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THE COMPLEX INTER-RELATIONSHIPS BETWEEN THERAPEUTIC INTERVENTIONS, NEUROANATOMY AND COGNITION IN MAJOR PSYCHOSES

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    The session, ‘The Complex Inter-Relationships Between Therapeutic Interventions, Neuroanatomy and Cognition in Major Psychoses’, moderated by Professors Paolo Brambilla and Carrie Bearden at EPA 2021 Virtual attempted to disentangle the connections between treatment, neuroanatomy, psychopathology and cognition in major psychoses. The speakers, including the moderators and Professor Jair Soares, focused on the importance of improving not only treatment but also quality of life of patients, which is often deteriorated by cognitive symptoms. It is now a well-known fact that patients with major psychiatric disorders such as schizophrenia, bipolar disorder, or major depression exhibit changes in brain anatomy as well as deficits in neurocognitive functioning.1 In addition, the enhancement of neuroprotective mechanisms and the utilisation of anti-inflammatory agents has recently been shown to be beneficial in these disorders.2 In this context, findings from proof-of-concept studies with aspirin and anti-inflammatory agents in the treatment of patients with bipolar depression were presented.

    Inflammation as a Potential Therapeutic Target in Bipolar Disorder

    Professor Jair Soares, ‎Chairman of Psychiatry and Behavioral Sciences at University of Texas Health Science Center at Houston, began the session by highlighting that bipolar disorder is a heterogeneous condition and hence requires multimodal treatment; a framework that both recognises the multidimensionality and comorbidity of the illness.3
    Importantly, recent research suggests that inflammation might be one of the connectors of this multidimensionality by being responsible for some of the underlying pathophysiological changes, including the ones in the brain. Indeed, brain volume changes are quite prevalent in different psychiatric disorder such as depression,which has been considered to be related to stress-induced neuronal microdamage that triggers an injury repair response consisting of a neuroinflammatory phase to clear cellular debris and a spontaneous tissue regeneration phase involving neurotrophins and neurogenesis.4 Such a response may be associated with chronic inflammation as well.5
     
    Professor Soares then continued by emphasizing that inflammation has been receiving growing interest in the field of research in bipolar depression, and that several hypotheses have now been generated to explain this relationship, including altered levels of peripheral cytokines.7 Notwithstanding, there is also the possibility that pathological brain rewiring occurs as shown by MRI studies demonstrating cortical abnormalities in individuals with bipolar disorder, consisting of reduced cortical thickness in the frontal, medial parietal and occipital regions.8
     
    Continuing the lecture, Professor Soares talked about the importance of treatment early in the disease course in case of bipolar disorder as it is associated with greater efficacy. He also stated that while a number of agents are now approved to treat bipolar disorder, non-pharmacological interventions are also promising. To give an example, positive results have been seen with aerobic exercise and resistance training.9 With regards to inflammation, he showed some interesting results that have been obtained with the use of anti-inflammatory agents such as celecoxib and non-steroidal anti-inflammatory drugs.10 Treatment of bipolar depression with minocycline and aspirin has also been investigated with promising results, in addition to the TNF antagonist infliximab for treatment-resistant depression.11,12
     
    In summary, Professor Soares stressed that inflammation may be a key mediator of both cerebral and systemic abnormalities in patients with bipolar disorder and early clinical results suggest it to be a valid potential therapeutic target.

    The Impact of Long-Acting Injection (LAI) Antipsychotics on Myelin in Psychosis: A High-Resolution Myelin Water Imaging Study

    Following the presentation by Professor Soares, Professor Paolo Brambilla, Director of the Department of Psychiatry at the University of Milan, spoke about the use of long-acting antipsychotics (LAIs). LAIs can have a number of advantages, started Professor Brambilla, for instance maintaining therapeutic drug concentration for several weeks, thus minimising the risk of non-adherence with reduced relapse rates and long-term clinical benefits.13 In addition, they can also help patients to achieve improvement in the quality of life, remission and eventually recovery, which are important long-term goals of treatment.13
     
    Within this context, Professor Brambilla said that myelin, the fatty substance that surrounds nerve cell axons, has been recently in the research spotlight for several reasons. First, there is increasing evidence that myelin is involved in the disconnection hypothesis, a theory suggesting that the communication between multiple brain circuits and regions may be disrupted in schizophrenia which in turn contributes to the central pathophysiology.14 Second, deficits in white matter tracts correlate with pathogenic events for psychosis, as shown by studies utilising magnetic resonance diffusion.14 He then described results of a study that used myelin water imaging, a magnetic resonance method that provides in vivo measurement of myelin and changes in myelin content in the brain.15 The aim of the study was to investigate whether changes in clinical symptomatology correlate with changes in myelin.15 In particular, 10 psychotic patients were assessed with myelin water imaging for 36 brain regions of interest at baseline and after 12 months on a LAI.15 Importantly, there were significant changes in the myelin water fraction which appeared to correlate with improvements in clinical symptomatology.15
     
    Professor Brambilla closed his presentation by saying that the available data suggests that LAIs may improve the trajectory of myelination in first-episode patients and have a beneficial impact on cognitive performance. In this regard, the better adherence provided by LAIs may underlie the modified trajectory of myelin development, and recovery seems more pronounced following a long-acting therapy. 

    Distinct and Shared Contribution of Diagnosis and Symptoms to Neurocognition in Severe Mental Illnesses in the Paisa Population of Colombia


    Prof. Llorca observed that treatment guidelines stated that antipsychotic monotherapy should be preferred and that antipsychotic polypharmacy should be avoided if possible. These recommendations were based on the results of high-quality studies in acute-phase treatment but results from the large observational study performed by Prof. Tiihonen et al, suggested that certain combinations of two antipsychotics with different receptor profiles may be superior to monotherapy for preventing rehospitalisation and maintenance schizophrenia treatment.4

    Professor Carrie Bearden, Assistant Professor of Clinical Psychology at the University of California Los Angeles, USA, began the last presentation of the symposium by presenting data from the recent Paisa Project.16 This interesting study analysed the relationship between genetic risk and severe mental illnesses at the level of diagnoses, specific symptoms and quantitative traits that may index core deficits.16 The goal of the study was to understand the dimensional traits which may better represent the biology underlying an illness within a certain diagnostic category.16 This was a case-control study in which cases with severe mental illness, including schizophrenia, bipolar I and II disorder and major depressive disorder, were ascertained through electronic medical records.16 All participants were assessed for speed and accuracy using the Penn Computerized Neurocognitive Battery (PCNB). In addition, 5 neurocognitive test domains were also analysed (executive, memory, complex cognition, social cognition, sensorimotor). 
     
    In describing the results, Professor Bearden said that individuals with bipolar I disorder and schizophrenia showed similar impairments in accuracy and speed across cognitive domains.16 In contrast, those with bipolar II disorder and major depressive disorder performed similarly to controls, with subtle deficits in executive and social cognition.16 She said that a three-factor model (psychosis, mania, and depression) represented best the symptom data.16 The study also found that, controlling for diagnosis, premorbid IQ, disease severity and high lifetime psychosis scores were associated with reduced accuracy and speed across cognitive domains, whereas high depression scores were associated with increased social cognition accuracy.16
     
    She concluded her presentation by highlighting that the neuropsychological impairment profile in these individuals was bifurcated by diagnosis (schizophrenia and bipolar I disorder vs. major depressive disorder and bipolar II disorder).16 Moreover, deficits were not accounted for by current symptom severity or medication, and there appeared to be a partially independent contribution of diagnosis and lifetime symptomatology to cognitive functioning.16 Importantly, the study identified a set of common risk factors predisposing to both psychosis and impaired cognition across categories of serious mental illnesses.16 Lastly, in looking towards the future, genetic investigations across diagnoses may help to establish a more biologically valid nosology for severe psychiatric disorders.

    References

    1. Tsitsipa E, Fountoulakis KN. The neurocognitive functioning in bipolar disorder: a systematic review of data. Ann Gen Psychiatry. 2015;14:42 (2015).
    2. Pereira AC, et al. Inflammation in Bipolar Disorder (BD): Identification of new therapeutic targets. Pharmacol Res. 163:105325 (2021).
    3. McIntyre RS, et al. Comorbidity in bipolar disorder: a framework for rational treatment selection. Hum Psychopharmacol. 219:369-386 (2004). 
    4. Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry. 54(3):338-532 (2003). 
    5. Wager-Smith K, Markou A. Depression: a repair response to stress-induced neuronal microdamage that can grade into a chronic neuroinflammatory condition? Neurosci Biobehav Rev. 35:742-764 (2011). 
    6. Poletti S, et al. Adverse childhood experiences influence the detrimental effect of bipolar disorder and schizophrenia on cortico-limbic grey matter volumes. J Affect Disord. 189:290-297 (2016). 
    7. Kohler O, K, et al. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment. Curr Neuropharmacol. 14:732-42 (2016). 
    8. Hibar DP, W, et al. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry. 23:932-942 (2018). 
    9. Mead GE, et al. Exercise for depression. Cochrane Database Syst Rev. 3:CD004366 (2009). 
    10. Nery FG, et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol. 23:87-94 (2008). 
    11. Savitz JB, et al. Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry. 8:27 (2018). 
    12. Raison CL, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 70:31-41 (2013). 
    13. Correll CU, Lauriello J. Using Long-Acting Injectable Antipsychotics to Enhance the Potential for Recovery in Schizophrenia. J Clin Psychiatry. 81:MS19053AH5C (2020). 
    14. Haroutunian V, et al. Variations in oligodendrocyte-related gene expression across multiple cortical regions: implications for the pathophysiology of schizophrenia. Int J Neuropsychopharmacol. 10:565-73 (2007).
    15. Squarcina L, et al. Similar white matter changes in schizophrenia and bipolar disorder: A tract-based spatial statistics study. PLoS One. 12:e0178089 (2017). 
    16. Service SK, et al. Distinct and shared contributions of diagnosis and symptom domains to cognitive performance in severe mental illness in the Paisa population: a case-control study. Lancet Psychiatry. 2020 7:411-419 (2020). 

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