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Understanding the Physiology of Schizophrenia [CME]

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Abstract

The physiology of schizophrenia includes complex genetic and environmental interactions. Current treatment largely focuses on positive symptoms, but many patients with schizophrenia present with additional symptoms and conditions that hinder their social and occupational functioning. The study of the physiology of this disorder has expanded beyond dopamine dysfunction to include the glutamate, serotonin, and nicotinic/acetylcholine systems, as well as physiologic abnormalities such as diabetes and inflammation. Clinicians who understand these additional problem areas can incorporate them into their assessment and treatment plans for patients with schizophrenia.

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... Other peripheral findings in schizophrenia may similarly reflect altered limbic functioning associated with the psychiatric disorder (Kirkpatrick, 2013). Some possibilities warranting consideration include peripheral features of catatonia (Castillo et al., 1989); inflammatory markers like monocytosis (Bergink et al., 2014;Kirpatrick and Miller, 2013); insulin resistance (Kirkpatrick, 2013) and other neurohormone findings (Bergink et al., 2014;Kudielka et al., 2009). ...
... Other peripheral findings in schizophrenia may similarly reflect altered limbic functioning associated with the psychiatric disorder (Kirkpatrick, 2013). Some possibilities warranting consideration include peripheral features of catatonia (Castillo et al., 1989); inflammatory markers like monocytosis (Bergink et al., 2014;Kirpatrick and Miller, 2013); insulin resistance (Kirkpatrick, 2013) and other neurohormone findings (Bergink et al., 2014;Kudielka et al., 2009). ...
Article
Objective: To identify the mechanism of unexplained hyponatremia and primary polydipsia in schizophrenia and its relationship to the underlying psychiatric illness. Methods: Briefly review previous studies that led to the conclusion the hyponatremia reflects altered hippocampal inhibition of peripheral neuroendocrine secretion. In greater detail, present the evidence supporting the hypothesis that circuit dysfunction associated with the hyponatremia and the polydipsia contributes to the underlying mental disorder. Results: Polydipsic patients with and without hyponatremia exhibit enhanced neuroendocrine responses to psychological stress in proportion to structural deformations on their anterior hippocampus, amygdala and anterior hypothalamus. Nonpolydipsic patients exhibit blunted responses and deformations on other hippocampal and amygdala surfaces. The deformations in polydipsic patients are also proportional to diminished peripheral oxytocin levels and impaired facial affect recognition that is reversed by intranasal oxytocin. The anterior hippocampus is at the hub of a circuit that modulates neuroendocrine and other responses to psychological stress and is implicated in schizophrenia. Preliminary data indicate that other measures of stress reactivity are also enhanced in polydipsics and that the functional connectivity of the hippocampus with the other structures in this circuitry differs in schizophrenia patients with and without polydipsia. Conclusion: Polydipsia may identify a subset of schizophrenia patients whose enhanced stress reactivity contributes to their mental illness. Stress reactivity may be a symptom dimension of chronic psychosis that arises from circuit dysfunction that can be modeled in animals. Hence polydipsia could be a biomarker that helps to clarify the pathophysiology and heterogeneity of psychosis as well as identify novel therapies. Clinical investigators should consider obtaining indices of water balance, as these may help them unravel and more concisely interpret their findings. Basic researchers should assess if the polydipsic subset is a patient group particularly suitable to test hypotheses arising from their translational studies.
... schizophrenia), a lack of mGluR signaling is thought to be a contributor to disease severity and mGluR agonists have been successful in providing some symptomatic relief [44,45]. However, this research is plagued by the high side effects associated with mGluR agonists (reviewed in [46]). Current efforts are focused on developing a molecule with better tolerance and a higher penetrance for symptomatic relief in schizophrenia patients [46]. ...
... However, this research is plagued by the high side effects associated with mGluR agonists (reviewed in [46]). Current efforts are focused on developing a molecule with better tolerance and a higher penetrance for symptomatic relief in schizophrenia patients [46]. In many other cases, overstimulation of GluRs by excessive Glu release or persistence of Glu in the synaptic cleft is correlated with disease onset or symptomatic severity -a phenomenon called excitotoxicity [47]. ...
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Glutamate, a nonessential amino acid, is the major excitatory neurotransmitter in the central nervous system. As such, glutamate has been shown to play a role in not only neural processes, such as learning and memory, but also in bioenergetics, biosynthetic and metabolic oncogenic pathways. Glutamate has been the target of intense investigation for its involvement not only in the pathogenesis of benign neurodegenerative diseases (NDDs) such as Parkinson's disease, Alzheimer's disease, schizophrenia, multiple sclerosis, and amyotropic lateral sclerosis (ALS), but also in carcinogenesis and progression of malignant diseases. In addition to its intracellular activities, glutamate in secreted form is a phylogenetically conserved cell signaling molecule. Glutamate binding activates multiple major receptor families including the metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated in various signaling pathways in cancer. Inhibition of extracellular glutamate release or glutamate receptor activation via competitive or non-competitive antagonists decreases growth, migration and invasion and induces apoptosis in breast cancer, melanoma, glioma and prostate cancer cells. In this review, we discuss the current state of glutamate signaling research as it relates to benign and malignant diseases. In addition, we provide a synopsis of clinical trials using glutamate antagonists for the treatment of NDD and malignant diseases. We conclude that in addition to its potential role as a metabolic biomarker, glutamate receptors and glutamate-initiated signaling pathways may provide novel therapeutic opportunities for cancer.
... For example, symptom assessment can be subjective [7]. Symptoms can overlap, making it difficult to distinguish similar disorders from each other [8,9], and comorbidity is common. Additionally, criteria established for one ethnic or cultural group may not be applicable to others [10]. ...
Article
Biomarkers are biological measures that are indicative of a specific disorder, its severity or response to treatment. They are widely used in many areas of medicine, but biomarker development for brain-based disorders lags behind. Using examples from the field of psychiatry, this article reviews the concepts of biomarkers, challenges to their development and the recent progress along those lines. In addition to discussing historical biomarker candidates such as cortisol or catecholamine levels, we include progress from recent genetic, epigenetic, proteomic, neuroimaging and EEG studies. Successful identification of biomarkers will advance the field of psychiatry towards the goal of biological tests for diagnosis, symptom management and treatment response.
... Injection of pregnant rodents with the viral mimic polyinosinic-polycytidilic acid (Poly I:C) leads to a wide spectrum of schizophrenia-relevant behavioral deficits, such as pre-pulse inhibition of the acoustic startle response (PPI) (Gal et al., 2009;Klein et al., 2013;Kumari et al., 2008;Smith et al., 2007;Nyffeler et al., 2006;Schwarzkopf et al., 1992; for review see Yamada, 2000). Behavioral deficits are associated with schizophrenia-relevant neuropathological deficits including abnormalities in dopaminergic and glutamatergic neurotransmission (Winter et al., 2008; for review see Kirkpatrick, 2013), histopathological (Biscaro et al., 2012;Kühn et al., 2012) and structural changes (Piontkewitz et al., 2011a(Piontkewitz et al., , 2012. The relevance of maternal Poly I:C -induced deficits to schizophrenia is further supported by the responsiveness of adult behavioral deficits to neuroleptic treatment (Piontkewitz et al., 2011b). ...
Article
Adult neurogenesis in the hippocampus is impaired in schizophrenic patients and in an animal model of schizophrenia. Amongst a plethora of regulators, the immune system has been shown repeatedly to strongly modulate neurogenesis under physiological and pathological conditions. It is well accepted, that schizophrenic patients have an aberrant peripheral immune status, which is also reflected in the animal model. The microglia as the intrinsic immune competent cells of the brain have recently come into focus as possible therapeutic targets in schizophrenia. We here used a maternal immune stimulation rodent model of schizophrenia in which polyinosinic-polycytidilic acid (Poly I:C) was injected into pregnant rats to mimic an anti-viral immune response. We identified microglia IL-1β and TNF-α increase constituting the factors correlating best with decreases in net-neurogenesis and impairment in pre-pulse inhibition of a startle response in the Poly I:C model. Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1β production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.
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Schizophrenia is a mental illness characterized by episodes of psychosis, apathy, social withdrawal, and cognitive impairment. White matter lesions and glutamatergic hypofunction are reported to be the key pathogeneses underlying the multiple clinical symptoms of schizophrenia. Cuprizone (CPZ) is a copper chelator that selectively injures oligodendrocytes, and MK-801 is an antagonist of the N-methyl D-aspartate (NMDA) receptor. To better mimic the psychosis and complicated pathogenesis of schizophrenia, a novel possible mouse model was established by the combination of CPZ and MK-801. After exposure to CPZ for 5 weeks, the mice received a daily intraperitoneal injection of MK-801 for 2-weeks. Behavioral changes in the mouse model were evaluated using Y-maze, object recognition, and open field tests. Pathological changes were observed by transmission electron microscopy, oil red O staining, immunohistochemistry, and western blotting. The results showed that the novel mouse model induced by CPZ plus MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. Moreover, the mice showed obvious demyelination and white matter damage and decreased expression levels of myelin basic protein (MBP) and 2’,3’-cyclic nucleotide-3’-phosphodiesterase (CNPase) in the corpus callosum. Furthermore, the phosphorylation levels of Fyn and NMDA receptor 2B in the corpus callosum and NMDA receptor 1 in the cerebral cortex were noticeably decreased. Taken together, the novel mouse model induced by the combination of cuprizone and MK-801 showed comprehensive behavioral and neurobiological changes, which might make it a suitable animal model for schizophrenia.
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Beyond the Dopamine Hypothesis to the NMDA Glutamate Receptor Hypofunction Hypothesis of Schizophrenia - Volume 12 Issue 4 - Stephen M. Stahl
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Clinical concepts of mental illness have always been modulated by underlying theoretical considerations. For the past fifty years, schizophrenia has been considered primarily a disease of dopaminergic neurotransmission. Although this conceptualization has helped greatly in explaining the clinical effects of psychostimulants and guiding the clinical use of both typical and atypical antipsychotics, it has nevertheless shaded how we look at the disorder from both a pathophysiological and therapeutic perspective. For example, most explanatory research in schizophrenia has focused on dopamine-rich regions of the brain, with little investigation of regions of the brain that are relatively dopamine poor. Starting approximately twenty years ago, an alternative formulation of schizophrenia was proposed based upon actions of the "dissociative anesthetic" class of psychotomimetic agents, including phencyclidine (PCP), ketamine and various designer drugs. These compounds induce psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors, suggesting an alternative model for pathogenesis in schizophrenia. As opposed to dopamine, the glutamatergic system is widely distributed throughout the brain and plays a prominent role in sensory processing as well as in subsequent stages of cortical analysis. Glutamatergic theories of schizophrenia, thus, predict that cortical dysfunction will be regionally diffuse but process specific. In addition, NMDA receptors incorporate binding sites for specific endogenous brain compounds, including the amino acids glycine and D-serine and the redox modulator glutathione, and interact closely with dopaminergic, cholinergic and γ-aminobutyric acid (GABA)-ergic systems. Glutamatergic theories, thus, open new potential approaches for treatment of schizophrenia, most of which are only now entering clinical evaluation.
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Recent trials support the hypothesis of the role of inflammation in the pathogenesis of schizophrenia. The overall therapeutic benefit of anti-inflammatory medication, in particular cyclo-oxygenase-2 (COX-2) inhibitors in schizophrenia, is still controversial. There are suggestions that therapy with COX-2 inhibitors may influence the early stages of the disease. Taking these findings into account, we conducted a double-blind, placebo-controlled, randomized trial of celecoxib augmentation to amisulpride treatment in patients with a first manifestation of schizophrenia. Forty-nine patients diagnosed with schizophrenia were randomly assigned. They were treated either with amisulpride (200-1000 mg) plus celecoxib (400 mg) or amisulpride (200-1000 mg) plus placebo. Inclusion criterion was the diagnosis of schizophrenia during the past two years according to DSM-IV. The trial lasted six weeks. At weekly intervals an assessment of the psychopathology was performed using the Positive and Negative Symptom Scale (PANSS) and the Global Clinical Impression Scale (CGI). A significantly better outcome was observed in the patient group treated with amisulpride plus celecoxib compared to the group with amisulpride plus placebo (PANSS negative: p=0.03; PANSS global; p=0.05 and PANSS total: p=0.02). In addition, ratings by the CGI scale during therapy with amisulpride and celecoxib showed a significantly better result (p< or =0.001). A significantly superior therapeutic effect could be observed in the celecoxib group compared to placebo in the treatment of early stage schizophrenia. This is the first time an improvement in patients' negative symptoms has been demonstrated with celecoxib. In future, further trials are needed to investigate the effect of COX-2 inhibitors on prodromal and negative symptoms of schizophrenia.
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Some but not all previous studies have found abnormal glucose tolerance or fasting glucose concentrations in antipsychotic-naïve patients with nonaffective psychosis. Our finding of abnormal glucose tolerance in patients with nonaffective psychosis could not be attributed to confounding by age, ethnicity, gender, smoking, socioeconomic status (SES), hypercortisolemia, or body mass index (BMI). However, other factors merit consideration as potential confounders of this association. An extended sample of newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders and matched controls were administered an oral glucose tolerance test. Confounding factors related to diet, self-care/access to care, and drug abuse were evaluated. After accounting for the variance due to age, ethnicity, gender, smoking, SES, morning cortisol concentrations, BMI (or waist-hip ratio), our previous finding of abnormal glucose tolerance in these patients was confirmed. This difference could not be attributed to confounding by substance abuse; blood concentrations of vitamin B12, folate, or homocysteine; aerobic conditioning as measured by resting heart rate; or duration of untreated psychosis. These results provide further evidence that people with schizophrenia and related disorders have abnormal glucose tolerance and an increased risk of diabetes prior to antipsychotic treatment and independent of health habits and access to care. Other measures should also be examined.
Article
Recently attention has been addressed to the role of 5-HT in cognition and several experimental studies revealed that manipulations of the central 5-HT system can produce quite specific changes in cognitive functioning. These results may suggest new treatment strategies to improve cognition in psychiatric conditions characterized by neuropsychological impairments, such as schizophrenia. It is possible to investigate the involvement of 5-HT in cognition by examining the impact of genetic variation in key regulators of serotoninergic neurotransmission. Among these, the serotonin transporter (5-HTT) presents a functional polymorphism in the transcriptional control region of the gene (5-HTTLPR) affecting transcriptional efficiency. In the present study, we aimed to analyze the effect of 5-HTTLPR polymorphism on specific cognitive functions, known to be affected by 5-HT manipulation and altered in schizophrenia. 223 schizophrenia patients were tested with Wisconsin Card Sorting Test (WCST), for the evaluation of cognitive flexibility, Continuous Performance Test (CPT), for the evaluation of attention, and genotyped for the 5-HTTLPR. We found a significant association between HTT polymorphism and executive functions and inversely with sustained attention. The presence of the high-activity long (L) allele in homozygosis was a predictor of better executive performances and poorer performances of attention. Our findings suggest that factors affecting serotonin availability may play a specific role in cognitive processes, probably through complex modulation of the different performance components.
Article
Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P = 0.84). A systematic literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07-1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I(2) = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80-1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.
Article
Some studies suggest individuals with schizophrenia have an increased risk of diabetes prior to antipsychotic use. Small sample sizes and the potential for confounding by hypercortisolaemia have decreased confidence in those results. To examine diabetes-related factors in newly diagnosed, antipsychotic-naive people with non-affective psychosis. Participants with psychosis (the psychosis group; n = 50) and matched controls (the control group; n = 50) were given a 2 h oral glucose tolerance test. Fasting concentrations were also determined for adiponectin, interleukin-6 and C-reactive protein. Compared with the control group, the psychosis group had significant increases in 2 h glucose and interleukin-6 concentrations, and in the prevalence of abnormal glucose tolerance (16% of psychosis group v. 0% of control group). Adiponectin and C-reactive protein concentrations did not differ significantly between the two groups. These findings could not be attributed to differences in cortisol concentrations, smoking, gender, neighbourhood of residence, body mass index, aerobic conditioning, ethnicity, socioeconomic status or age. Individuals with non-affective psychosis appear to have an increased prevalence of abnormal glucose tolerance prior to antipsychotic treatment, as well as abnormalities in a related inflammatory molecule. These underlying problems may contribute to the metabolic side-effects of antipsychotic medications.
Article
Attempts to develop selective ("magic bullet") drugs for the treatment of schizophrenia have been frustrated by the complex etiology of the disease. The symptomatology of schizophrenia does not appear to arise from a single neurobiological entity, but rather may be derived from pathology at one or more receptor types. This has prompted multifactorial approaches to the development of new therapeutics, as embodied by polypharmacy and an alternative (or augmentative) strategy known as "intramolecular polypharmacy," in which a single drug possesses the capacity to affect multiple receptor types. Atypical antipsychotics are a well-known example of this approach; each atypical possesses a unique portfolio of activities at receptors that may contribute to therapeutic effects (as well as side effects). In this article we present a discussion of some of the receptor targets that are currently thought to mediate symptoms of schizophrenia, as well as their possible implications for the design of future multifunctional antipsychotics.
Article
SAP97 gene encodes the synaptic scaffolding PDZ proteins that interact with the L: -alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionate (AMPA), kainate and N-methyl-D: -aspartate (NMDA) type glutamate receptors. Because the disturbed glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia, we investigated association between the SAP97 gene and schizophrenia. We genotyped 23 SNPs capturing the known common haplotype variations of the gene in a sample comprising 229 schizophrenic patients and 214 matched controls. In a single marker analysis, ten SNPs displayed nominally significant (P < 0.05) association with schizophrenia, although the P values of these SNPs were non-significant after the Bonferroni correction. We also compared haplotype estimates based on case--control genotypes and observed significant association of eight-two- and three- SNP haplotypes with schizophrenia following permutation-based correction. Further examination of the above series of SNPs or haplotypes in each gender revealed significant associations between some of these SNPs or haplotypes and the disorder only in males. The present findings suggest that the SAP97 gene may be a susceptibility factor in male schizophrenics and that the modification of the glutamate receptors-SAP97 signaling pathway could be involved in the disease pathophysiology.
Article
: 1. After 50 years of antipsychotic drug development focused on the dopamine D2 receptor, schizophrenia remains a chronic, disabling disorder for most affected individuals. 2. Studies over the last decade demonstrate that administration of low doses of NMDA receptor antagonists can cause in normal subjects the negative symptoms, cognitive impairments and physiologic disturbances observed in schizophrenia. 3. Furthermore, a number of recently identified risk genes for schizophrenia affect NMDA receptor function or glutamatergic neurotransmission. 4. Placebo-controlled trials with agents that directly or indirectly activate the glycine modulatory site on the NMDA receptor have shown reduction in negative symptoms, improvement in cognition and in some cases reduction in positive symptoms in schizophrenic patients receiving concurrent antipsychotic medications. 5. Thus, hypofunction of the NMDA receptor, possibly on critical GABAergic inter-neurons, may contribute to the pathophysiology of schizophrenia.
Article
Schizophrenia is a severe mental illness to which hypofunction of the N-methyl-D-aspartate receptors has been linked. Association studies have implicated the N-methyl-D-aspartate receptor 2B subunit gene (GRIN2B) as a candidate for schizophrenia. Subsequent studies have attempted to replicate the association, but the results have been mixed and thus inconclusive. It is necessary to explain the inconsistency of these results and to clarify the contribution of the GRIN2B gene to schizophrenia. The current meta-analysis covers all published association studies up to January 2006 using systematic allelic and genotypic analyses involving five polymorphisms. The results show evidence of a statistically significant association for GRIN2B. The association seems weaker, but nonetheless interesting. The meta-analysis supports the involvement of the glutamate system of the brain in the pathogenesis of schizophrenia. This may be the first systematic meta-analysis study focusing on GRIN2B.
Article
To determine whether there is an association between Type 2 diabetes mellitus and schizophrenia, independent of medication. In this cross-sectional study we performed an oral glucose tolerance test on 38 non-obese white Caucasians who fulfilled the criteria for first-episode drug-naïve schizophrenia, 38 control subjects (matched for age, gender, smoking status, alcohol intake and ethnicity) and 44 first-degree relatives of the patients. The frequency of impaired glucose tolerance (IGT), defined by World Health Organization criteria, was 10.5% (n = 4) in patients with schizophrenia, 18.2% (n = 8) in unaffected relatives and 0.0% in healthy control subjects (chi(2) = 4.22, d.f. = 2, P < 0.05). The high point prevalence of IGT in never-treated patients and relatives supports either shared environmental or genetic predisposition to IGT. Both patients and their relatives present an ideal cost-effective opportunity to screen for Type 2 diabetes mellitus, as they are both easily identifiable.
Article
Serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders including major depressive disorder (MDD) and schizophrenia (SCZ). The serotonin transporter (5-HTT) is a major regulator of 5-HT function. 5-HTT gene polymorphic variants have been associated with both MDD and SCZ. A case-control design was used for candidate gene-disease association in 194 MDD patients, 155 schizophrenic psychosis patients, and 246 healthy controls, all North European Caucasians. Four polymorphisms were analyzed in terms of genotype, allele, and haplotype-based associations. Linkage disequilibrium (LD) analysis was also carried out. Bonferroni correction was used for multiple testing. Haplotype-based analyses showed significant associations between 5-HTT and SCZ but not MDD. No single locus associations were observed. In agreement with published meta-analysis our results indicate that 5-HTT associates with SCZ but not with MDD. It appears that risk for SCZ maps within a specific 5-HTT haplotype block.
Article
Despite improvements in mental health services in recent decades, it is unclear whether the risk of mortality in schizophrenia has changed over time. To explore the distribution of standardized mortality ratios (SMRs) for people with schizophrenia. Broad search terms were used in MEDLINE, PsychINFO, Web of Science, and Google Scholar to identify all studies that investigated mortality in schizophrenia, published between January 1, 1980, and January 31, 2006. References were also identified from review articles, reference lists, and communication with authors. Population-based studies that reported primary data on deaths in people with schizophrenia. Operationalized criteria were used to extract key study features and mortality data. We examined the distribution of SMRs and pooled selected estimates using random-effects meta-analysis. We identified 37 articles drawn from 25 different nations. The median SMR for all persons for all-cause mortality was 2.58 (10%-90% quantile, 1.18-5.76), with a corresponding random-effects pooled SMR of 2.50 (95% confidence interval, 2.18-2.43). No sex difference was detected. Suicide was associated with the highest SMR (12.86); however, most of the major causes-of-death categories were found to be elevated in people with schizophrenia. The SMRs for all-cause mortality have increased during recent decades (P = .03). With respect to mortality, a substantial gap exists between the health of people with schizophrenia and the general community. This differential mortality gap has worsened in recent decades. In light of the potential for second-generation antipsychotic medications to further adversely influence mortality rates in the decades to come, optimizing the general health of people with schizophrenia warrants urgent attention.
Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents
  • S Miyamoto
  • N Miyake
  • L F Jarskog
Miyamoto S, Miyake N, Jarskog LF, et al. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents [published online ahead of print May 15, 2012].
Alpha7 nicotinic cholinergic neuromodulation may reconcile multiple neurotransmitter hypotheses of schizophrenia
  • A J Kucinski
  • M K Stachowiak
  • S R Wersinger
Kucinski AJ, Stachowiak MK, Wersinger SR, et al. Alpha7 neuronal nicotinic receptors as targets for novel therapies to treat multiple domains of schizophrenia. Curr Pharm Biotechnol. 2011;12(3):437-448. PubMed Understanding the Physiology of Schizophrenia | Depression Tribune https://depressiontribunegrel.wordpress.com/2013/06/16/understanding-the-physiology-of-schizophrenia/[11/8/2017 2:33:53 PM] 20. Bencherif M, Stachowiak MK, Kucinski AJ, et al. Alpha7 nicotinic cholinergic neuromodulation may reconcile multiple neurotransmitter hypotheses of schizophrenia. Med Hypotheses. 2012;78(5):594-600. PubMed