Curr Psychiatry Rep (2015) 17:32 DOI 10.1007/s11920-015-0570-4
SCHIZOPHRENIA AND OTHER PSYCHOTIC DISORDERS (SJ SIEGEL, SECTION EDITOR)
Neurology Issues in Schizophrenia Katharina Hüfner & Beatrice Frajo-Apor & Alex Hofer
# Springer Science+Business Media New York 2015
Abstract Schizophrenia ranks among the leading causes of disability worldwide. The presence of neurological signs cooccurring with the psychiatric symptoms is indicative of an organic brain pathology. In the present article, we review the current literature on neurology issues in schizophrenia. Firstly, common neurological signs found in patients with schizophrenia (neurological soft signs and smell abnormalities) and their association with imaging findings are reviewed. Secondly, the significant association of schizophrenia with epilepsy and stroke is described as well as the absent association with other organic brain diseases such as multiple sclerosis. Thirdly, we discuss the potential role of NMDA receptor antibodies in schizophrenia. Fourthly, neurological side effects of antipsychotic drugs and their treatment are reviewed; and lastly, we discuss neurocognitive deficits in patients with schizophrenia and their treatment. The focus of the review remains on articles with relevance to the clinician.
growing understanding of the pathophysiological mechanisms leading up to the phenotype of schizophrenia, many questions still remain unsolved. Indisputably, schizophrenia is a highly heritable disease . Since the genes responsible for the phenotype of schizophrenia are expressed not only in the brain but also in several tissues and cellular types , schizophrenia can be considered a systemic disease. It is thus associated with a high rate of somatic comorbidities. Therefore, the clinical management of schizophrenia patients requires expertise beyond primary psychiatric issues. This current review aims to highlight some important aspects concerning neurological soft signs in schizophrenia, the association of neurological diseases with schizophrenia, and medication issues. The emphasis is on clinically relevant topics and studies published in the last 3 years have been taken into account, without aiming to achieve a complete coverage.
Introduction Growing evidence points towards the presence of an organic brain pathology in first-episode untreated schizophrenia  and neurological signs co-occurring with the psychiatric pathology are thus regarded a trait feature of schizophrenia [2, 3•]. Despite This article is part of the Topical Collection on Schizophrenia and Other Psychotic Disorders K. Hüfner (*) : B. Frajo-Apor : A. Hofer Department of Psychiatry & Psychotherapy, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria e-mail: [email protected]
Findings of Neurological Soft Signs From Structural and Functional Imaging Studies So-called neurological soft signs (NSS) have conventionally been defined as subtle findings in the neurological examination with no definite localizing feature [5•]. Typically, they are classified into signs relating to motor coordination, sequencing of complex motor tasks, sensory-motor integration, and disinhibition . So far, a number of scales have been developed to measure such signs, e.g., the NSS Neurological Evaluation Scale (NES)  and the Cambridge Neurological Inventory (CNI) . From a neurological point of view, this terminology seems misleading since the neurological deficits might be Bsubtle,^ but neither are those findings Balmost insignificant^ nor Bindicative of a harmless disease,^ two possible implications of the term Bsoft.^ Also the Bnon-localizing^
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feature of the so called NSS is challenged in recent imaging studies in which substrates of morphofunctional alterations are associated with distinct pathologies commonly classified as Bsoft signs.^ In a meta-analysis of structural magnetic resonance imaging (MRI) studies, which included not only patients with schizophrenia but also those with related psychotic disorders, NSS were associated with bilateral atrophy of the precentral gyrus, the left postcentral gyrus, the left inferior frontal gyrus, the right temporal lobe, the left inferior parietal lobule, the thalamus, and the cerebellum. In this context, both gray and white matter abnormalities were detected (Fig. 1). In the same study, a meta-analysis of functional MRI studies (using different variations of a go/no go paradigm frequently
used to measure response inhibition) was also performed, which showed that NSS-related tasks were significantly associated with altered brain activation in the right inferior frontal gyrus, the left superior temporal gyrus, the globus pallidus and putamen, and the cerebellum [5•]. The authors concluded that these data support the concept of NSS as a manifestation of the cerebello-thalamo-prefontal brain network dysfunction in schizophrenia and related psychotic disorders [5•]. While the reported meta-analysis helps to specify the vague concept of NSS by identifying specific brain regions involved, a major limitation is that, in addition to patients with schizophrenia, those with Brelated psychotic disorders,^ such as bipolar disorder, borderline personality disorder, and obsessive-
a Inferior frontal gyrus
Inferior frontal gyrus
c Prefrontal gyrus
Middle temporal gyrus 1.5
Fig. 1 (a) Activation likelihood estimation (ALE) of structural magnetic resonance imaging studies in patients with neurological soft signs, adapted from Zhao et al. [5•]. Red labels are the ALE meta-analysis results of the gray matter foci negatively correlated with neurological soft signs (NSS) scores. Blue labels are the ALE meta-analysis results of the white matter foci negatively correlated with the NSS scores (P<.05, false discovery rate corrected). (b, c) Cortex morphology (gyrification/ sulcation) as a marker of brain development and the correlation with NSS, adapted from Gay et al. . Lateral views of the left hemispheres of two subjects illustrating in (b) a low degree of overall sulcation (sulcal index) in a first-episode psychosis patient with NSS and in (c) a high degree of
overall sucation in a first-episode psychosis patient without NSS. The gray matter ribbon has been removed to emphasize the folding surface in the depth of the sulci. In (d) the bar plots (mean±1 SD) of the sulcal index is shown in paitents with NSS (red) and without NSS (blue) for the left and right hemispheres. (From Gay, Plaze, Oppenheim, et al.: Cortex Morphology in First-Episode Psychosis Patients with Neurological Soft Signs, Schizophrenia Bulletin, 2013 and Zhao, Li, Huang, et al.: Neurological Soft Signs are not BSoft^ in Brain Structure and Functional Networks: Evidence from ALE Meta-Analysis, Schizophrenia Bulletin, 2014, by permission of Oxford University Press)
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compulsive disorder, were included. A second limitation, also stated by the authors themselves, is the fact that the NSS scales were considered as a whole, while in the fMRI analysis, only one paradigm was used, which only assessed the functional deficit of one specific neurological soft sign (disinhibition). Gray matter tensor-based morphometry was used in a longitudinal study to compare patients with first-episode schizophrenia to healthy control subjects. Patients were dichotomized into those with a decrease in NSS scores over time and those with persistently elevated scores (10 per group). The latter showed much more widespread alterations in gray matter than those with decreasing NSS scores . It is puzzling that no direct comparison between the two patient groups was performed, and accordingly, no conclusion can be drawn regarding potential differences in brain morphometry between the two groups . Three studies with an overlapping patient cohort of first-episode or recent-onset schizophrenia investigated the association of NSS, which were assessed using the Heidelberg scale, with different morphometric markers. In sum, higher NSS scores were associated with reduced brain stem volume  and with changes in cortical thickness in the paracentral gyrus, the postcentral lobule, the precuneus, the inferior parietal lobule, and the temporal lobe . In addition, shape changes in pons and midbrain as well as morphometric alterations of the basal ganglia were found [9, 11]. Cortex morphology (gyrification/sulcation) as a marker of brain development and thus neurodevelopmental deviation was assessed in 44 patients with first-episode psychosis (Fig. 1). Reductions of cortical sulcation in both hemispheres were found in patients with NSS as compared to those with nonsignificant NSS. Exploratory analyses revealed correlations between NSS dimensional subscores and distinct regional cortical sulcation. The authors conclude that their findings provide evidence for the affliction of distinct neurodevelopmental pathways in patients with NSS [3•]. Correlation of NSS With the Course of Schizophrenia A longitudinal study of 110 first-episode psychosis patients (53 with schizophrenia) younger than 18 years of age revealed more NSS in patients than controls at baseline and at the 2year follow-up, suggesting them to be a trait marker of the investigated diseases . Correlation analyses between subscales of the Neurological Evaluation Scale and clinical and pharmacological parameters were also performed, but only p values without correction for multiple comparisons were reported using a quite liberal statistical threshold. Accordingly, further replication is warranted. In a 4-year longitudinal study of 68 first-episode patients with schizophrenia, a connection between the dynamics of NSS (as measured by the Neurological Evaluation Scale) and the clinical course of the disease was found. While NSS
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subscales (sensory integration, sequencing of motor acts) decreased in remitters, an increase in the subscale Bothers^ (which includes signs such as primitive reflexes, ocular motor abnormalities, or tremor) was found in non-remitters. Direct comparisons between remitters and non-remitters were also performed and showed lower NSS scores in most domains in remitters. Unfortunately, neither the NSS total score nor subscores could predict whether patients were to be future remitters or non-remitters . Neurological soft signs were evaluated using the Cambridge Neurological Inventory in (partly medicated) patients suffering from schizophrenia, bipolar disorder, or major depression, and in healthy controls (30 participants per group) . Patients with schizophrenia showed more NSS than patients with major depression and healthy controls, but neither the NSS total score nor any of the subscores allowed for a differentiation between patients with schizophrenia and bipolar disorder. However, a preliminary linear discriminant analysis classified 77.5 % of patients correctly in either the bipolar disorder/ schizophrenia group or major depression/ healthy control group. A different study in patients with schizophrenia spectrum disorders (n=161), bipolar I disorder (n=88), and healthy controls confirmed that patients with schizophrenia and bipolar disorder showed more NSS than controls. Furthermore, in this study, schizophrenia patients showed significantly greater neurological impairment than patients suffering from bipolar disorder . We can only speculate as to the reason for this discrepancy. The different patient samples included as well as the different tools used for the assessment of neurological symptoms might play a role. NSS and Theory of Mind One study investigated the potential correlation between NSS and Theory of Mind deficits in 90 patients with schizophrenia. Scores on the sequencing subscale of the Neurological Evaluation Scale but no other subscale correlated significantly with Theory of Mind deficits (first- and second-order false belief task). The authors conclude that shared underlying neural substrates might be affected . Olfactory Function and Schizophrenia Olfactory dysfunction indisputably exists in patients with schizophrenia, details on the affected qualities as well as their role as trait or state markers remain to be established. A recent meta-analysis of 67 studies in patients with schizophrenia (including also schizophreniform and schizoaffective disorder) and 15 publications of at-risk individuals/relatives showed large, albeit heterogeneous effect sizes of olfactory dysfunction in patients and at-risk individuals, while effects in firstdegree relatives were smaller. Tasks of odor memory and identification yielded the largest effect sizes as compared to odor
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detection threshold, odor hedonics, or odor discrimination . Deficits in odor identification and detection threshold in patients with schizophrenia were also found in a second meta-analysis by a different group of authors. In addition, this analysis demonstrated smaller effects in at-risk individuals and relatives . Despite presenting comparable results, the two author groups do, however, not agree as to the role of olfactory impairment as a possible biomarker in schizophrenia and at-risk individuals. This issue is discussed in [18•]. Several original articles on the topic have been published in the past years, e.g., [19–22]. By examining patients with schizophrenia (n=65), first-degree relatives (n=24) as well as youths at clinical (n=10) or genetic risk (n=14) for schizophrenia, isolated deficits in odor identification were identified as genetic markers of vulnerability for schizophrenia, while odor discrimination deficits were proposed as possible biomarkers associated with the development of overt schizophrenia . However, findings on smell identification in individuals at clinical high risk for schizophrenia are inconclusive, and a recent study did not find any utility of two smell identification tasks in predicting emergent schizophrenia .
was that only patients who had health insurance and sought medical attention for their problems were included . A meta-analysis of six cohort studies and a naturalistic 12-year follow-up study confirmed a modest but statistically significant positive association between schizophrenia and stroke incidence and mortality [27, 29]. This elevated risk persisted after adjustment for risk factors of stroke such as diabetes, hypertension, or hyperlipidemia, which are known to be more prevalent in patients with schizophrenia . Currently, the exact pathophysiological mechanisms underlying increased stroke events in schizophrenia patients are not well understood. Antipsychotic treatment was only taken into account in the last study  (see 7.4. for the effect of antipsychotic treatment on stroke). Cardiovascular disease (CVD), a condition associated with manifest stroke, has been reported in a single center autopsy study to be one of the leading causes of death in schizophrenia , and an exploratory, non-blinded study proposed the noninvasive measurement of arterial stiffness as a predictive value for CVD morbidity and mortality in patients with schizophrenia .
Comorbidity of Schizophrenia With Other Neurological Disorders
A systematic review found that 5.6 % of individuals with epilepsy suffer from comorbid psychotic illness and that patients with epilepsy have an almost eightfold increased risk of psychosis. The prevalence rate of psychosis was higher in temporal lobe epilepsy; however, no separate analysis of patients with schizophrenia was conducted, although 17 out of 58 studies had specifically assessed schizophrenia. Accordingly, other diagnoses, e.g., organic mental disorders (ICD-10: F06), were included into the analysis as well . The authors highlight this dilemma which is aggravated by the fact that a specific classification of psychotic symptoms associated with epilepsy does not exist in ICD-10 or DSM-5. A large, population-based study found an eightfold increased risk of having schizophrenia in individuals with a diagnosis of epilepsy . Vice versa, patients with schizophrenia more frequently suffer from epilepsy compared to a control population . In addition, a strong evidence of clustering of the association between epilepsy and psychosis within families has been reported .
Stroke In a very large population-based study (over 80,000 schizophrenia patients and more than 240,000 control subjects) patients with schizophrenia were 1.13 times more likely to have a stroke after adjusting for demographic characteristics and comorbid medical conditions. The limitation of this study
Contrary to other psychiatric disorders, schizophrenia is not more prevalent in patients with multiple sclerosis than in the general population. This is astonishing considering that inflammatory processes have been implied in the pathogenesis of schizophrenia [33, 34]. Other autoimmune diseases affecting the central nervous system such as systemic lupus erythematodes are known to manifest with psychosis, but, to our knowledge, an association with schizophrenia is not known . Patients with schizophrenia show high rates of sleep apnea syndrome, which can aggravate daytime sleepiness, cognitive difficulties, and psychosis. Clinical data on this issue are limited [36, 37].
The Role of N-Methyl-D-Aspartate Glutamate Receptor Antibodies in Schizophrenia N-methyl-D-aspartate glutamate receptor (NMDA-r) antibody positive encephalitis is a relatively recently recognized entity which is characterized by autoantibodies (against the NMDA receptor NR1 subunit) directed at surface antigens of cerebral gray matter. In some cases (4 % in the cited study), the disease can clinically present with isolated psychiatric symptoms which can mimic schizophrenia [38•], and the diagnosis should also be considered in patients with the initial clinical suspicion of neurologic malignant syndrome . On the other hand, 9.9 % of patients with schizophrenia show serum
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antibodies from various immunoglobulin classes reactive to different NMDA-r epitopes , but not isolated IgG antibodies against the NMDA-r NR1 subunit only, which are thought to be specific for NMDA-r encephalitis . This finding was largely confirmed by a second study, which extended the findings by showing that a history of neurotrauma increased the chance of neurological symptoms in patients with NMDA-r antibodies . The rates of NMDA-r positivity in healthy controls varied considerably between the two studies (0.4 vs. 10 %) [40, 41], probably due to methodological issues in determining the NMDA-r antibodies . Which antibody classes and which epitopes of the NMDA-r are of relevance in the context of schizophrenia needs further clarification, since current meta-analyses show conflicting results [42, 43]. It has been suggested that thalamic hypofunction in schizophrenia could be mediated by reduced NMDA-r activation, which, in turn, may result in a relative cortico-thalamocortical disconnection, thereby impairing sensorimotor integration . Except for the NMDA-r autoantibodies, no other autoantibodies were elevated in patients with schizophrenia .
Neurological Side Effects of Antipsychotic Drugs Extrapyramidal Side Effects Using data from the European First-Episode Schizophrenia Trial (EUFEST), Rybakowski et al. examined the occurrence of extrapyramidal symptoms (EPS) in first-episode schizophrenia patients treated with haloperidol, amisulpride, olanzapine, quetiapine, or ziprasidone [46•]. Parkinsonism and akathisia occurred most frequently, with a peak after 1 month of treatment. Parkinsonism was observed most frequently in the haloperidol group, whereas akathisia most often occurred in the ziprasidone group. After 1 year of treatment, the incidence of akathisia was similar in the ziprasidone (6.5 %), quetiapine (7.2 %), and haloperidol (4.6 %) groups and was absent in the olanzapine and the amisulpride groups. Interestingly, EPS were also found in drug-naïve patients (Parkinsonism 8.1 %; akathisia 11.3 %). One could speculate that they represented NSS with an origin in schizophreniarelated organic brain pathology. Tardive Syndromes In their evidence-based guidelines [47•], Bhidayasiri et al. reviewed the literature from over four decades in order to provide treatment recommendations on tardive syndromes (TDS). These are limited due to low evidence levels for most agents, but, in essence, clonazepam as well as ginkgo biloba may improve TDS (both level B), but treatment with amantadine and tetrabenazine might be considered as well (level C).
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For several other treatment approaches, including vitamin E and vitamin B6, baclofen, second-generation antipsychotics, and electroconvulsive treatment, data are insufficient. Seizures Clozapine is particularly known for lowering the seizure threshold, and guidelines recommend a very cautious increase of daily dose in the first weeks of treatment. On the other hand, a recently published naturalistic cohort study in 111 schizophrenia patients showed that rapid titration (patients received 25–100 mg of clozapine as needed every 6 h at initiation of the trial) may be safe and effective. None of study participants experienced any major complications such as seizures, syncope, or agranulocytosis . However, these results have to be scrutinized in larger controlled trials. Cerebrovascular Events In schizophrenia, use of antipsychotics has been shown to be associated with a twofold risk of stroke. The risk was especially high in the first 60 days of newly initiated treatment and when first-generation antipsychotics were used . Though the pathophysiology of antipsychotic-induced stroke remains unclear, a recent investigation on the effects of antipsychotics on microvascular endothelial cells  has shown that first and second-generation antipsychotics adversely affect endothelial cells and thus the blood-brain barrier. These effects may contribute to the development of cerebral edema, neuroleptic malignant syndrome, or stroke. EPSinduced immobility or orthostatic hypotension may also add to an increased risk for stroke.
Treatment of Neurocognitive Deficits—Pharmacological and Cognitive Training Interventions Previous studies have shown that neurocognitive deficits frequently persist after the remission of psychosis and hardly respond to treatment with antipsychotic medication. As a result of the Measurement and Treatment to Improve Cognition in Schizophrenia (MATRICS) initiative , studies on several potentially cognition-enhancing drugs were initiated. A selection of these investigations is presented in Table 1. Taken together, some of these compounds could represent useful new treatment options to improve neurocognition in schizophrenia patients; however, further clinical trials are needed to evaluate long-term outcomes. In addition to pharmacological interventions, cognitive training and remediation programs have proven to be effective in schizophenia . Recent studies on cognitive training basically support these previous findings. Recently published work on this topic is summarized in Table 2.
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Iowa Gambling Task (IGT) N-Back task Probabilistic learning task CogState computerized cognitive battery
Rimonabant (cannabinoid-1 receptor antagonist)
RCT randomized controlled trial
− Indicates no difference in the tested functions
+ Indicates improvement of respective cognitive function
+ Neurocognitive composite score
RCT, double blind
RCT, double blind
RCT, double blind
RCT, double blind
Study design RCT, double blind
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Chinese MATRICS Consensus Cognitive Battery (MCCB) Tests
Scales CogState Schizophrenia Battery (CSB) Scale of the Assessment of Negative Symptoms (SANS) Tests of auditory verbal learning and memory (USC-REMT) MATRICS Consensus Cognitive Battery (MCCB) Tests
Sodium benzoate (D-amino acid oxidase inhibitor)
CDP-choline (direct agonist on alpha-7 nicotinic receptor) + galantamine
Results + Executive functioning + Negative symptoms − Other six CSB domains + Free recall (auditory verbal learning and memory) − Processing speed − Attention/vigilance − Working memory − Verbal learning − Visuospatial learning + Speed of processing + Visual learning and memory + Neurocognition composite score − Attention/vigilance − Working memory − Verbal learning − Reasoning and problem-solving − Social cognition + Possible improvement of reinforcement learning − Other neurocognitive domains
Pharmacological compounds recently tested in schizophrenia patients for the improvement of neurocognition
Pharmacological interventions for the treatment of neurocognitive deficits in schizophrenia
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Cognitive remediation programs and their impact on neurocognitive functioning
Wechsler Adult Intelligence Scale-III (WAIS-III) Conners’ Continuous Performance Test II (CPT II) Symbol Digit Modalities Test (SDMT) F-A-S test California Verbal Learning Test (CVLT) Wisconsin Card Sorting Test (WCST-CV3) Wisconsin Card Sorting Test (WCST) Wechsler Memory Scale (WMS-R) Trail Making Test (TMT) Part A+B Continuous Performance Test (CPT) Stroop-color test Trail Making Test (TMT) Part A Wechsler General Intelligence Scale (WAIS-III) Hopkins Verbal Learning Test (HVLT) Spanish version of the National Adult Reading Test (Barcelona Test)
+ Indicates improvement of respective cognitive function
Neuropsychological rehabilitation (REHACOP)
Computer-assisted cognitive training (X-Cog®)
Scales Trail Making Test (TMT) Part A Wechsler Memory Scale (WMS-III) Hopkins Verbal Learning Test-Revised (HVLT-R) Brief Visuospatial Memory Test-Revised (BVMT-R) Delis-Kaplan Executive Function System (D-KEFS) Tower Test
Method Neuroplasticity-based auditory training targeting verbal learning/auditory processing performance
Cognitive training programs for the treatment of neurocognitive deficits in schizophrenia
Results + Global cognition + Verbal memory + Problem-solving − Speed of processing − Working memory − Verbal learning + Speed of processing + Working memory + Reasoning and problem-solving − Attention/vigilance − Verbal learning
Study design RCT, double blind
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Some studies have addressed possible benefits beyond the improvement of neurocognition through cognitive remediation programs. It has been shown, for example, that a combination of neurocognitive and social-cognitive training improves particular social-cognitive abilities more effectively than social-cognitive interventions alone [62•]. Beyond that, cognitive training may reduce negative symptoms or functional disabilities [61, 63]. Though all patients seem to benefit from cognitive remediation, it has to be emphasized that a delivery in early stages of the illness results in more pronounced cognitive improvements .
Conclusion—for the Clinician Subtle neurological deficits are a frequent finding in schizophrenia. Two main challenges arise from this for the clinican: 1) Neurological deficits and dyfunction are difficult to explore and examine in patients with schizophrenia, especially in the stage of acute psychosis, due to psychiatric symptoms. 2) Once neurological deficits are identified in a patient with schizophrenia, the clinician needs to explore if these deficits are indicative of an underlying acute neurological disease (e.g., see the association of schizophrenia and stroke) or are part of the phenotype of schizophrenia.
Compliance with Ethics Guidelines
Conflict of Interest Alex Hofer has received a resaerch grant from Janssen-Cilag. He has received speaker´s or consultancy fees from BMS, Janssen-Cilag, and Lundbeck. He has received reimbursement for travel and meeting expenses from AOP Orphan, Janssen-Cilag, Lundbeck, Pfizer, and Roche. Katharina Hüfner has received paid travel accommodations from AOP Pharma and Lundbeck. Beatrice Frajo-Apor has received paid travel accommodations from AOP Pharma and Lundbeck. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance
Ren W, Lui S, Deng W, Li F, Li M, Huang X, et al. Anatomical and functional brain abnormalities in drug-naive first-episode schizophrenia. Am J Psychiatry. 2013;170(11):1308–16. Mayoral M, Bombin I, Castro-Fornieles J, Gonzalez-Pinto A, Otero S, Parellada M, et al. Longitudinal study of neurological soft signs
in first-episode early-onset psychosis. J Child Psychol Psychiatr allied Discip. 2012;53(3):323–31. Gay O, Plaze M, Oppenheim C, Mouchet-Mages S, Gaillard R, Olie JP, et al. Cortex morphology in first-episode psychosis patients with neurological soft signs. Schizophr Bull. 2013;39(4):820–9. This study investigated the cortical sulcation, as a potential marker for neurodevelopmental deviation, in 44 patients with first onset psychosis. Reductions of cortical sulcation in both hemispheres were found in patients with neurological soft signs as compared to those with non-significant NSS. Kaluzynska O, Rabe-Jablonska J. Neurological soft signs as a candidate for endophenotype of schizophrenia. Psychiatr Pol. 2014;48(1):5–18. Zhao Q, Li Z, Huang J, Yan C, Dazzan P, Pantelis C, et al. Neurological soft signs are not "soft" in brain structure and functional networks: evidence from ALE meta-analysis. Schizophr Bull. 2014;40(3):626–41. This metanalysis of 6 structural and 15 functional magnetic resonance imaging studies provides evidence for significant and localized changes in brain structure and function associated with specific neurological soft signs. The study thus does away with the conventional believ that neurological soft signs cannot be attributed to specific brain regions. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res. 1989;27(3):335–50. Chen EY, Shapleske J, Luque R, McKenna PJ, Hodges JR, Calloway SP, et al. The Cambridge Neurological Inventory: a clinical instrument for assessment of soft neurological signs in psychiatric patients. Psychiatry Res. 1995;56(2):183–204. Kong L, Bachmann S, Thomann PA, Essig M, Schroder J. Neurological soft signs and gray matter changes: a longitudinal analysis in first-episode schizophrenia. Schizophr Res. 2012;134(1):27–32. Hirjak D, Wolf RC, Stieltjes B, Hauser T, Seidl U, Thiemann U, et al. Neurological soft signs and brainstem morphology in firstepisode schizophrenia. Neuropsychobiology. 2013;68(2):91–9. Hirjak D, Wolf RC, Stieltjes B, Hauser T, Seidl U, Schroder J, et al. Cortical signature of neurological soft signs in recent onset schizophrenia. Brain Topogr. 2014;27(2):296–306. Hirjak D, Wolf RC, Stieltjes B, Seidl U, Schroder J, Thomann PA. Neurological soft signs and subcortical brain morphology in recent onset schizophrenia. J Psychiatr Res. 2012;46(4):533–9. Prikryl R, Ceskova E, Tronerova S, Kasparek T, Kucerova HP, Ustohal L, et al. Dynamics of neurological soft signs and its relationship to clinical course in patients with first-episode schizophrenia. Psychiatry Res. 2012;200(2–3):67–72. Zhao Q, Ma YT, Lui SS, Liu WH, Xu T, Yu X, et al. Neurological soft signs discriminate schizophrenia from major depression but not bipolar disorder. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;43:72–8. Rigucci S, Dimitri-Valente G, Mandarelli G, Manfredi G, Comparelli A, De Filippis S, et al. Neurological soft signs discriminate schizophrenia from bipolar disorder. J Psychiatr Pract. 2014;20(2):147–53. Romeo S, Chiandetti A, Siracusano A, Troisi A. An exploratory study of the relationship between neurological soft signs and theory of mind deficits in schizophrenia. Psychiatry Res. 2014;218(1–2): 7–11. Moberg PJ, Kamath V, Marchetto DM, Calkins ME, Doty RL, Hahn CG, et al. Meta-analysis of olfactory function in schizophrenia, first-degree family members, and youths at-risk for psychosis. Schizophr Bull. 2014;40(1):50–9. Cohen AS, Brown LA, Auster TL. Olfaction, "olfiction," and the schizophrenia-spectrum: an updated meta-analysis on identification and acuity. Schizophr Res. 2012;135(1–3):152–7.
Curr Psychiatry Rep (2015) 17:32 18.• Turetsky BI, Kamath V, Calkins ME, Brewer WJ, Wood SJ, Pantelis C, et al. Olfaction and schizophrenia clinical risk status: just the facts. Schizophr Res. 2012;139(1–3):260–1. author reply 2–3. This critical commentary discusses the findings from the Cohen et al. 2012 metanalysis and advocates olfactory impairment as a possible biomarker of schizophrenia. 19. Kamath V, Moberg PJ, Kohler CG, Gur RE, Turetsky BI. Odor hedonic capacity and anhedonia in schizophrenia and unaffected first-degree relatives of schizophrenia patients. Schizophr Bull. 2013;39(1):59–67. 20. Kamath V, Turetsky BI, Calkins ME, Bilker WB, Frishberg N, Borgmann-Winter K, et al. The effect of odor valence on olfactory performance in schizophrenia patients, unaffected relatives and atrisk youth. J Psychiatr Res. 2013;47(11):1636–41. 21. Clepce M, Reich K, Gossler A, Kornhuber J, Thuerauf N. Olfactory perception in schizophrenia: the rating range for hedonic judgements is increased during acute episodes. Psychiatry Res. 2013;208(1):81–3. 22. Kastner A, Malzahn D, Begemann M, Hilmes C, Bickeboller H, Ehrenreich H. Odor naming and interpretation performance in 881 schizophrenia subjects: association with clinical parameters. BMC Psychiatr. 2013;13:218. 23. Kamath V, Turetsky BI, Calkins ME, Kohler CG, Conroy CG, Borgmann-Winter K, et al. Olfactory processing in schizophrenia, non-ill first-degree family members, and young people at-risk for psychosis. World J Biol Psychiatr : Off J World Fed Soc Biol Psychiatr. 2014;15(3):209–18. 24. Gill KE, Evans E, Kayser J, Ben-David S, Messinger J, Bruder G, et al. Smell identification in individuals at clinical high risk for schizophrenia. Psychiatry research. 2014. 25. Clancy MJ, Clarke MC, Connor DJ, Cannon M, Cotter DR. The prevalence of psychosis in epilepsy; a systematic review and metaanalysis. BMC Psychiatr. 2014;14:75. 26. Clarke MC, Tanskanen A, Huttunen MO, Clancy M, Cotter DR, Cannon M. Evidence for shared susceptibility to epilepsy and psychosis: a population-based family study. Biol Psychiatry. 2012;71(9):836–9. 27. Schoepf D, Uppal H, Potluri R, Heun R. Physical comorbidity and its relevance on mortality in schizophrenia: a naturalistic 12-year follow-up in general hospital admissions. Eur Arch Psychiatry Clin Neurosci. 2014;264(1):3–28. 28. Tsai KY, Lee CC, Chou YM, Su CY, Chou FH. The incidence and relative risk of stroke in patients with schizophrenia: a five-year follow-up study. Schizophr Res. 2012;138(1):41–7. 29. Li M, Fan YL, Tang ZY, Cheng XS. Schizophrenia and risk of stroke: a meta-analysis of cohort studies. Int J Cardiol. 2014;173(3):588–90. 30. Liao CH, Chang CS, Wei WC, Chang SN, Liao CC, Lane HY, et al. Schizophrenia patients at higher risk of diabetes, hypertension and hyperlipidemia: a population-based study. Schizophr Res. 2011;126(1–3):110–6. 31. Sweeting J, Duflou J, Semsarian C. Postmortem analysis of cardiovascular deaths in schizophrenia: a 10-year review. Schizophr Res. 2013;150(2–3):398–403. 32. Phillips AA, Warburton DE, Flynn SW, Fredrikson D, Lang DJ. Assessment of arterial stiffness among schizophrenia-spectrum disorders using aortic pulse wave velocity and arterial compliance: a pilot study. Psychiatry Res. 2014;215(1):14–9. 33. Marrie RA, Fisk JD, Yu BN, Leung S, Elliott L, Caetano P, et al. Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance. BMC Neurol. 2013;13:16. 34. Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophrenia research. 2014.
Page 9 of 10 32 35.
Streifler JY, Molad Y. Connective tissue disorders: systemic lupus erythematosus, Sjogren’s syndrome, and scleroderma. Handb Clin Neurol. 2014;119:463–73. Kalucy MJ, Grunstein R, Lambert T, Glozier N. Obstructive sleep apnoea and schizophrenia—a research agenda. Sleep Med Rev. 2013;17(5):357–65. Annamalai A, Palmese LB, Chwastiak LA, Srihari VH, Tek C. High rates of obstructive sleep apnea symptoms among patients with schizophrenia. Psychosomatics. 2014. Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti-Nmethyl-d-aspartate receptor encephalitis. JAMA Neurol. 2013;70(9):1133–9. Observational cohort study to investigate the frequency of isolated psychiatric symptoms in patients with NMDAr encephalitis. These symptoms can occur at the time of initial diagnosis or at relapse. Pratical recommendations are given. Punja M, Pomerleau AC, Devlin JJ, Morgan BW, Schier JG, Schwartz MD. Anti-N-methyl-D-aspartate receptor (antiNMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium. Clin Toxicol. 2013;51(8):794–7. Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatr. 2013;70(3):271–8. Hammer C, Stepniak B, Schneider A, Papiol S, Tantra M, Begemann M, et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Molecular psychiatry. 2013. Pollak TA, McCormack R, Peakman M, Nicholson TR, David AS. Prevalence of anti-N-methyl-d-aspartate (NMDA) receptor antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychol Med. 2014;44(12): 2475–87. Pearlman DM, Najjar S. Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder. Schizophrenia research. 2014. Vukadinovic Z. NMDA receptor hypofunction and the thalamus in schizophrenia. Physiol Behav. 2014;131:156–9. Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Saschenbrecker S, et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol. 2014;76(1):82–94. Rybakowski JK, Vansteelandt K, Remlinger-Molenda A, Fleischhacker WW, Kahn RS, Peuskens J. Extrapyramidal symptoms during treatment of first schizophrenia episode: results from EUFEST. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2014. An important evaluation of antipsychotic-induced EPS in first episode schizophrenia. Bhidayasiri R, Fahn S, Weiner WJ, Gronseth GS, Sullivan KL, Zesiewicz TA. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;81(5):463–9. Very good overview on evidence levels of treatment approaches for tardive syndromes. Ifteni P, Nielsen J, Burtea V, Correll CU, Kane JM, Manu P. Effectiveness and safety of rapid clozapine titration in schizophrenia. Acta Psychiatr Scand. 2014;130(1):25–9. Hsieh PH, Hsiao FY, Gau SS, Gau CS. Use of antipsychotics and risk of cerebrovascular events in schizophrenic patients: a nested case-control study. J Clin Psychopharmacol. 2013;33(3):299–305. Elmorsy E, Elzalabany LM, Elsheikha HM, Smith PA. Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood brain barrier. Brain research. 2014.
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Page 10 of 10 Green MF, Nuechterlein KH. The MATRICS initiative: developing a consensus cognitive battery for clinical trials. Schizophr Res. 2004;72(1):1–3. Lieberman JA, Dunbar G, Segreti AC, Girgis RR, Seoane F, Beaver JS, et al. A randomized exploratory trial of an alpha-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia. Neuropsychopharmacology. 2013;38(6):968–75. Deutsch SI, Schwartz BL, Schooler NR, Brown CH, Rosse RB, Rosse SM. Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy. Schizophr Res. 2013;148(1–3): 138–44. Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70(12):1267–75. Interesting novel therapeutic approach in schizophrenia treatment – for both, neurocognitive functions and clinical symptoms. Boggs DL, Kelly DL, McMahon RP, Gold JM, Gorelick DA, Linthicum J, et al. Rimonabant for neurocognition in schizophrenia: a 16-week double blind randomized placebo controlled trial. Schizophr Res. 2012;134(2–3):207–10. Harvey PD, Siu CO, Hsu J, Cucchiaro J, Maruff P, Loebel A. Effect of lurasidone on neurocognitive performance in patients with schizophrenia: a short-term placebo- and active-controlled study follo wed by a 6-month d oub le-b lind ex tension . Eu r Neuropsychopharmacol : J Eur Coll Neuropsychopharmacol. 2013;23(11):1373–82. Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A metaanalysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry. 2011;168(5):472–85.
Fisher M, Loewy R, Carter C, Lee A, Ragland JD, Niendam T, et al. Neuroplasticity-Based Auditory Training Via Laptop Computer Improves Cognition in Young Individuals With Recent Onset Schizophrenia. Schizophr Bull. 2014. 59. Garrido G, Barrios M, Penades R, Enriquez M, Garolera M, Aragay N, et al. Computer-assisted cognitive remediation therapy: cognition, self-esteem and quality of life in schizophrenia. Schizophr Res. 2013;150(2–3):563–9. 60. Trapp W, Landgrebe M, Hoesl K, Lautenbacher S, Gallhofer B, Gunther W, et al. Cognitive remediation improves cognition and good cognitive performance increases time to relapse—results of a 5 year catamnestic study in schizophrenia patients. BMC Psychiatr. 2013;13:184. 61. Sanchez P, Pena J, Bengoetxea E, Ojeda N, Elizagarate E, Ezcurra J, et al. Improvements in negative symptoms and functional outcome after a new generation cognitive remediation program: a randomized controlled trial. Schizophr Bull. 2014;40(3):707–15. 62.• Lindenmayer JP, McGurk SR, Khan A, Kaushik S, Thanju A, Hoffman L, et al. Improving social cognition in schizophrenia: a pilot intervention combining computerized social cognition training with cognitive remediation. Schizophr Bull. 2013;39(3):507–17. Interesting publication on the benefits of a combination of neurocognitive and social cogntive training. 63. Eack SM, Pogue-Geile MF, Greenwald DP, Hogarty SS, Keshavan MS. Mechanisms of functional improvement in a 2-year trial of cognitive enhancement therapy for early schizophrenia. Psychol Med. 2011;41(6):1253–61. 64. Bowie CR, Grossman M, Gupta M, Oyewumi LK, Harvey PD. Cognitive remediation in schizophrenia: efficacy and effectiveness in patients with early versus long-term course of illness. Early Interv Psychiatr. 2014;8(1):32–8.
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