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1.  Cognitive remission: a novel objective for the treatment of major depression? 
BMC Medicine  2016;14:9.
Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD.
Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10.
The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to ‘cognitive remission’, which may aid functional recovery in MDD.
PMCID: PMC4724131  PMID: 26801406
Antidepressants; Cognition; Cognitive enhancers; Erythropoietin; Lisdexamfetamine dimesylate; Major depression; Novel targets; Vortioxetine; Psychiatry
2.  Differential regulation of inflammation and apoptosis in Fas-resistant hepatocyte-specific Bid-deficient mice 
Journal of hepatology  2014;61(1):107-115.
Activation of Fas death receptor results in apoptosis in multiple organs, particularly liver, in a process dependent on Bid cleavage. Mice injected with an anti-Fas antibody die within hours of acute liver failure associated with massive apoptosis and hemorrhage. Our aim was to investigate the crosstalk of apoptotic and inflammatory pathways and the contribution of selective hepatocellular apoptosis during in vivo Fas activation.
We generated hepatocytes-specific Bid deficient mice (hBid−/−). Acute liver injury was induced by Fas-activating antibody (Jo2) in a time-course study.
In contrast to controls, Jo2 injected hBid−/− nearly all survived. Their livers showed complete protection against hepatocellular apoptosis with minimal focal hemorrhagic changes and mainly non-parenchymal cell apoptosis. In agreement, the hepatocytes had no mitochondrial cytochrome c release in cytosol, or caspase 3 activation. hBid−/− livers showed marked increase in acute inflammatory foci composed of neutrophils and monocytes associated with the increased expression of proinflammatory chemokines and cytokines, in the manner dependent on noncanonical interleukin-1β activation and amplified in the absence of caspase-3 activation. In addition, hBid−/− mice were completely protected from hepatotoxicity and the infiltrated cells were cleared 2 weeks post single Jo2 injection.
Hepatocyte Bid suppression is critical for the resistance to the lethal effects of Fas activation in vivo. Fas signaling induces differential activation of noncanonical interleukin-1β maturation, amplified in the absence of apoptotic Bid-mitochondrial loop, in hepatocytes. These findings may have important pathophysiological and therapeutic implications in a variety of liver disorders associated with Fas activation.
PMCID: PMC4712949  PMID: 24681344
hepatoprotection; inflammation; Fas-mediated hepatic apoptosis; acute liver failure; crosstalk of inflammatory and apoptotic pathways; noncanonical IL-1β maturation
3.  Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies 
BMC Medicine  2015;13:289.
The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels.
We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder.
Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges’ g = −0.57, P = 0.010) and depressive (Hedges’ g = −0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one.
In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0529-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4666054  PMID: 26621529
Biomarker; Bipolar disorder; Brain-derived neurotrophic factor; Meta-analysis
4.  Th17 Pathway–Mediated Immunopathogenesis of Schizophrenia: Mechanisms and Implications 
Schizophrenia Bulletin  2014;40(6):1412-1421.
Schizophrenia is a highly complex and severe neuropsychiatric disorder with an unknown etiopathology. Evidence for a dysregulated immune system in both the risk for and progression of schizophrenia has recently been overwhelming. Importantly, chronic low-grade inflammation both in the periphery and central nervous system has been shown to contribute predominantly to the pathogenesis of schizophrenia in a subset of individuals. Inflammation in the central nervous system is mediated by a range of proinflammatory cytokines, resident immune cells such as microglia, and brain infiltrating peripheral immunocompetent cells, such as T lymphocytes. Recently, Th17 cells, a subset of T helper cells have emerged as crucial players in mucosal defense against infections. It is linked to atopic, inflammatory, and autoimmune disorders. The risk factors/mechanisms leading to low-grade inflammation in schizophrenia are diverse and include infectious agents, stress, trauma, environmental toxins, genetic vulnerability, physical inactivity, obesity, poor diet, and sleep disruption. Herein, we propose that fetal programming of cellular immune components driven by intrauterine adversity can lead to the generation of long-lasting effector/memory Th17 cells. Th17 cells can disrupt the blood-brain barrier, infiltrate the central nervous system, and, along with other cytokines and microglia, lead to neuroprogression through neuroinflammation in schizophrenia.
PMCID: PMC4193719  PMID: 24711545
Th17 cells; IL-17 cytokine; inflammation; neuroprogression; schizophrenia; pathogenesis; etiology; fetal
5.  Evaluating discussion board engagement in the MoodSwings online self-help program for bipolar disorder: protocol for an observational prospective cohort study 
BMC Psychiatry  2015;15:243.
Online, self-guided programs exist for a wide range of mental health conditions, including bipolar disorder, and discussion boards are often part of these interventions. The impact engagement with these discussion boards has on the psychosocial well-being of users is largely unknown. More specifically we need to clarify the influence of the type and level of engagement on outcomes.
The primary aim of this exploratory study is to determine if there is a relationship between different types (active, passive or none) and levels (high, mid and low) of discussion board engagement and improvement in outcome measures from baseline to follow up, with a focus on self-reported social support, stigma, quality of life and levels of depression and mania. The secondary aim of this study is to identify any differences in demographic variables among discussion users.
The present study is a sub-study of the MoodSwings 2.0 3-arm randomised controlled trial (discussion board only (arm 1), discussion board plus psychoeducation (arm 2), discussion board, psychoeducation plus cognitive behavioural therapy-based tools (arm 3)). Discussion engagement will be measured via online participant activity monitoring. Assessments include online self-report as well as blinded phone interviews at baseline, 3, 6, 9 and 12 months follow up.
The results of this study will help to inform future programs about whether or not discussion boards are a beneficial inclusion in online self-help interventions. It will also help to determine if motivating users to actively engage in online discussion is necessary, and if so, what level of engagement is optimal to produce the most benefit. Future programs may benefit through being able to identify those most likely to poorly engage, based on demographic variables, so motivational strategies can be targeted accordingly.
Trial registration NCT02118623 registered April 15 2014 and NCT02106078 registered May 16 2013.
PMCID: PMC4604761  PMID: 26462799
Bipolar disorder; Internet; Online; Support group; Mental health
6.  Stage managing bipolar disorder 
Bipolar disorders  2013;16(5):471-477.
Clinical staging is widespread in medicine—it informs prognosis, clinical course and treatment, and assists individualized care. Staging places an individual on a probabilistic continuum of increasing potential disease severity, ranging from clinically at-risk or latency stage through first threshold episode of illness or recurrence and finally to late or end-stage disease. The aim of this paper was to examine and update the evidence regarding staging in bipolar disorder, and how this might inform targeted and individualized intervention approaches.
We provide a narrative review of the relevant information.
In bipolar disorder, the validity of staging is informed by a range of findings that accompany illness progression, including neuroimaging data suggesting incremental volume loss, cognitive changes, and a declining likelihood of response to pharmacological and psychosocial treatments. Staging informs the adoption of a number of approaches, including the active promotion of both indicated prevention for at-risk individuals and early intervention strategies for newly diagnosed individuals, and the tailored implementation of treatments according to the stage of illness.
The nature of bipolar disorder implies the presence of an active process of neuroprogression that is considered at least partly mediated by inflammation, oxidative stress, apoptosis and changes in neurogenesis. It further supports the concept of neuroprotection, in that a diversity of agents have putative effects against these molecular targets. Clinically, staging suggests that the at-risk state or first episode is a period that requires particularly active and broad-based treatment, consistent with the hope that the temporal trajectory of the illness can be altered. Prompt treatment may be potentially neuroprotective and attenuate the neurostructural and neurocognitve changes that emerge with chronicity. Staging highlights the need for interventions at a service delivery level and implementing treatments at the earliest stage of illness possible.
PMCID: PMC3864129  PMID: 23782499
bipolar disorder; clinical staging; depression; early intervention; mania; neuroprogression; treatment
7.  Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet induced NASH model 
Digestive diseases and sciences  2014;59(6):1197-1206.
Hepatocyte cell death is a key feature of nonalcoholic steohepatitis (NASH). As the contribution of specific caspases remains unclear, our aim was to ascertain the effect of caspase 3 suppression on liver injury and fibrogenesis.
C57BL/6 wild-type (WT), and caspase 3 knock out (Casp3−/−) mice were placed on a methionine- and choline-deficient (MCD) diet for 6 weeks to induce steatohepatitis and liver fibrosis. Thereafter, liver injury, liver fibrosis and hepatocellular apoptosis were quantified in liver sections. Additionally, expression of proteins associated with liver inflammation and fibrogenesis were analyzed.
WT mice fed MCD diet showed marked activation of caspase 3 in hepatocytes, in conjunction with steatohepatitis and increased hepatic triglyceride levels, hepatocyte ballooning, inflammation and fibrosis. Casp3−/− fed the MCD diet showed similar serum ALT levels and NAFLD activity scores (NAS) compared to WT MCD-fed mice. However Casp3−/− mice on the MCD diet showed a marked reduction in expression of transcripts for pro-fibrogenic genes i which translated into reduced hepatic collagen deposition. These changes were associated with decreased levels of apoptosis, and a significant reduction in the expression of cytokines involved in inflammatory signaling. Casp3−/− mice on the MCD showed a reduction in expression of chemokine receptor 2 (CCR2) leading to ameliorated infiltration of inflammatory lymphocyte antigen 6 complex, locus C1 (Ly6c) positive monocytes.
These findings support a prominent role for hepatocyte caspase 3 activation in NASH related apoptosis, fibrogenesis and fibrosis which in part is mediated via CCR2 dependent infiltration of Ly6c positive monocytes.
PMCID: PMC4512760  PMID: 24795036
nonalcoholic fatty liver disease; caspases; apoptosis; liver injury; liver fibrosis
8.  Excessive daytime sleepiness and falls among older men and women: cross-sectional examination of a population-based sample 
BMC Geriatrics  2015;15:74.
Excessive daytime sleepiness (EDS) has been associated with an increased risk for falls among clinical samples of older adults. However, there is little detailed information among population-representative samples. The current study aimed to assess the relationship between EDS and falls among a cohort of population-based older adults.
This study assessed 367 women aged 60-93years (median 72, interquartile range 65-79) and 451 men aged 60-92years (median 73, interquartile range 66-80) who participated in the Geelong Osteoporosis Study between the years 2001 and 2008. Falls during the prior year were documented via self-report, and for men, falls risk score was obtained using an Elderly Fall Screening Test (EFST). Sleepiness was assessed using the Epworth Sleepiness Scale (ESS), and scores of ≥ 10 indicated EDS. Differences among those with and without EDS in regard to falls were tested using logistic regression models.
Among women, 50 (13.6 %) individuals reported EDS. Women with EDS were more likely to report a fall, and were more likely to report the fall occurring outside. EDS was similarly associated with an increased risk of a fall following adjustment for use of a walking aid, cases of nocturia and antidepressant medication use (adjusted OR = 2.54, 95 % CI 1.24-5.21). Multivariate modelling revealed antidepressant use (current) as an effect modifier (p < .001 for the interaction term). After stratifying the data by antidepressant medication use, the association between EDS and falls was sustained following adjustment for nocturia among antidepressant non-users (adjusted OR = 2.63, 95 % CI 1.31-5.30). Among men, 72 (16.0 %) individuals reported EDS. No differences were detected for men with and without EDS in regard to reported falls, and a trend towards significance was noted between EDS and a high falls risk as assessed by the EFST (p = 0.06), however, age explained this relationship (age adjusted OR = 2.20, 95 % CI 1.03-1.10).
For women, EDS is independently associated with at least one fall during the previous year, and this is more likely to occur whilst located outside. Amelioration of EDS may assist in improving functional outcomes among these individuals by reducing the risk for falls.
PMCID: PMC4491238  PMID: 26141865
Excessive daytime sleepiness; Falls; Older adults; Epidemiology; Population; Elderly
9.  Impact of Cannabis Use on Long-Term Remission in Bipolar I and Schizoaffective Disorder 
Psychiatry Investigation  2015;12(3):349-355.
To investigate the impact of regular cannabis use on long-term remission of mood symptoms in bipolar spectrum disorders.
The 24-month prospective observational study included patients (n=239) with bipolar I disorder and schizoaffective disorder, bipolar type. Participants were classified as regular cannabis users (three times or more per week) or non-users. The primary outcome measure was the achievement of remission on the evaluations during the 24 months.
Of the 234 participants for whom data was available, 25 (10.7%) were regular cannabis users, and the group comprised significantly more males than females. In the total population, cannabis use was significantly associated with decreased likelihood of remission during the 24-month follow-up period. Subgroup analyses showed that cannabis use was significantly associated with lower remission rates on the Hamilton Depression Rating Scale in females (n=139) and patients prescribed mood stabilizers alone (n=151), whereas in males (n=95) and patients prescribed olanzapine and/or a mood stabilizer (n=83), cannabis use was significantly associated with lower remission rates on the Young Mania Rating Scale. Remission rates were lowest in the concurrent cannabis and tobacco smoking group (n=22) followed by the tobacco smoking only group (n=97), and the non-smoker group (n=116). The post-hoc analysis revealed that all remission rates were significantly lower in the concurrent cannabis and the tobacco smoking group compared to the non-smoker group.
Cannabis use negatively affects the long-term clinical outcome in patients with bipolar spectrum disorders. A comprehensive assessment and integrated management of cannabis use are required to achieve better treatment outcomes for bipolar spectrum disorders.
PMCID: PMC4504917  PMID: 26207128
Cannabis; Bipolar disorder; Schizoaffective disorder; Observational study; Substance; Remission
10.  Mechanisms Underlying Neurocognitive Dysfunctions in Recurrent Major Depression 
Recent work shows that depression is intimately associated with changes in cognitive functioning, including memory, attention, verbal fluency, and other aspects of higher-order cognitive processing. Changes in cognitive functioning are more likely to occur when depressive episodes are recurrent and to abate to some degree during periods of remission. However, with accumulating frequency and duration of depressive episodes, cognitive deficits can become enduring, being evident even when mood improves. Such changes in cognitive functioning give depression links to mild cognitive impairment and thereby with neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and multiple sclerosis. Depression may then be conceptualized on a dimension of depression – mild cognitive impairment – dementia. The biological underpinnings of depression have substantial overlaps with those of neurodegenerative conditions, including reduced neurogenesis, increased apoptosis, reactive oxygen species, tryptophan catabolites, autoimmunity, and immune-inflammatory processes, as well as decreased antioxidant defenses. These evolving changes over the course of depressive episodes drive the association of depression with neurodegenerative conditions. As such, the changes in cognitive functioning in depression have important consequences for the treatment of depression and in reconceptualizing the role of depression in wider neuroprogressive conditions. Here we review the data on changes in cognitive functioning in recurrent major depression and their association with other central conditions.
PMCID: PMC4459569  PMID: 26017336
Cognition; Depression; Inflammation; Neurogenesis; Oxidants
11.  Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness 
There is evidence of cognitive impairment that persists in the remission phase of bipolar disorder; however, the extent of the deficits that occur from the first onset of the disorder remains unclear. This is the first systematic review on cognitive functioning in the early stages of bipolar I disorder. The aim of the study was to identify the patterns and degree of cognitive impairment that exists from first-episode mania. Three electronic databases (MEDLINE, PsycINFO and PubMed) were systematically searched for studies published from January 1980 to June 2014. Eligible studies were separated into two groups: acute and remission. The Newcastle-Ottawa quality assessment scale was utilised to measure the quality of the included studies. A total of seven studies (three acute and four remission), including 230 first-episode mania and 345 healthy control participants, were eligible for the review. The studies in the acute phase only examined aspects of executive functioning, with impairments identified in cognitive flexibility, though not in response inhibition and verbal fluency relative to healthy controls. The most consistent finding during the remission phase was a deficit in working memory, whereas in the other domains, the findings were equivocal. Non-verbal memory and verbal fluency were not impacted in remission from first-episode mania. In conclusion, deficits are present in some but not all areas of cognitive functioning during the early stages of bipolar I disorder. Further research is warranted to understand the longitudinal trajectory of change from first-episode mania.
Electronic supplementary material
The online version of this article (doi:10.1186/s40345-015-0024-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4408302  PMID: 25914866
Mania; Cognition; Bipolar disorder; Depression; First episode; Early intervention
13.  Oxidant/antioxidant imbalance is an inherent feature of depression 
BMC Psychiatry  2015;15:71.
50% to 60% of the people who have recovered from the first episode of depression experience a relapse. The immune system of the people suffering from depression is in a permanent state of pathological pro-inflammatory readiness. There are some reports that depressive episodes cause sensitization of immune-inflammatory pathways and that staing of depression (e.g. number of depressive episodes) is correlated with immune-inflammatory markers.
The main objective of the study was to delineate whether recurrent major depression (rDD) is characterized by alterations in selected immune-inflammatory biomarkers as compared with first episode of depression (ED-I), i.e. expression of mRNA and enzymatic activity of manganese superoxide dismutase (MnSOD, SOD-2), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS, NOS-2), and cyclooxygenase-2 (COX-2).
The study was carried out in a group of 131 patients: ED-I group – 42 patients, rDD group – 89 patients. Depression severity was assessed with the 17-item Hamilton Depression Rating Scale (HDRS). The number of depression episodes and the disease duration periods were recorded in each patient. For the patients, HDRS was administered at admission during the symptomatic phase, which would generally be either before or shortly after modification of the previous antidepressant drug regimen. Reassessment of the mental condition was conducted after 8 weeks of the pharmacological treatment also with the use of the HDRS scale.
No significant statistical differences were found between the analysed groups as regards the intensity of depressive disorders. No differences in the expression of MnSOD, MPO, COX-2 and i-NOS genes on the level of both mRNA and protein were observed between both groups. No significant interrelation was noticed between the number of depression episodes experienced and the expression of selected genes on the mRNA level and protein level.
There is no significant difference in MnSOD, MPO, COX-2 and i-NOS between patients with recurrent depressive disorders and those in a first episode of depression. These findings suggest that these enzymes are trait markers of depression and are not related to staging of depression.
PMCID: PMC4392866  PMID: 25880127
Depression episode; rDD; MnSOD; MPO; COX-2; i-NOS
14.  Psychiatric disorders, psychotropic medication use and falls among women: an observational study 
BMC Psychiatry  2015;15:75.
Psychotropic agents known to cause sedation are associated with an increased risk of falls, but the role of psychiatric illness as an independent risk factor for falls is not clear. Thus, this study aimed to investigate the association between psychiatric disorders, psychotropic medication use and falls risk.
This study examined data collected from 1062 women aged 20-93 yr (median 50 yr) participating in the Geelong Osteoporosis Study, a large, ongoing, population-based study. Depressive and anxiety disorders for the preceding 12-month period were ascertained by clinical interview. Current medication use and falls history were self-reported. Participants were classified as fallers if they had fallen to the ground at least twice during the same 12-month period. Anthropometry, demographic, medical and lifestyle factors were determined. Logistic regression was used to test the associations, after adjusting for potential confounders.
Fifty-six women (5.3%) were classified as fallers. Those meeting criteria for depression within the past 12 months had a 2.4-fold increased odds of falling (unadjusted OR = 2.4, 95% CI 1.2-4.5). Adjustment for age and mobility strengthened the relationship (adjusted OR = 2.7, 95% CI 1.4-5.2) between depression and falling, with results remaining unchanged following further adjustment for psychotropic medication use (adjusted OR = 2.7, 95% CI 1.3-5.6). In contrast, past (prior to 12-month) depression were not associated with falls. No association was observed between anxiety and falls risk. Falling was associated with psychotropic medication use (unadjusted OR = 2.8, 95% CI 1.5-5.2), as well as antidepressant (unadjusted OR = 2.4, 95% CI 1.2-4.8) and benzodiazepine use (unadjusted OR = 3.4, 95% CI 1.6-7.3); associations remained unchanged following adjustment for potential confounders.
The likelihood of falls was increased among those with depression within the past 12 months, independent of psychotropic medication use and other recognised confounders, suggesting an independent effect of depression on falls risk. Psychotropic drug use was also confirmed as an independent risk factor for falls, but anxiety disorders were not. Further research into the underlying mechanisms is warranted.
PMCID: PMC4394398  PMID: 25884941
Depression; Anxiety; Falls; Psychotropic medication; Antidepressants; Benzodiazepine
15.  Microparticles Release by Adipocytes Act as “Find-Me” Signals to Promote Macrophage Migration 
PLoS ONE  2015;10(4):e0123110.
Macrophage infiltration of adipose tissue during weight gain is a central event leading to the metabolic complications of obesity. However, what are the mechanisms attracting professional phagocytes to obese adipose tissue remains poorly understood. Here, we demonstrate that adipocyte-derived microparticles (MPs) are critical “find-me” signals for recruitment of monocytes and macrophages. Supernatants from stressed adipocytes stimulated the attraction of monocyte cells and primary macrophages. The activation of caspase 3 was required for release of these signals. Adipocytes exposed to saturated fatty acids showed marked release of MPs into the supernatant while common genetic mouse models of obesity demonstrate high levels of circulating adipocyte-derived MPs. The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase. Further analysis identified these MPs as a central chemoattractant in vitro and in vivo. In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice. These data identify adipocyte-derived MPs as novel “find me” signals that contributes to macrophage infiltration associated with obesity.
PMCID: PMC4388837  PMID: 25849214
16.  Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature  
Autism is a disorder of unknown etiology. There are few FDA approved medications for treating autism. Co-occurring autism and epilepsy is common, and glutamate antagonists improve some symptoms of autism. Ceftriaxone, a beta-lactam antibiotic, increases the expression of the glutamate transporter 1 which decreases extracellular glutamate levels. It is hypothesized that modulating astrocyte glutamate transporter expression by ceftriaxone or cefixime might improve some symptoms of autism. This case report of a child with autism and epilepsy suggests a decrease in seizures after taking cefixime
PMCID: PMC4322506  PMID: 25767546
Cefixime; Antibiotic; Glutamate; Transporter; Therapy; Inflammation
17.  The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders 
BMC Medicine  2015;13:68.
Mitochondrial dysfunction and defects in oxidative metabolism are a characteristic feature of many chronic illnesses not currently classified as mitochondrial diseases. Examples of such illnesses include bipolar disorder, multiple sclerosis, Parkinson’s disease, schizophrenia, depression, autism, and chronic fatigue syndrome.
While the majority of patients with multiple sclerosis appear to have widespread mitochondrial dysfunction and impaired ATP production, the findings in patients diagnosed with Parkinson’s disease, autism, depression, bipolar disorder schizophrenia and chronic fatigue syndrome are less consistent, likely reflecting the fact that these diagnoses do not represent a disease with a unitary pathogenesis and pathophysiology. However, investigations have revealed the presence of chronic oxidative stress to be an almost invariant finding in study cohorts of patients afforded each diagnosis. This state is characterized by elevated reactive oxygen and nitrogen species and/or reduced levels of glutathione, and goes hand in hand with chronic systemic inflammation with elevated levels of pro-inflammatory cytokines.
This paper details mechanisms by which elevated levels of reactive oxygen and nitrogen species together with elevated pro-inflammatory cytokines could conspire to pave a major road to the development of mitochondrial dysfunction and impaired oxidative metabolism seen in many patients diagnosed with these disorders.
PMCID: PMC4382850  PMID: 25889215
Autism; Bipolar disorder; Schizophrenia; Chronic fatigue syndrome; Cytokines; Depression; Immune dysfunction; Inflammatory; Mitochondrial dysfunction; Multiple sclerosis; Nitric oxide; Oxidative stress; Parkinson’s disease; Peroxynitrite; Psychiatry; Neurology
18.  N-Acetyl Cysteine in the Treatment of Obsessive Compulsive and Related Disorders: A Systematic Review 
Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established. N-acetyl cysteine (NAC) is a glutamate modulator with promising therapeutic effect. This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders. A further objective was to detail the methodology of current clinical trials being conducted in the area.
PubMed, Web of Science and Cochrane Library Database were searched for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder (OCD) or obsessive compulsive related disorders. Researchers with known involvement in NAC studies were contacted for any unpublished data.
Four clinical trials and five case reports/series were identified. Study durations were commonly 12-weeks, using 2,400–3,000 mg/day of NAC. Overall, NAC demonstrates activity in reducing the severity of symptoms, with a good tolerability profile and minimal adverse effects. Currently there are three ongoing randomized controlled trials using NAC for OCD (two adults and one pediatric), and one for excoriation.
Encouraging results have been demonstrated from the few pilot studies that have been conducted. These results are detailed, in addition to a discussion of future potential research.
PMCID: PMC4423164  PMID: 25912534
Obsessive-compulsive disorder; Trichotillomania, acetylcysteine; Glutamate; Review, systematic
19.  Effects of Persisting Emotional Impact from Child Abuse and Norepinephrine Transporter Genetic Variation on Antidepressant Efficacy in Major Depression: A Pilot Study 
Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and anti-depressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials.
Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history.
No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85–514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error.
The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.
PMCID: PMC4423165  PMID: 25912538
Abuse; Child; Antidepressants; Norepinephrine transporter; Remission
20.  Tobacco Use in Bipolar Disorder 
Tobacco use in mental health in general and bipolar disorder in particular remains disproportionally common, despite declining smoking rates in the community. Furthermore, interactions between tobacco use and mental health have been shown, indicating the outcomes for those with mental health disorders are impacted by tobacco use. Factors need to be explored and addressed to improve outcomes for those with these disorders and target specific interventions for people with psychiatric illness to cease tobacco smoking. In the context of bipolar disorder, this review explores; the effects of tobacco smoking on symptoms, quality of life, suicidal behaviour, the biological interactions between tobacco use and bipolar disorder, the interactions between tobacco smoking and psychiatric medications, rates and factors surrounding tobacco smoking cessation in bipolar disorder and suggests potential directions for research and clinical translation. The importance of this review is to bring together the current understanding of tobacco use in bipolar disorder to highlight the need for specific intervention.
PMCID: PMC4423166  PMID: 25912533
Bipolar disorder; Smoking; Smoking cessation; Quality of life; Psychotropic drugs
21.  A brief review of exercise, bipolar disorder, and mechanistic pathways 
Despite evidence that exercise has been found to be effective in the treatment of depression, it is unclear whether these data can be extrapolated to bipolar disorder. Available evidence for bipolar disorder is scant, with no existing randomized controlled trials having tested the impact of exercise on depressive, manic or hypomanic symptomatology. Although exercise is often recommended in bipolar disorder, this is based on extrapolation from the unipolar literature, theory and clinical expertise and not empirical evidence. In addition, there are currently no available empirical data on program variables, with practical implications on frequency, intensity and type of exercise derived from unipolar depression studies. The aim of the current paper is to explore the relationship between exercise and bipolar disorder and potential mechanistic pathways. Given the high rate of medical co-morbidities experienced by people with bipolar disorder, it is possible that exercise is a potentially useful and important intervention with regard to general health benefits; however, further research is required to elucidate the impact of exercise on mood symptomology.
PMCID: PMC4349127  PMID: 25788889
bipolar disorder; exercise; mechanistic pathways; depression; hypomania; neurogenesis
22.  Prevention of Schizophrenia—Will a Broader Prevention Agenda Support This Aim? 
Schizophrenia Bulletin  2014;40(2):237-239.
PMCID: PMC3932093  PMID: 24391020
23.  Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses 
BMC Medicine  2015;13:28.
The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.
Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.
It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.
PMCID: PMC4320458  PMID: 25856766
Immune; Inflammation; Oxidative stress; Toll-like receptor; Fatigue; Mitochondria; Multiple sclerosis; Chronic fatigue syndrome; Parkinson’s disease
24.  A shared framework for the common mental disorders and Non-Communicable Disease: key considerations for disease prevention and control 
BMC Psychiatry  2015;15:15.
Historically, the focus of Non Communicable Disease (NCD) prevention and control has been cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), cancer and chronic respiratory diseases. Collectively, these account for more deaths than any other NCDs. Despite recent calls to include the common mental disorders (CMDs) of depression and anxiety under the NCD umbrella, prevention and control of these CMDs remain largely separate and independent.
In order to address this gap, we apply a framework recently proposed by the Centers for Disease Control with three overarching objectives: (1) to obtain better scientific information through surveillance, epidemiology, and prevention research; (2) to disseminate this information to appropriate audiences through communication and education; and (3) to translate this information into action through programs, policies, and systems. We conclude that a shared framework of this type is warranted, but also identify opportunities within each objective to advance this agenda and consider the potential benefits of this approach that may exist beyond the health care system.
PMCID: PMC4342822  PMID: 25652365
Non-Communicable Disease; Common mental disorders; Prevention; Depression; Anxiety; Cardiovascular disease; Type 2 diabetes mellitus; Co-morbidity
25.  The impact of maternal smoking during pregnancy on depressive and anxiety behaviors in children: the Norwegian Mother and Child Cohort Study 
BMC Medicine  2015;13:24.
Maternal smoking during pregnancy (MSDP) is associated with multiple adverse childhood outcomes including externalizing behaviors. However, the association between MSDP and internalizing (anxiety and depressive) behaviors in offspring has received less investigation. We aimed to assess the association between MSDP and childhood internalizing (anxiety and depressive) behaviors in a very large, well-characterized cohort study.
We assessed the association between MSDP and internalizing behaviors in offspring utilizing information drawn from 90,040 mother-child pairs enrolled in the Norwegian Mother and Child Cohort Study. Mothers reported smoking information, including status and frequency of smoking, twice during pregnancy. Mothers also reported their child’s internalizing behaviors at 18 months, 36 months, and 5 years. Associations between MSDP and childhood internalizing behaviors, including dose-response and timing of smoking in pregnancy, were assessed at each time point.
MSDP was associated with increased internalizing behaviors when offspring were aged 18 months (B = 0.11, P <0.001) and 36 months (B = 0.06, P <0.01), adjusting for numerous potential confounders. Higher rates of smoking (e.g., >20 cigarettes per day) were associated with higher levels of internalizing behaviors. Maternal smoking during early pregnancy appeared to be the critical period for exposure.
We found evidence supporting a potential role for MSDP in increasing internalizing (anxiety and depressive) behaviors in offspring. We also found evidence supportive of a possible causal relationship, including dose-dependency and support for a predominant role of early pregnancy exposure. Further investigation utilizing genetically informed designs are warranted to assess this association.
PMCID: PMC4314755  PMID: 25644294
Anxiety; Depression; Cigarette smoking; Pregnancy; Obstetrics; Psychiatry

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