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DRUG REPURPOSING AND EMERGING ADJUNCTIVE TREATMENTS FOR SCHIZOPHRENIA
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Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
relapse and consider whether these may be potential state markers of acute psychosis. I will consider a number of markers of neurobiological changes associated with acute psychosis. These include dynamic changes in brain structure in the frontal and temporal regions, neurochemical alterations in dopamine and glutamate and evidence for neuroinflammation through microglial activation. We propose that with the use of repeat longitudinal assessments of brain imaging markers over the course of a psychosis relapse, the neurobiological trajectory indicative of a “relapse signature” for psychosis will be identified (Cropley et al, Int Clin Psychopharmacol, 2013, doi: 10.1097/YIC.0b013e32835ab37c).
FATTY ACID MARKERS OF PSYCHOSIS PROGRESSION AND TREATMENT RESPONSE Paul Amminger Orygen Youth Health Research Centre, The University of Melbourne, Melbourne, Australia/Vienna, Austria Long-chain omega-3 polyunsaturated fatty acids (PUFAs) may play a role in the pathogenesis of psychotic and major affective disorders. Alterations in fatty acids include a decrease in omega-3 PUFAs and increased omega6/omega-3 PUFA ratios in plasma, erythrocytes, adipose tissue and post mortem brain tissue. The patterns of these fatty acid alterations are not specific to psychotic or major mood disorders, but are also found in other conditions accompanied by increased oxidative stress such as Alzheimer’s disease, and during normal ageing. We have now first evidence that these alterations can be observed early in the course of a psychiatric condition. I will show that cell membrane fatty acids in individuals at ultra high–risk (UHR) for psychosis (Stage 1b) differ from healthy comparisons; show that cognitive impairment in UHR individuals correlates with cell membrane fatty acids; show that membrane fatty acids predict both transition to psychotic disorder but also response to treatment; and address if a brief period of supplementation with omega-3 PUFAs can prevent transition to psychotic disorder over the longer-term. In summary, our findings imply that membrane fatty acid abnormalities are present before the manifestation of schizophrenia, and may serve as markers to guide early interventions. As omega-3 PUFAs are potent anti-inflammatory agents, our findings also suggests that neuroinflammation could be a stage-specific phenomenon in UHR individuals that may precede the dopamine over-activity associated with a first psychotic episode.
STAGING AND NEUROPROTECTION Seetal Dodd 1,2 1 IMPACT Strategic Research Centre, Deakin University, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia; 2 Deakin University Staging models have been proposed in schizophrenia and bipolar disorder, and discussed for unipolar depression, panic disorder, substance use disorders, anorexia and bulimia nervosa, Illness staging offers a way of conceptualizing mental disorder where prevention of illness onset and neuroprogression is as important for consideration as symptom control and relapse prevention. The staging model in mental health follows similar models in physical health, commencing with stage 0, an asymptomatic stage where risk factors are present, stage 1, prodrome where symptoms are less severe than required for diagnostic thresholds, stage 2, a first episode of illness, stage 3, recurrence and stage 4, treatment resistance. Consequent from the staging model are the concepts of stage specific treatments and neuroprotection. There is evidence that some standard treatments for BD may impede the neuroprogression of the illness and some novel treatments may have neuroprotective properties. Molecular mechanisms implicated in neuroprogression include the dysregulation of neurotrophins, neurogenesis and apoptosis, neurotransmitters, inflammatory, oxidative and nitrosative stress, mitochondrial dysfunction, cortisol and the hypothalamic-pituitaryadrenal axis, and epigenetic influences. The staging model will be presented for various psychiatric disorders, and discrepancies for supporting evidence between various disorders will be demonstrated. Strong evidence is available for schizophrenia and bipolar disorder, whereas the evidence in major depression is less clear. Putative neuroprotective agents will be discussed, focusing on their mechanisms of action, efficacy and safety. Advantages and
limitations of considering stage of illness and neuroprotective strategies in clinical practice will be discussed.
DURATION OF THE ILLNESS AND RESPONSE TO TREATMENT Marta Rapado-Castro Hospital General Universitario Gregorio Marañón, CIBERSAM, Madrid, Spain Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Those people with chronic schizophrenia are characterized by non-remitting symptoms and functional decline over time suggestive of neuroprogression. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder. Conventionally higher dose medications and a combination of treatments are required to diminish consequences of long duration of the illness. While current therapies have some effectiveness, there are shortfalls in recovery. The staging model provides a clinical framework on which particular interventions may counteract the progression of the illness at a particular point of time. This approach could potentially guide treatment and assist in predicting outcome by improving the timing of interventions according to specific markers of progression over time. Conventional treatments of late stage illness would be reviewed and novel therapies with a benign adverse effect profile such as N-acetyl cysteine (NAC) would be presented as well as supportive evidence for its effectiveness in late stage illness.
Symposium DRUG REPURPOSING AND EMERGING ADJUNCTIVE TREATMENTS FOR SCHIZOPHRENIA Chairpersons: Vicki L. Ellingrod and Joshua Roffman Discussant: Peter Buckley Wednesday, 9 April 2014 1:30 PM – 3:30 PM Overall Abstract: Despite a growing armamentarium for the treatment of schizophrenia, many patients are left with residual positive, negative and cognitive symptoms. This clinical conundrum has resulted in numerous, diverse lines of research focusing on the use of adjunctive treatments. Despite the vast differences in the pharmacology of these agents, each has the potential to effectively treat residual symptoms and affect patient outcomes in a positive manner. With recent declines in the industrial pipeline of innovative schizophrenia medications, the notion of medication repurposing, defined as the practice of using old drugs in new ways, is garnering much attention from researchers worldwide. This emerging treatment tactic may prove beneficial for not only the treatment of schizophrenia, but for advancing our understanding of the pathophysiology of this complex disorder. The overall goals of this symposium are to highlight different innovative lines of research involving repurposed treatments for schizophrenia, and to discuss ongoing and future research efforts in this area. To do this, we will focus on four divergent repurposed pharmacologic interventions. First, we will focus on the role of one carbon metabolism and the use of folate and B-vitamins in the reduction of negative symptoms. We will include recent clinical trial results and new MRI data on folate-related changes in brain structure and function. Second, we will discuss the use of minocycline for the treatment of schizophrenia, including new data that relates symptom improvement to reduced inflammation and related biomarkers. Next, we will extend our discussion of the role of inflammation within schizophrenia by describing the utility of aspirin on positive symptoms in patients with high levels of serum CRP, indicating potentially greater inflammation. Lastly, this symposium will discuss the place of nitroprusside in schizophrenia treatment as results from a recent trial shows immediate and sustained improvements in positive and negative symptoms. Thus, despite the current thought that our new medication pipeline for schizophrenia is currently waning; new lines of innovative research centering on medication repurposing schizophrenia provide reasons for optimism. In addition to shedding new light onto the pathophysiology of this illness, the findings presented here suggest new treatments that can potentially be rapidly translated into practice and into improved outcomes for those with schizophrenia.
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
relapse and consider whether these may be potential state markers of acute psychosis. I will consider a number of markers of neurobiological changes associated with acute psychosis. These include dynamic changes in brain structure in the frontal and temporal regions, neurochemical alterations in dopamine and glutamate and evidence for neuroinflammation through microglial activation. We propose that with the use of repeat longitudinal assessments of brain imaging markers over the course of a psychosis relapse, the neurobiological trajectory indicative of a “relapse signature” for psychosis will be identified (Cropley et al, Int Clin Psychopharmacol, 2013, doi: 10.1097/YIC.0b013e32835ab37c).
FATTY ACID MARKERS OF PSYCHOSIS PROGRESSION AND TREATMENT RESPONSE Paul Amminger Orygen Youth Health Research Centre, The University of Melbourne, Melbourne, Australia/Vienna, Austria Long-chain omega-3 polyunsaturated fatty acids (PUFAs) may play a role in the pathogenesis of psychotic and major affective disorders. Alterations in fatty acids include a decrease in omega-3 PUFAs and increased omega6/omega-3 PUFA ratios in plasma, erythrocytes, adipose tissue and post mortem brain tissue. The patterns of these fatty acid alterations are not specific to psychotic or major mood disorders, but are also found in other conditions accompanied by increased oxidative stress such as Alzheimer’s disease, and during normal ageing. We have now first evidence that these alterations can be observed early in the course of a psychiatric condition. I will show that cell membrane fatty acids in individuals at ultra high–risk (UHR) for psychosis (Stage 1b) differ from healthy comparisons; show that cognitive impairment in UHR individuals correlates with cell membrane fatty acids; show that membrane fatty acids predict both transition to psychotic disorder but also response to treatment; and address if a brief period of supplementation with omega-3 PUFAs can prevent transition to psychotic disorder over the longer-term. In summary, our findings imply that membrane fatty acid abnormalities are present before the manifestation of schizophrenia, and may serve as markers to guide early interventions. As omega-3 PUFAs are potent anti-inflammatory agents, our findings also suggests that neuroinflammation could be a stage-specific phenomenon in UHR individuals that may precede the dopamine over-activity associated with a first psychotic episode.
STAGING AND NEUROPROTECTION Seetal Dodd 1,2 1 IMPACT Strategic Research Centre, Deakin University, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220, Australia; 2 Deakin University Staging models have been proposed in schizophrenia and bipolar disorder, and discussed for unipolar depression, panic disorder, substance use disorders, anorexia and bulimia nervosa, Illness staging offers a way of conceptualizing mental disorder where prevention of illness onset and neuroprogression is as important for consideration as symptom control and relapse prevention. The staging model in mental health follows similar models in physical health, commencing with stage 0, an asymptomatic stage where risk factors are present, stage 1, prodrome where symptoms are less severe than required for diagnostic thresholds, stage 2, a first episode of illness, stage 3, recurrence and stage 4, treatment resistance. Consequent from the staging model are the concepts of stage specific treatments and neuroprotection. There is evidence that some standard treatments for BD may impede the neuroprogression of the illness and some novel treatments may have neuroprotective properties. Molecular mechanisms implicated in neuroprogression include the dysregulation of neurotrophins, neurogenesis and apoptosis, neurotransmitters, inflammatory, oxidative and nitrosative stress, mitochondrial dysfunction, cortisol and the hypothalamic-pituitaryadrenal axis, and epigenetic influences. The staging model will be presented for various psychiatric disorders, and discrepancies for supporting evidence between various disorders will be demonstrated. Strong evidence is available for schizophrenia and bipolar disorder, whereas the evidence in major depression is less clear. Putative neuroprotective agents will be discussed, focusing on their mechanisms of action, efficacy and safety. Advantages and
limitations of considering stage of illness and neuroprotective strategies in clinical practice will be discussed.
DURATION OF THE ILLNESS AND RESPONSE TO TREATMENT Marta Rapado-Castro Hospital General Universitario Gregorio Marañón, CIBERSAM, Madrid, Spain Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Those people with chronic schizophrenia are characterized by non-remitting symptoms and functional decline over time suggestive of neuroprogression. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder. Conventionally higher dose medications and a combination of treatments are required to diminish consequences of long duration of the illness. While current therapies have some effectiveness, there are shortfalls in recovery. The staging model provides a clinical framework on which particular interventions may counteract the progression of the illness at a particular point of time. This approach could potentially guide treatment and assist in predicting outcome by improving the timing of interventions according to specific markers of progression over time. Conventional treatments of late stage illness would be reviewed and novel therapies with a benign adverse effect profile such as N-acetyl cysteine (NAC) would be presented as well as supportive evidence for its effectiveness in late stage illness.
Symposium DRUG REPURPOSING AND EMERGING ADJUNCTIVE TREATMENTS FOR SCHIZOPHRENIA Chairpersons: Vicki L. Ellingrod and Joshua Roffman Discussant: Peter Buckley Wednesday, 9 April 2014 1:30 PM – 3:30 PM Overall Abstract: Despite a growing armamentarium for the treatment of schizophrenia, many patients are left with residual positive, negative and cognitive symptoms. This clinical conundrum has resulted in numerous, diverse lines of research focusing on the use of adjunctive treatments. Despite the vast differences in the pharmacology of these agents, each has the potential to effectively treat residual symptoms and affect patient outcomes in a positive manner. With recent declines in the industrial pipeline of innovative schizophrenia medications, the notion of medication repurposing, defined as the practice of using old drugs in new ways, is garnering much attention from researchers worldwide. This emerging treatment tactic may prove beneficial for not only the treatment of schizophrenia, but for advancing our understanding of the pathophysiology of this complex disorder. The overall goals of this symposium are to highlight different innovative lines of research involving repurposed treatments for schizophrenia, and to discuss ongoing and future research efforts in this area. To do this, we will focus on four divergent repurposed pharmacologic interventions. First, we will focus on the role of one carbon metabolism and the use of folate and B-vitamins in the reduction of negative symptoms. We will include recent clinical trial results and new MRI data on folate-related changes in brain structure and function. Second, we will discuss the use of minocycline for the treatment of schizophrenia, including new data that relates symptom improvement to reduced inflammation and related biomarkers. Next, we will extend our discussion of the role of inflammation within schizophrenia by describing the utility of aspirin on positive symptoms in patients with high levels of serum CRP, indicating potentially greater inflammation. Lastly, this symposium will discuss the place of nitroprusside in schizophrenia treatment as results from a recent trial shows immediate and sustained improvements in positive and negative symptoms. Thus, despite the current thought that our new medication pipeline for schizophrenia is currently waning; new lines of innovative research centering on medication repurposing schizophrenia provide reasons for optimism. In addition to shedding new light onto the pathophysiology of this illness, the findings presented here suggest new treatments that can potentially be rapidly translated into practice and into improved outcomes for those with schizophrenia.