholine (ACH) or cholinergic neurons that emanate from the nucleus basalis of Meynert. This landmark finding was on the one hand startling, since it had been thought that more widespread neurochemical deficits would be found. On the other hand, it was consistent with decades of work that showed that anticholinergic medications disrupted cognitive functions and, in particular, memory in nonpatient populations. Regarding schizophrenia, a small but compelling literature indicates that anticholinergics counter the therapeutic action of neuroleptics.14 Findings from recent clinical trials indicate that both muscarinic and nicotinic agonists hold promise in the treatment of cognitive symptoms of schizophrenia.
While awaiting new cholinergic agonists, we can begin to address the cholinergic deficit in schizophrenia. First is to “do no harm” by avoiding the use of highly anticholinergic regimens that can exacerbate cognitive deficits. For example, if the use of anticholinergics to treat extrapyramidal syndrome (EPS) appears to be exacerbating cognitive symptoms, consider amantadine, which treats EPS but is not an anticholinergic. In a double-blind, cross-over study, Silver and Geraisy17 showed that biperiden (an anticholinergic), but not amantadine, interferes with memory and, in particular, visual memory.

It is extremely important to help those with schizophrenia to stop smoking; bear in mind, however, that they may smoke because nicotine improves their cognitive symptoms. While the smoking itself should cease, nicotine replacement therapy may need to be continued indefinitely to prevent a worsening of cognition.

D1 dopamine–mediated processes

A link has been shown between prefrontal dysfunction and the cognitive deficits observed in schizophrenia.18,19 Goldman–Rakic20 has suggested that disruption of D1 dopamine receptor activity can contribute to the cognitive symptoms of schizophrenia, while stimulation of the D1 dopamine receptor improves cognition.21

Modafinil has been found to improve short–term verbal memory span, visual memory, and spatial planning in patients with chronic schizophrenia. It is reasonable to hypothesize that it does this, at least in part, by stimulating D1 dopamine receptors.22

Hypofunction of the NMDAglutamate system

In the 1980s, phencyclidine (PCP), “angel dust,” was a widely used recreational drug of abuse. Some people were brought to psychiatric emergency departments with schizophrenia–like symptoms, including positive, negative, and cognitive symptoms. The hypothesis that schizophrenia may be a result of hypofunction of the NMDA glutamate system emerged when it was found that PCP blocked calcium efflux through channels controlled by NMDA glutamate receptors.

In the NMDA glutamate system, glutamate binding to a subset of receptors leads to the opening of the calcium channel, but only if a second site is simultaneously occupied by either glycine or D–serine, both of which are released into the synapse by astrocytes. Glycine’s action is terminated when it binds to a glycine transporter protein and is brought back to the astrocytes where it is oxidized. High doses of dietary glycine added to antipsychotic regimens can lead to clinical improvement, but in clinical practice, glycine–induced nausea limits its utility.23

Recently, another promising strategy has emerged. Glycine levels in the synapses can be raised by glycine transport inhibitors that prevent glycine from entering the surroundingastrocytes. Consequently, more glycine remains in the synapse.

Several glycine transport inhibitors are presently in or are entering clinical trials. One promising candidate is N–methylglycine, or sarcosine.24 Preliminary studies indicate that added to antipsychotics, 1 to 2 g of sarcosine per day can lead to significant improvement in positive, negative, and cognitive symptoms.

Cognitive Symptoms in Schizophrenia Recognizing and Treating Cognitive Deficits in Schizophrenia

Влияние гипертензии и индекса массы тела на когнитивные функции больных шизофренией

Objective: In recent years there has been a greater appreciation of the elevated prevalence of cardiovascular risk factors in the schizophrenia population and the liability some treatments have for their development. These vascular risk factors are in turn important risk factors in the development of dementia and more subtle cognitive impairments. However, their impact on the cognitive functions of patients with schizophrenia remains underexplored. The authors investigated whether vascular risk factors influence the cognitive impairments of schizophrenia and whether their effects on cognition in schizophrenia are different from those observed in nonpsychiatric comparison subjects.

Method: The authors compared 100 patients with schizophrenia and 53 comparison subjects on cognitive test performance in 2x2 matrices composed of individual vascular risk factors and group (schizophrenia patients and comparison subjects).

Results: Hypertension exerted a significant negative effect on immediate delayed and recognition memory in both groups. Patients with schizophrenia and hypertension were adversely affected in recognition memory, whereas comparison subjects were not. A body mass index above 25 was associated with negative effects on delayed memory in both groups, although the association fell short of statistical significance.

Conclusions: Given that patients with schizophrenia have a higher prevalence of vascular risk factors than the general population and are undertreated for them, treatment of these risk factors may significantly improve cognitive outcome in schizophrenia.

The Effects of Hypertension and Body Mass Index on Cognition in Schizophrenia

Виагра, когнитивные функции, негативная симптоматика шизофрении

We know that sildenafil (Viagra) helps restore erectile functioning, but not many people know that it also has cognitive-enhancing and neuroprotective effects in rodents. A double-blind, placebo-controlled study from Iran by Akhondzadeh et al suggests that sildenafil can significantly improve negative symptoms of schizophrenia. The study may lead to an important adjunctive use of this drug if it is replicated with a larger sample. The putative mechanism is the inhibition of phosphodiesterase 5 (PDE5), resulting in increased cyclic guanosine monophosphate (cGMP), which may correct the hypofunctioning N-methyl-D-aspartic acid (NMDA) glutamate receptor believed to be associated with elevated dopamine in the mesolimbic tract (causing positive symptoms) and a decline in dopamine in the mesocortical tract (causing cognitive deficits and negative symptoms).

Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial

Интраназальный инсулин и когнитивные функции

A small, randomized trial of 2 doses of intranasal insulin showed improvements in memory and functioning and improved CSF biomarker profiles among patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) with treatment over placebo.

The SNIFF-120 trial was a 4-month, randomized, double-blind trial of placebo vs 2 doses of intranasal insulin: 20 or 40 IU daily. One hundred four patients with AD or amnestic MCI participated; patients with diabetes were excluded.

Intranasal Insulin Shows Benefit in Mild Cognitive Impairment and Alzheimer's Disease

Patients who received cognitive enhancement therapy demonstrated significantly greater preservation of gray matter volume over 2 years in the left hippocampus, parahippocampal gyrus, and fusiform gyrus, and significantly greater gray matter increases in the left amygdala (all corrected P < .04) compared with those who received enriched supportive therapy. Less gray matter loss in the left parahippocampal and fusiform gyrus and greater gray matter increases in the left amygdala were significantly related to improved cognition and mediated the beneficial cognitive effects of cognitive enhancement therapy.

Neuroprotective Effects of Cognitive Enhancement Therapy Against Gray Matter Loss in Early Schizophrenia

Влияние современных антиконвульсантов на когнитивные функции

"BACKGROUND: Antiepileptic drugs (AEDs) can be associated with neurotoxic side effects including cognitive dysfunction, a problem of considerable importance given the usual long-term course of treatment. Pregabalin is a relatively new AED widely used for the treatment of seizures and some types of chronic pain including fibromyalgia. We measured the cognitive effects of 12 weeks of pregabalin in healthy volunteers. METHODS: Thirty-two healthy volunteers were randomized in a double-blind parallel study to receive pregabalin or placebo (1:1). Pregabalin was titrated over 8 weeks to 600 mg/d. At baseline, and after 12 weeks of treatment, all subjects underwent cognitive testing. Test-retest changes in all cognitive and subjective measures were Z scored against test-retest regressions previously developed from 90 healthy volunteers. Z scores from the placebo and pregabalin groups were compared using Wilcoxon tests. RESULTS: Thirty subjects completed the study (94%). Three of 6 target cognitive measures (Digit Symbol, Stroop, Controlled Oral Word Association) revealed significant test-retest differences between the pregabalin and placebo groups, all showing negative effects with pregabalin (p < 0.05). These cognitive effects were paralleled by complaints on the Portland Neurotoxicity Scale, a subjective measure of neurotoxicity (p < 0.01). CONCLUSION: At conventional doses and titration, pregabalin induced mild negative cognitive effects and neurotoxicity complaints in healthy volunteers. These effects are one factor to be considered in the selection and monitoring of chronic AED therapy. Class of Evidence: This study provides Class I evidence that pregabalin 300 mg BID negatively impacts cognition on some tasks in healthy volunteers."

Cognitive effects of pregabalin in healthy volunteers: a double-blind, placebo-controlled trial.

"OBJECTIVE: To evaluate the cognitive effects of topiramate (TPM) and gabapentin (GBP). METHODS: Forty healthy volunteers were randomized to a 12-week course of TPM, GBP, or placebo. Doses were gradually escalated over 10 weeks to a maximum of 400 mg/day of TPM or 3,600 mg/day of GBP or to the highest tolerated dose. Subjects were interviewed and examined biweekly. Cognitive testing was performed prior to initiating the drug and again 12 weeks later, at least 2 weeks after achieving plateau dosing. For each subject and cognitive measure, test-retest Z scores were calculated based on regression equations derived from 73 healthy volunteers. Group comparisons utilized the Wilcoxon test. RESULTS: There were significant TPM vs GBP and TPM vs placebo differences in test-retest Z scores for four of six target cognitive measures (Digit Symbol, Story Recall, Selective Reminding, Controlled Oral Word Association), always indicating worse retest performance for subjects receiving TPM. Overall, 12 of 24 cognitive measures were similarly affected. TPM effects were large, and several target measures averaged >2 SD of negative change. One measure was significantly affected by GBP. CONCLUSIONS: Topiramate (TPM) impaired cognitive test performance, whereas gabapentin had minimal effects. The effects of TPM were of sufficient magnitude potentially to affect daily and occupational function."

Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers.

Possible Dose-Side Effect Relationship of Antipsychotic Drugs: Expert Commentary

Нелекарственная терапия при шизофрении

Treatments
Medication. All participants received Food and Drug Administration-approved antipsychotic medications for the treatment of schizophrenia, schizoaffective disorder, and schizophreniform disorder as indicated by a study psychiatrist. Medication changes were allowed, although every effort was made to stabilize participants on a tolerable and efficacious antipsychotic regimen before the initiation of psychosocial treatment. All participants were seen by a clinical nurse specialist at least biweekly to monitor medication side effects and efficacy. Most participants (>98%) were given second-generation antipsychotics throughout the study, and no significant differences emerged with regard to antipsychotic dosage, type, or clinician-estimated compliance between treatment groups. [A table detailing the between-group differences in baseline demographic, clinical, and medication characteristics is available as an online supplement to this article at ps.psychiatryonline.org.]

Cognitive enhancement therapy. CET is a comprehensive, developmental approach to the remediation of social and nonsocial cognitive deficits in schizophrenia. It seeks to facilitate the development of adult social-cognitive milestones (such as perspective taking and appraisal of one's social context) by shifting thinking from reliance on effortful, serial processing to a "gistful" and spontaneous abstraction of social themes. The treatment consists of approximately 60 hours of computer-assisted neurocognitive training in attention, memory, and problem solving and 45 social-cognitive group sessions that use experiential learning opportunities to foster the development of social wisdom and success in interpersonal interactions. A broad, theoretically driven array of social-cognitive abilities are targeted in the social-cognitive groups, which range from abstracting the "gist" or main point in social interactions to perspective taking, social context appraisal, and emotion management (39,43). Participants engage in the social-cognitive groups by responding to unrehearsed social exchanges, presenting homework, participating in cognitive exercises that focus on experiential learning, providing feedback to peers, and chairing homework sessions. CET typically begins with approximately three months of weekly one-hour neurocognitive training in attention, after which participants begin the weekly 1.5-hour social-cognitive groups. Neurocognitive training then proceeds concurrently with social-cognitive groups throughout the remaining course of treatment. A complete description of the treatment has been provided elsewhere (16).

Enriched supportive therapy. Enriched supportive therapy (EST) is an illness management and psychoeducation approach that draws on components of the basic and intermediate phases of the demonstrably effective personal therapy (44). In this approach, outpatients are seen on an individual basis to learn and practice stress management techniques designed to forestall late postdischarge relapse and enhance adjustment. The EST treatment is divided into two phases. Phase 1 focuses on basic psychoeducation about schizophrenia, the role of stress in the disorder, and ways to avoid or minimize stress. Phase 2 involves a personalized approach to the identification and management of life stressors that pose particular challenges to adequate social and role functioning. Participants move through the two phases of EST at their own pace, although each phase is typically provided for a year. By design, phase 1 was provided on a weekly basis, and phase 2 was provided on a biweekly basis. Although no attempt was made to match CET and EST approaches with regard to hours of treatment, EST served as the active control for this trial, in part to control for the potential effects on outcome of illness management and education interventions (45), which are provided in both CET and EST. All psychosocial interventions were administered by three master's-level psychiatric nurse specialists, and clinical supervision was provided by the two treatment developers.

Cognitive Enhancement Therapy for Early-Course Schizophrenia: Effects of a Two-Year Randomized Controlled Trial

Снижение когнитивных функций у больных шизофренией

Cognitive impairment in schizophrenia

Эффект модафинила на познавательные функции больных шизофренией

A Review of the Effects of Modafinil on Cognition in Schizophrenia