Inverse relationship between serum high density lipoprotein and negative syndrome in antipsychotic-naive schizophrenia

Background: Recent literature suggests a role for apolipoprotein L (apoL) aberrations in the pathogenesis of schizophrenia. ApoL is almost exclusively associated with apolipoprotein A-I in high-density lipoproteins (HDLs). The objective of this study was to examine the correlation between symptom scores and serum HDL in antipsychotic-naive schizophrenia patients. Methods: In this cross-sectional study, 60 antipsychotic-naive schizophrenia patients were systematically examined for their symptom scores, with good inter-rater reliability. Concurrently, an overnight fasting serum lipid profile from these patients was assessed. Results: Serum HDL had a significant inverse correlation with a total negative syndrome score (ρ=−0.43; p=0.001). Conclusions: The study observation supports the potential role for HDL abnormalities in the genesis of negative symptoms in schizophrenia. Clin Chem Lab Med 2010;48:95–8.Peer Reviewe

Retinal vascular tortuosity in schizophrenia and bipolar disorder

\u3cp\u3eThe micro-vasculature of retina and brain share common morphological, physiological, and pathological properties. Retina being easily accessible, retinal vascular examination provides an indirect assessment of cerebral vasculature. Considering the high prevalence of vascular morbidity in SCZ and BD a few studies have examined retinal vascular caliber and have reported increased retinal venular caliber in schizophrenia (SCZ). Retinal vascular tortuosity could serve as a better structural measure than caliber as it is static and less susceptible to pulse period variations. However, to date, no study has examined retinal vascular tortuosity in SCZ and bipolar disorder (BD). Hence, we examined retinal vascular tortuosity in comparison with healthy volunteers (HV). We included 255 subjects (78 HV, 79 SCZ, and 86 BD) in the age range of 18 to 50 years. Trained personnel acquired images using a non-mydriatic fundus camera. To measure the average retinal arteriolar tortuosity index (RATI) and retinal venular tortuosity index (RVTI), we used a previously validated, semi-automatic algorithm. The results showed significant differences across the three groups in RATI but not in RVTI; both BD and SCZ had significantly increased RATI compared to HV. There was also a significant difference between SCZ and BD, with BD having higher RATI. If shown to be of predictive utility in future longitudinal studies, it has the potential to identify patients at risk of development of adverse vascular events. As retinal vascular imaging is non-invasive and inexpensive, it could serve as a proxy marker and window to cerebral vasculature.\u3c/p\u3

The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair

In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA2 GPCR axis. In IEC-6 crypt cells and jejunum enteroids quantitative RT-PCR showed a time- and dose-dependent upregulation of lpa2 in response to γ-irradiation that was abolished by mutation of the NF-κB site in the lpa2 promoter or by inhibition of ATM/ATR kinases with CGK-733, suggesting that lpa2 is a DNA damage response gene upregulated by ATM via NF-κB. The resolution kinetics of the DNA damage marker γ-H2AX in LPA-treated IEC-6 cells exposed to γ-irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA2 delayed the resolution of γ-H2AX. In LPA2-reconstituted MEF cells lacking LPA1&3 the levels of γ-H2AX decreased rapidly, whereas in Vector MEF were high and remained sustained. Inhibition of ERK1&2 or PI3K/AKT signaling axis by pertussis toxin or the C311A/C314A/L351A mutation in the C-terminus of LPA2 abrogated the effect of LPA on DNA repair. LPA2 transcripts in Lin(-)Sca-1(+)c-Kit(+) enriched for bone marrow stem cells were 27- and 5-fold higher than in common myeloid or lymphoid progenitors, respectively. Furthermore, after irradiation higher residual γ-H2AX levels were detected in the bone marrow or jejunum of irradiated LPA2-KO mice compared to WT mice. We found that γ-irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNFα. These findings identify ATX and LPA2 as radiation-regulated genes that appear to play a physiological role in DNA repair

Investigational drugs for schizophrenia targeting the dopamine receptor: phase II trials

Introduction: For over half a century now, the dopamine hypothesis has provided the most widely accepted heuristic model linking pathophysiology and treatment in schizophrenia. Despite dopaminergic drugs being available for six decades, this system continues to represent a key target in schizophrenia drug discovery. The present article reviews the scientific rationale for dopaminergic medications historically and the shift in our thinking since, which is clearly reflected in the investigational drugs detailed. Areas covered: We searched for investigational drugs using the key words `dopamine,' `schizophrenia,' and `Phase II' in American and European clinical trial registers (clinicaltrials. gov; clinicaltrialsregister.eu), published articles using National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. We provide a brief description of drugs targeting dopamine synthesis, release or metabolism, and receptors (agonists/partial agonists/antagonists). Expert opinion: There are prominent shifts in how we presently conceptualize schizophrenia and its treatment. Current efforts are not as much focused on developing better antipsychotics but, instead, on treatments that can improve other symptom domains, in particular cognitive and negative. This new era in the pharmacotherapy of schizophrenia moves us away from the older `magic bullet' approach toward a strategy fostering polypharmacy and a more individualized approach shaped by the individual's specific symptom profile

Targeting the dopamine receptor in schizophrenia: investigational drugs in Phase III trials

Introduction: Antipsychotic drugs date back to the 1950s and chlorpromazine. Soon after, it was established that blockade of dopamine and, in particular, the D-2 receptor was central to this effect. Dopamine continues to represent a critical line of investigation, although much of the work now focuses on its potential in other symptom domains. Areas covered: A search was carried out for investigational drugs using the key words `dopamine', `schizophrenia' and `Phase III' in an American clinical trial registry (clinicaltrials.gov), published articles using the National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. Drugs were excluded that were already FDA approved. Expert opinion: There remains interest, albeit diminished, in developing better antipsychotic compounds. The greatest enthusiasm currently centres on dopamine's role in negative and cognitive symptom domains. With theories conceptualising hypodopaminergic activity as underlying these deficits, considerable effort is focused on drug strategies that will enhance dopamine activity. Finally, a small body of research is investigating dopaminergic compounds vis-a-vis side-effect treatments. In domains beyond psychosis, however, dopamine arguably is not seen as so central, reflected in considerable research following other lines of investigation

Proton magnetic resonance spectroscopy in depression

Magnetic Resonance Spectroscopy (MRS) is a unique technique that can directly assess the concentration of various biochemical metabolites in the brain. Thus, it is used in the study of molecular pathophysiology of different neuropsychiatric disorders, such as, the major depressive disorder and has been an area of active research. We conducted a computer-based literature search using the Pubmed database with ‘magnetic resonance spectroscopy’, ‘MRS’, ‘depression’, and ‘major depressive disorder’ as the key words, supplemented by a manual search of bibliographic cross-referencing. Studies in depression report abnormalities in the frontal cortex, basal ganglia, hippocampus, anterior cingulate cortex, and the occipital cortex. These abnormalities improve after treatment with selective serotonin reuptake inhibitor, electroconvulsive therapy, and yoga, and thus, are possibly state-dependent. The findings are consistent with other morphometric and clinical studies and support the proposed pathophysiological theory of dysfunction in the neuronal circuits involving the frontal cortex, limbic cortex, and basal ganglia. Spectroscopy also has potential implications in predicting the response to treatment and formulating individualized pharmacotherapy

Neuroanatomical, Neurochemical, and Neurodevelopmental Basis of Obsessive-Compulsive Symptoms in Schizophrenia

The prevalence of the obsessive-compulsive symptoms in schizophrenia (OCSS) appears to be higher than that expected on the basis of comorbidity rates. Review of brain abnormalities in schizophrenia and obsessive-compulsive disorder (OCD) reveals involvement of similar regions namely the frontal lobe, the basal ganglia, the thalamus, and the cerebellum, in both the disorders. Neurodevelopmental etiopathogenesis has been proposed to explain schizophrenia as well as OCD. Significant overlap in neurotransmitter dysfunction (serotonin, glutamate, and dopamine) has been documented between schizophrenia and OCD. The New-onset obsessive-compulsive (OC) symptoms have been reported with the use of atypical antipsychotics in the schizophrenia patients In this background, OCSS is an emerging area of recent interests. This article attempts to review the literature on the neurobiology of OCSS. Neuroimaging, neuropsychological, and neuromotor abnormalities in OCSS discussed in the context of neurodevelopmental etiopathogenesis suggest glutamate abnormalities in OCSS. Atypical antipsychotic induced OCSS points towards the possible roles of glutamate and serotonin. Dopamine may be responsible for the beneficial role of antipsychotics in the treatment of OCD. In summary, we propose that glutamate, serotonin, and dopamine abnormalities may be the probable basis for OCSS

Successful Use of Add - On Topiramate for Antipsychotic - Induced Weight Gain

Antipsychotic induced weight gain is the most common and distressing side effect. This also affects the compliance toward the treatment and hence the prognosis. Non - pharmacological interventions such as exercise and diet modifications alone might not be sufficient most of the times; also ensuring compliance toward this is difficult in patients with psychiatric illness. So, the role of weight - reducing drugs become important. In this case report, we describe the use of low - dose topiramate as a weight - reducing agent, in a patient with a bipolar affective disorder - mania with psychotic symptoms, who had significant risperidone - induced weight gain