The Mental Health Research Institute

Parkville, Australia

The Mental Health Research Institute

Parkville, Australia
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Malhi G.S.,Royal North Shore Hospital | Malhi G.S.,University of Sydney | Hitching R.,Royal North Shore Hospital | Hitching R.,University of Sydney | And 9 more authors.
Acta Psychiatrica Scandinavica | Year: 2013

Objective: To be used in conjunction with 'Psychological management of unipolar depression' [Lampe et al. Acta Psychiatr Scand 2013;127(Suppl. 443):24-37] and 'Lifestyle management of unipolar depression' [Berk et al. Acta Psychiatr Scand 2013;127(Suppl. 443):38-54]. To provide clinically relevant recommendations for the use of pharmacological treatments in depression derived from a literature review. Method: Using our previous Clinical Practice Guidelines [Malhi et al. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand 2009;119(Suppl. 439):27-46] as a foundation, these clinician guidelines target key practical considerations when prescribing pharmacotherapy. A comprehensive review of the literature was conducted using electronic database searches (PubMed, MEDLINE), and the findings have been synthesized and integrated alongside clinical experience. Results: The pharmacotherapy of depression is an iterative process that often results in partial and non-response. Beyond the initiation of antidepressants, the options within widely used strategies, such as combining agents and switching between agents, are difficult to proscribe because of the paucity of pertinent research. However, there is some evidence for second-line strategies, and a non-prescriptive algorithm can be derived that is based broadly on principles rather than specific steps. Conclusion: Depression is by its very nature a heterogeneous illness that is consequently difficult to treat. Invariably, situation-specific factors often play a significant role and must be considered, especially in the case of partial and non-response. Consulting with colleagues and trialling alternate treatment paradigms are essential strategies in the management of depression. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.


Fodero-Tavoletti M.T.,University of Melbourne | Brockschnieder D.,Bayer AG | Villemagne V.L.,Austin Health | Villemagne V.L.,The Mental Health Research Institute | And 11 more authors.
Nuclear Medicine and Biology | Year: 2012

Purpose: Amyloid-β (Aβ) plaques are a major pathological hallmark of Alzheimer's disease (AD). The noninvasive detection of Aβ plaques may increase the accuracy of clinical diagnosis as well as monitor therapeutic interventions. While [ 11C]-PiB is the most widely used Aβ positron emission tomography (PET) radiotracer, due to the short half-life of 11C (20min), its application is limited to centers with an on-site cyclotron and 11C radiochemistry expertise. Therefore, novel [ 18F] (half-life 110min)-labeled Aβ PET tracers have been developed. We have demonstrated that [ 18F]-florbetaben-PET can differentiate individuals diagnosed with AD from healthy elderly, Parkinson's disease and frontotemporal lobe dementia (FTLD-tau) patients. While [ 18F]-florbetaben-PET retention matched the reported postmortem distribution of Aβ plaques, the nature of [ 18F]-florbetaben binding to other pathological lesions comprising misfolded proteins needs further assessment. The objective of this study was to determine whether Florbetaben selectively binds to Aβ plaques in postmortem tissue specimens containing mixed pathological hallmarks (i.e., tau and α-synuclein aggregates). Method: Human AD, FTLD-tau and dementia with Lewy bodies (DLB) brain sections were analyzed by [ 18F]-florbetaben autoradiography and [ 3H]-florbetaben high-resolution emulsion autoradiography and [ 19F]-florbetaben fluorescence microscopy. Results: Both autoradiographical analyses demonstrated that Florbetaben exclusively bound Aβ plaques in AD brain sections at low nanomolar concentrations. Furthermore, at concentrations thousand-folds higher than those during a PET scan, [ 19F]-florbetaben did not bind to α-synuclein or tau aggregates in DLB and FTLD-tau brain sections, respectively. Detection of [ 19F]-florbetaben staining by fluorescence microscopy in several AD brain regions demonstrated that Florbetaben identified Aβ plaques in all brain regions examined. Conclusion: This study provides further evidence that [ 18F]-florbetaben-PET is a highly selective radiotracer to assess Aβ plaque deposition in the brain. © 2012 Elsevier Inc.


Dean B.,The Mental Health Research Institute | Dean B.,University of Melbourne | Tawadros N.,The Mental Health Research Institute | Tawadros N.,University of Melbourne | And 4 more authors.
Journal of Affective Disorders | Year: 2010

Background: From studies in the periphery, changed levels of tumour necrosis factor (TNF) have been implicated in the pathophysiology of major depressive disorders (MDD). Therefore we decided to determine whether TNF was altered in the frontal cortex (Brodmann's areas (BA) 24 and 46) from 10 subjects with MDD and 10 control subjects. Methods: Tissue homogenates were prepared from the left hemisphere and levels of TNF trans-membrane (tmTNF) and TNF soluble (sTNF) forms measured by Western blots. Results: tmTNF was significantly increased in BA 46 (mean ± SEM: 7.70 ± 0.92 vs. 3.18 ± 0.87 Ratio Internal Control, p < 0.001), but not BA 24, from subjects with MDD, there was no change in levels of sTNF in either CNS region. Limitations: As the report of tmTNF in postmortem CNS from subjects with MDD, our findings need to be replicated in another group of cases. Conclusions: Our data supports the hypothesis that changes in pro-inflammatory pathways may be involved in the pathophysiology of MDD. Targeting these pathways may be a new approach to treating the disorder. © 2009 Elsevier B.V. All rights reserved.


Rowe C.C.,Austin Health | Ellis K.A.,University of Melbourne | Ellis K.A.,The Mental Health Research Institute | Ellis K.A.,National Ageing Research Institute | And 21 more authors.
Neurobiology of Aging | Year: 2010

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, a participant of the worldwide Alzheimer's Disease Neuroimaging Initiative (ADNI), performed 11C-Pittsburgh Compound B (PiB) scans in 177 healthy controls (HC), 57 mild cognitive impairment (MCI) subjects, and 53 mild Alzheimer's disease (AD) patients. High PiB binding was present in 33% of HC (49% in ApoE-ε4 carriers vs 21% in noncarriers) and increased with age, most strongly in ε4 carriers. 18% of HC aged 60-69 had high PiB binding rising to 65% in those over 80 years. Subjective memory complaint was only associated with elevated PiB binding in ε4 carriers. There was no correlation with cognition in HC or MCI. PiB binding in AD was unrelated to age, hippocampal volume or memory. Beta-amyloid (Aβ) deposition seems almost inevitable with advanced age, amyloid burden is similar at all ages in AD, and secondary factors or downstream events appear to play a more direct role than total beta amyloid burden in hippocampal atrophy and cognitive decline. © 2010.


Adlard P.A.,The Mental Health Research Institute | Adlard P.A.,University of Melbourne | Bica L.,University of Melbourne | White A.R.,University of Melbourne | And 9 more authors.
PLoS ONE | Year: 2011

We have previously demonstrated that brief treatment of APP transgenic mice with metal ionophores (PBT2, Prana Biotechnology) rapidly and markedly improves learning and memory. To understand the potential mechanisms of action underlying this phenomenon we examined hippocampal dendritic spine density, and the levels of key proteins involved in learning and memory, in young (4 months) and old (14 months) female Tg2576 mice following brief (11 days) oral treatment with PBT2 (30 mg/kg/d). Transgenic mice exhibited deficits in spine density compared to littermate controls that were significantly rescued by PBT2 treatment in both the young (+17%, p<0.001) and old (+32%, p<0.001) animals. There was no effect of PBT2 on spine density in the control animals. In the transgenic animals, PBT2 treatment also resulted in significant increases in brain levels of CamKII (+57%, p = 0.005), spinophilin (+37%, p = 0.04), NMDAR1A (+126%, p = 0.02), NMDAR2A (+70%, p = 0.05), pro-BDNF (+19%, p = 0.02) and BDNF (+19%, p = 0.04). While PBT2-treatment did not significantly alter neurite-length in vivo, it did increase neurite outgrowth (+200%, p = 0.006) in cultured cells, and this was abolished by co-incubation with the transition metal chelator, diamsar. These data suggest that PBT2 may affect multiple aspects of snaptic health/efficacy. In Alzheimer's disease therefore, PBT2 may restore the uptake of physiological metal ions trapped within extracellular β-amyloid aggregates that then induce biochemical and anatomical changes to improve cognitive function. © 2011 Adlard et al.


PubMed | The Mental Health Research Institute
Type: Journal Article | Journal: Progress in neuro-psychopharmacology & biological psychiatry | Year: 2010

Apolipoprotein D (ApoD) has many actions critical to maintaining mammalian CNS function. It is therefore significant that levels of ApoD have been shown to be altered in the CNS of subjects with schizophrenia, suggesting a role for ApoD in the pathophysiology of the disorder. There is also a large body of evidence that cortical and hippocampal glutamatergic, serotonergic and cholinergic systems are affected by the pathophysiology of schizophrenia. Thus, we decided to use in vitro radioligand binding and autoradiography to measure levels of ionotropic glutamate, some muscarinic and serotonin 2A receptors in the CNS of ApoD(-/-) and isogenic wild-type mice. These studies revealed a 20% decrease (mean+/-SEM: 104+/-10.2 vs. 130+/-10.4 fmol/mg ETE) in the density of kainate receptors in the CA 2-3 of the ApoD(-/-) mice. In addition there was a global decrease in AMPA receptors (F(1,214)=4.67, p<0.05) and a global increase in muscarinic M2/M4 receptors (F(1,208)=22.77, p<0.0001) in the ApoD(-/-) mice that did not reach significance in any single cytoarchitectural region. We conclude that glutamatergic pathways seem to be particularly affected in ApoD(-/-) mice and this may contribute to the changes in learning and memory, motor tasks and orientation-based tasks observed in these animals, all of which involve glutamatergic neurotransmission.


PubMed | the Mental Health Research Institute
Type: Journal Article | Journal: CNS & neurological disorders drug targets | Year: 2010

Cognitive deficits in patients with schizophrenia are the biggest obstacle to achieving an independent and productive lifestyle, with these deficits being refractory to current drug treatments. Significantly, both nicotinic and muscarinic receptors (cholinoceptors) have been shown to have an important role in cognition and are therefore viewed as potential therapeutic targets for drugs designed to lessen cognitive deficits. Importantly, the demonstration that acetylcholinesterase inhibitors, which result in higher synaptic levels of acetylcholine, can reduce the cognitive deficits of schizophrenia suggested that under-stimulation of cholinoceptors could be associated with the cognitive deficits associated with this disorder. This has lead to a focus on the development of receptor agonists, partial agonists and allosteric agonists that can be used to stimulate cholinergic pathways and thus reduce the cognitive deficits of schizophrenia. In addition, muscarinic receptors have now been associated with the modulation of dopamine and may constitute an alternative target for the treatment of psychoses. Given these exciting new therapeutic initiatives, this review will outline current evidence that involves the cholinoceptors in the pathophysiology of schizophrenia and how these data can inform on approaches to more targeted treatments for the disorder.


PubMed | The Mental Health Research Institute
Type: Journal Article | Journal: PloS one | Year: 2011

We have previously demonstrated that brief treatment of APP transgenic mice with metal ionophores (PBT2, Prana Biotechnology) rapidly and markedly improves learning and memory. To understand the potential mechanisms of action underlying this phenomenon we examined hippocampal dendritic spine density, and the levels of key proteins involved in learning and memory, in young (4 months) and old (14 months) female Tg2576 mice following brief (11 days) oral treatment with PBT2 (30 mg/kg/d). Transgenic mice exhibited deficits in spine density compared to littermate controls that were significantly rescued by PBT2 treatment in both the young (+17%, p<0.001) and old (+32%, p<0.001) animals. There was no effect of PBT2 on spine density in the control animals. In the transgenic animals, PBT2 treatment also resulted in significant increases in brain levels of CamKII (+57%, p=0.005), spinophilin (+37%, p=0.04), NMDAR1A (+126%, p=0.02), NMDAR2A (+70%, p=0.05), pro-BDNF (+19%, p=0.02) and BDNF (+19%, p=0.04). While PBT2-treatment did not significantly alter neurite-length in vivo, it did increase neurite outgrowth (+200%, p=0.006) in cultured cells, and this was abolished by co-incubation with the transition metal chelator, diamsar. These data suggest that PBT2 may affect multiple aspects of snaptic health/efficacy. In Alzheimers disease therefore, PBT2 may restore the uptake of physiological metal ions trapped within extracellular -amyloid aggregates that then induce biochemical and anatomical changes to improve cognitive function.


PubMed | The Mental Health Research Institute
Type: Journal Article | Journal: Cell metabolism | Year: 2010

The insulin-like signaling (ILS) pathway regulates metabolism and is known to modulate adult life span in C. elegans. Altered stress responses and resistance to a wide range of stressors are also associated with changes in ILS and contribute to enhanced longevity. The transcription factors DAF-16 and HSF-1 are key effectors of the longevity phenotype. We demonstrate that increased intrinsic thermotolerance, due to lower ILS, is not dependent on stress-induced transcriptional responses but instead requires active protein translation. Translation profiling experiments reveal genes that are posttranscriptionally regulated in response to altered ILS during heat shock in a DAF-16-dependent manner. Furthermore, several novel proteins are specifically required for ILS effects on thermotolerance. We propose that lowered ILS results in metabolic and physiological changes. These DAF-16-induced changes precondition a translational response under acute stress to modulate survival.


PubMed | The Mental Health Research Institute
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2010

Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn(2+) levels, which is predicted to regulate normal cognitive function. Surprisingly, previous studies found that 6- to 10-week-old ZnT3 knock-out (KO) mice did not show impairment in the Morris water maze. We hypothesized that older ZnT3 KO animals would display a cognitive phenotype. Here, we report that ZnT3 KO mice exhibit age-dependent deficits in learning and memory that are manifest at 6 months but not at 3 months of age. These deficits are associated with significant alterations in key hippocampal proteins involved in learning and memory, as assessed by Western blot. These include decreased levels of the presynaptic protein SNAP25 (-46%; p < 0.01); the postsynaptic protein PSD95 (-37%; p < 0.01); the glutamate receptors AMPAR (-34%; p < 0.01), NMDAR2a (-64%; p < 0.001), and NMDAR2b (-49%; p < 0.05); the surrogate marker of neurogenesis doublecortin (-31%; p < 0.001); and elements of the BDNF pathway, pro-BDNF (-30%; p < 0.05) and TrkB (-22%; p < 0.01). In addition, there is a concomitant decrease in neuronal spine density (-6%; p < 0.05). We also found that cortical ZnT3 levels fall with age in wild-type mice (-50%; p < 0.01) in healthy older humans (ages, 48-91 years; r(2) = 0.47; p = 0.00019) and particularly in Alzheimers disease (AD) (-36%; p < 0.0001). Thus, age-dependent loss of transsynaptic Zn(2+) movement leads to cognitive loss, and since extracellular beta-amyloid is aggregated by and traps this pool of Zn(2+), the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.

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