Antipsychotic-minocycline-acetylcysteine combination for positive, cognitive, and negative symptoms of schizophrenia

Koola, Maju Mathew

doi:10.1016/j.ajp.2019.02.007

Cited by 13 publications

(12 citation statements)

References 28 publications

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“…However, small sample size alone is not the culprit because single studies with an adequate or large sample size also failed to detect a meaningful signal ( N = 157, Buchanan et al, 2007b; N = 140, Berk et al, 2008; N = 138, Lieberman et al, 2009; N = 669, Kinon et al, 2011; N = 185, Lieberman et al, 2013; N = 215, Umbricht et al, 2014; N = 1013, Downing et al, 2014; N = 307, Keefe et al, 2015; N = 207, Deakin et al, 2018; N = 200, Weiser et al, 2019; N = 170, Breier et al, 2019). These results shed light on the fact that combination treatments are imperative to detect a clinically meaningful signal for the three domains of psychopathology (Koola, 2019a). To date, the field has not found an effective treatment for one domain (psychosis, only partial response to antipsychotic/s in many patients), and treatments are needed for three domains.…”

Section: Why Did We Fail To Bend the Curve?mentioning

confidence: 88%

“…Many of the failed RCTs (Girgis et al, 2019) had limitations and methodological issues (Koola, 2018a). The studies may have failed to detect a clinically meaningful signal for the three domains of psychopathology due to use of only one add‐on medication targeting one pathophysiological mechanism (Koola, 2019a; Y. S. Yang, Marder, & Green, 2017). Thus, the primary reason for the failed RCTs could be that the main pathophysiological processes were not targeted (Spedding, 2006) as shown in Figures 1–3.…”

Section: Why Did We Fail To Bend the Curve?mentioning

confidence: 99%

“… Major pathophysiological mechanisms and biomarkers of schizophrenia The galantamine‐memantine combination is likely to stabilize these pathophysiological mechanisms and improve the biomarkers (Koola et al, 2018a, 2018b, 2019). AMPA, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid; BDNF, Brain‐derived neurotrophic factor; ERK, Extracellular signal‐regulated kinase; GABA, γ‐aminobutyric acid; MAPK‐ mitogen‐activated protein kinase; MMN, mismatch negativity; NMDA, N ‐methyl‐D‐aspartate; PPI, prepulse inhibition …”

Section: Why Did We Fail To Bend the Curve?mentioning

confidence: 99%

“…Unfortunately, the field does not take those issues into consideration (Koola, 2018a) and underestimates the promising findings . If we combine the meta‐analyses findings of two medications (preferably target nicotinic [varenicline is an option, Koola, 2019a, 2019b] and NMDA receptors concurrently), we are likely to get a clinically significant efficacy signal with an ES of at least 0.8 for positive, cognitive, and negative symptoms. The minocycline‐NAC combination has synergistic effect (Baki, Schwab, Haber, Fenton, & Bergold, 2010; Koola, 2019a).…”

Section: Why Did We Fail To Bend the Curve?mentioning

confidence: 99%

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Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

Koola

2020

Human Psychopharmacology

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Development of novel treatments for positive, cognitive, and negative symptoms continue to be a high‐priority area of schizophrenia research and a major unmet clinical need. Given that all randomized controlled trials (RCTs) conducted to date failed with one add‐on medication/mechanism of action, future RCTs with the same approach are not warranted. Even if the field develops a medication for cognition, others are still needed to treat negative and positive symptoms. Therefore, fixing one domain does not completely solve the problem. Also, targeting the cholinergic system, glutamatergic system, and cholinergic plus alpha7 nicotinic and N‐methyl‐D‐aspartate (NMDA) receptors failed independently. Hence, targeting other less important pathophysiological mechanisms/targets is unlikely to be successful. Meta‐analyses of RCTs targeting major pathophysiological mechanisms have found some efficacy signal in schizophrenia; thus, combination treatments with different mechanisms of action may enhance the efficacy signal. The objective of this article is to highlight the importance of conducting RCTs with novel combination treatments in schizophrenia to develop antischizophrenia treatments. Positive RCTs with novel combination treatments that target the alpha7 nicotinic and NMDA receptors simultaneously may lead to a disease‐modifying therapeutic armamentarium in schizophrenia. Novel combination treatments that concurrently improve the three domains of psychopathology and several prognostic and theranostic biomarkers may facilitate therapeutic discovery in schizophrenia.

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Section: Why Did We Fail To Bend the Curve?mentioning

confidence: 88%

Section: Why Did We Fail To Bend the Curve?mentioning

confidence: 99%

Section: Why Did We Fail To Bend the Curve?mentioning

confidence: 99%

Section: Why Did We Fail To Bend the Curve?mentioning

confidence: 99%

See 2 more Smart Citations

Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

Koola

2020

Human Psychopharmacology

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“…Given the inflammatory processes still evident in the chronic recovery phase of TBI, the combination of an anti-inflammatory treatment such as minocycline and AVL-3288 may provide synergistic effects [68, 95, 96]. Minocycline in combination with N-acetylcysteine (NAC) has shown efficacy in improving cognition in schizophrenia patients [97].…”

Section: Discussionmentioning

confidence: 99%

Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury

et al. 2019

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Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer’s disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI.

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New Strategies to Improve Cognitive Symptom Domain in the Treatment of Schizophrenia

Barlati

Ariu

Garozzo³

et al. 2022

Psychosis and Personality Disorders

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Antipsychotic-minocycline-acetylcysteine combination for positive, cognitive, and negative symptoms of schizophrenia

Cited by 13 publications

References 28 publications

Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury

New Strategies to Improve Cognitive Symptom Domain in the Treatment of Schizophrenia

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