Machine Learning and Pharmacogenomics at the Time of Precision Psychiatry.

Traditional medicine and biomedical sciences are reaching a turning point because of the constantly growing impact and volume of Big Data. Machine Learning (ML) techniques and related algorithms play a central role as diagnostic, prognostic, and decision-making tools in this field. Another promising area becoming part of everyday clinical practice is personalized therapy and pharmacogenomics. Applying ML to pharmacogenomics opens new frontiers to tailored therapeutical strategies to help clinicians choose drugs with the best response and fewer side effects, operating with genetic information and combining it with the clinical profile. This systematic review aims to draw up the state-of-the-art ML applied to pharmacogenomics in psychiatry. Our research yielded fourteen papers; most were published in the last three years. The sample comprises 9,180 patients diagnosed with mood disorders, psychoses, or autism spectrum disorders. Prediction of drug response and prediction of side effects are the most frequently considered domains with the supervised ML technique, which first requires training and then testing. The random forest is the most used algorithm; it comprises several decision trees, reduces the training set's overfitting, and makes precise predictions. ML proved effective and reliable, especially when genetic and biodemographic information were integrated into the algorithm. Even though ML and pharmacogenomics are not part of everyday clinical practice yet, they will gain a unique role in the next future in improving personalized treatments in psychiatry.

How to save a life: From neurobiological underpinnings to psychopharmacotherapies in the prevention of suicide.

The impact of suicide on our societies, mental healthcare, and public health is beyond questionable. Every year approximately 700 000 lives are lost due to suicide around the world (WHO, 2021); more people die by suicide than by homicide and war. Although suicide is a key issue and reducing suicide mortality is a global imperative, suicide is a highly complex biopsychosocial phenomenon, and in spite of several suicidal models developed in recent years and a high number of suicide risk factors identified, we still have neither a sufficient understanding of underpinnings of suicide nor adequate management strategies to reduce its prevalence. The present paper first overviews the background of suicidal behavior including its epidemiology, age and gender correlations, and its association with neuropsychiatric disorders as well as its clinical assessment. Then we give an overview of the etiological background, including its biopsychosocial contexts, genetics and neurobiology. Based on the above, we then provide a critical overview of the currently available intervention options to manage and reduce risk of suicide, including psychotherapeutic modalities, traditional medication classes also providing an up-to-date overview on the antisuicidal effects of lithium, as well as novel molecules such as esketamine and emerging medications and further molecules in development. Finally we give a critical overview on our current knowledge on using neuromodulatory and biological therapies, such as ECT, rTMS, tDCS, and other options.

Neural functional correlates of hypnosis and hypnoanalgesia: Role of the cingulate cortex.

Hypnosis is a hetero-induced or self-induced altered state of consciousness that involves focused attention and reduced peripheral awareness. It is determined by response to suggestions and can be used in the management of various clinical conditions. Nowadays there is growing attention to the neurobiological correlates of hypnosis because of its future clinical applications. The greater attention is due to the wide range of applications that might stem from its knowledge. Functional neuroimaging studies show that hypnosis affects attention by modulating the activation of the anterior cingulate cortex and other brain areas, modifying the conflict monitoring and cognitive control. During hypnoanalgesia, several changes in brain functions occur in all the areas of the pain network, and other brain areas. Among these, the anterior cingulate cortex is significantly involved in modulating the activity of pain circuits under hypnosis, both in the affective, sensory-cognitive, and behavioral aspects. The study of the functionality of the cingulate cortices, mainly the anterior and medial portions, appears to be crucial for better understanding the hypnotic phenomena, related to both the neurocognitive and somatosensory aspects.

Prognostic value of skeletal muscle mass during tyrosine kinase inhibitor (TKI) therapy in cancer patients: a systematic review and meta-analysis.

Low muscle mass has been associated with worse clinical outcomes in various cancers. This work investigated whether, during tyrosine kinases inhibitors (TKIs) therapy, low muscle mass was associated with treatment toxicity and survival outcomes. A systematic literature search was performed in Pubmed, Web of Science, and Scopus databases from inception to June 2020, based on fixed inclusion and exclusion criteria. Effect sizes were estimated with hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI) and heterogeneity was assessed by measuring inconsistency (I2) based on the Chi squared test. A total of 24 retrospective studies were identified, enrolling patients treated with sorafenib (n = 12), sunitinib (n = 6), lenvatinib (n = 3), regorafenib (n = 2), gefitinib (n = 1), imatinib (n = 1), and pazopanib (n = 1). Thirteen studies were deemed eligible for pooled analyses. Meta-analyses found a significant effect of low muscle mass on dose-limiting toxicity (DLT) (OR 2.40, 95% CI 1.26-4.58, p = 0.008, I2 = 51%) in patients treated with TKI therapy. A subgroup analysis by treatment showed an association between DLT and low muscle during sorafenib or sunitinib, although not significant. A significant association between low skeletal muscle index and poorer overall survival was observed in HCC patients treated with sorafenib (HR 1.45, 95% CI 1.07-1.96, p = 0.02). For other TKIs, although some results showed an association between low muscle mass and worse outcomes, the number of studies for each TKI therapy was too small to reach conclusions. Skeletal muscle mass could influence the prognosis of some TKI-treated patients. This effect is demonstrated in sorafenib-treated HCC patients but remains almost unexplored in other cancer patients undergoing TKI therapy. Further prospective studies with large sample size and sufficient follow-up are needed to clarify the role of muscle mass in the metabolism of TKI-based cancer treatment, and its association with toxicity and survival.

Skeletal Muscle Loss during Multikinase Inhibitors Therapy: Molecular Pathways, Clinical Implications, and Nutritional Challenges.

In cancer patients, loss of muscle mass is significantly associated with low tolerability of chemotherapy and poor survival. Despite the great strides in the treatment of cancer, targeted therapies such as tyrosine kinase inhibitors (TKIs) could exacerbate muscle wasting. Over recent years, the impact of skeletal muscle loss during TKI therapy on clinical outcomes has been in the spotlight. In this review, we focus on the different molecular pathways of TKIs potentially involved in muscle wasting. Then, we report the results of the studies assessing the effects of different TKI therapies-such as sorafenib, regorafenib, sunitinib, and lenvatinib-on muscle mass, and highlight their potential clinical implications. Finally, we discuss an integrative nutritional approach to be adopted during TKI treatment. The assessment of muscle mass from computerized tomography imaging could be helpful in predicting toxicity and prognosis in patients treated with TKI such as sorafenib. Early recognition of low muscle mass and effective personalized nutritional support could prevent or attenuate muscle mass wasting. However, the role of nutrition is still overlooked, and future clinical trials are needed to find the optimal nutritional support to countermeasure muscle mass depletion during TKI therapy.

Influence of Spiritual Dimensions on Suicide Risk: The Role of Regional Differences.

The field of suicide prevention has been enriched by research on the association between spirituality and suicide. Many authors have suggested focusing on the various dimensions of religiosity in order to better understand the association between religion and suicidal risk, but it is unclear whether the relationship between spirituality and suicidality differs between countries with different cultures, life values, and sociohistorical experiences. To explore this, the aim of this multicenter study was to investigate the possible relationship between suicide and spirituality in Italy and Austria. In the two countries, two different groups of subjects participated: psychiatric patients and university students. The patients were evaluated with the Mini International Neuropsychiatric Interview. In addition, the following measures were used: a sociodemographic questionnaire, the Columbia-Suicide Severity Rating Scale-B, the Symptom-Checklist-90-Standard, and the Multidimensional Inventory for Religious/Spiritual Well-Being. Our results confirmed the multifactorial nature of the relation between suicide risk and the various religious/spiritual dimensions, including religious/spiritual well-being and hope immanent. However, regional differences moderated this relationship in both the clinical and nonclinical samples.

The Meaning in Life in Suicidal Patients: The Presence and the Search for Constructs. A Systematic Review.

Background and Objectives: Research on suicidal behavior (SB) has frequently focused more on risk factors than protective factors. Since the historic works of Viktor E. Frankl, who inquired how some Nazi concentration camps prisoners maintained their will to live though confronted with pervasive absurdity, Meaning in Life (MiL) has been interpreted as a potent resiliency factor. MiL then declined along a multitude of theoretical perspectives and was associated with various functioning domains of the individual. Surprising, few studies investigated the role of MiL on SB. We aimed to review and synthetize current literature on possible associations between MiL and SB, which included suicidal ideation (SI), suicidal attempts (SA), and completed suicide, focusing on two MiL constructs (the presence of MiL and search for MiL) from Michael F. Steger's recent conceptualization. Material and Methods: A systematic strategy following PRISMA guidelines was used to search for relevant articles in Pubmed/MEDLINE, Scopus, PsycINFO, and ScienceDirect (January 1980-February 2019) and yielded 172 articles, 37 of which met our inclusion criteria. Results: MiL emerged as a protective factor against SI, SA, and completed suicides, directly or through mediation/moderation models with other SB-related variables. When distinguishing the presence of MiL and the search for MiL, a consensual protective impact was described for the former. Data for the latter were less consistent but rather oriented towards a non-protective impact Conclusions: These findings could have clinical repercussions for SB prevention, in both suicide risk assessment refinement and psychotherapeutic interventions. Further research is needed to examine dynamic interplay of the two constructs.

TACE with degradable starch microspheres (DSM-TACE) as second-line treatment in HCC patients dismissing or ineligible for sorafenib.

OBJECTIVES: To date, there is no approved second-line treatment for patients dismissing sorafenib or ineligible for this treatment, so it would be useful to find an effective alternative treatment option. The aim of our study was to evaluate safety, feasibility and effectiveness of transarterial chemoembolisation with degradable starch microspheres (DSM-TACE) in the treatment of patients with advanced hepatocellular carcinoma (HCC) dismissing or ineligible for multikinase-inhibitor chemotherapy administration (sorafenib) due to unbearable side effects or clinical contraindications. METHODS: Forty consecutive BCLC stage B or C patients (31 male; age, 70.6 ± 13.6 years), with intermediate or locally advanced HCC dismissing or ineligible for sorafenib administration, who underwent DSM-TACE treatment cycle via lobar approach were prospectively enrolled. Tumour response was evaluated on multidetector computed tomography based on mRECIST criteria. Primary endpoints were safety, tolerance and overall disease control (ODC); secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Technical success was achieved in all patients. No intra/peri-procedural death/major complications occurred. No signs of liver failure or systemic toxicity were detected. At 1-year follow-up, ODC of 52.5% was registered. PFS was 6.4 months with a median OS of 11.3 months. CONCLUSIONS: DSM-TACE is safe and effective as a second-line treatment in HCC patients dismissing or ineligible for sorafenib. KEY POINTS: • DSM-TACE is safe and effective as second-line treatment in HCC patients dismissing or ineligible for sorafenib • DSM-TACE allows the temporary occlusion of the smaller arterial vessels, improving overall therapeutic effectiveness by reducing the immediate wash-out of the cytostatic agent • DSM-TACE also decreases the risk of systemic toxicity and post-embolic syndrome.

Regorafenib: a promising treatment for hepatocellular carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors with 854,000 new cases per year and represents the second most frequent cause of cancer-death. Despite surveillance, the number of patients that are diagnosed at a stage in which they are eligible for curative treatments ranges from 30% to 60%. Advanced HCC (BCLC-C) is characterized by a median survival of 6 months. Sorafenib, the first systemic drug proven to be effective in prolonging survival of unresectable HCC, was approved by the FDA in 2007 but no second-line treatment was available for a decade for patients progressing on sorafenib. Finally, in 2016, the RESORCE trial demonstrated regorafenib as an effective second-line treatment. Areas covered: In this manuscript, the authors review the principal preclinical and clinical trials on regorafenib used in the treatment of unresectable HCC patients progressing on sorafenib and highlight both the advantages and the limitations of this drug. Expert opinion: Regorafenib is the only second-line treatment available for patients progressing on sorafenib. Despite its promising clinical application, many doubts still remain, necessitating further investigation to explore the tolerability of this drug in Child-Pugh B and sorafenib-intolerant patients, while its scarce cost-effectiveness must also be improved.

Subclinical atherosclerosis is linked to small intestinal bacterial overgrowth via vitamin K2-dependent mechanisms.

AIM: To assess the rate of matrix Gla-protein carboxylation in patients with small intestinal bacterial overgrowth (SIBO) and to decipher its association with subclinical atherosclerosis. METHODS: Patients with suspected SIBO who presented with a low risk for cardiovascular disease and showed no evidence of atherosclerotic plaques were included in the study. A glucose breath test was performed in order to confirm the diagnosis of SIBO and vascular assessment was carried out by ultrasound examination. Plasma levels of the inactive form of MGP (dephosphorylated-uncarboxylated matrix Gla-protein) were quantified by ELISA and vitamin K2 intake was estimated using a food frequency questionnaire. RESULTS: Thirty-nine patients were included in the study. SIBO was confirmed in 12/39 (30.8%) patients who also presented with a higher concentration of dephosphorylated-uncarboxylated matrix Gla-protein (9.5 µg/L vs 4.2 µg/L; P = 0.004). Arterial stiffness was elevated in the SIBO group (pulse-wave velocity 10.25 m/s vs 7.68 m/s; P = 0.002) and this phenomenon was observed to correlate linearly with the levels of dephosphorylated-uncarboxylated matrix Gla-protein (ß = 0.220, R2 = 0.366, P = 0.03). Carotid intima-media thickness and arterial calcifications were not observed to be significantly elevated as compared to controls. CONCLUSION: SIBO is associated with reduced matrix Gla-protein activation as well as arterial stiffening. Both these observations are regarded as important indicators of subclinical atherosclerosis. Hence, screening for SIBO, intestinal decontamination and supplementation with vitamin K2 has the potential to be incorporated into clinical practice as additional preventive measures.

Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: the role of dynamic contrast enhanced ultrasound.

BACKGROUND & AIMS: Sorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points. METHODS: Twenty-eight HCC patients treated with sorafenib 400mg bid were prospectively enrolled. CEUS was performed at baseline (T0) and after 15 (T1) and 30 (T2) days of treatment. Tumor vasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software (Q-Lab, Philips). Variations between T1/T2 and T0 were calculated for five D-CEUS functional parameters (peak intensity, PI; time to PI, TP; area under the curve, AUC; slope of wash in, Pw; mean transit time, MTT) and were compared for responders and non-responders. The correlation between D-CEUS parameters, overall survival (OS), and progression-free survival (PFS) was also assessed. A p value <0.05 was considered statistically significant. RESULTS: The percentage variation at T1 significantly correlated with response in three D-CEUS parameters (AUC, PI and Pw; p=0.002, <0.001, and 0.003, respectively). A decrease of AUC (p=0.045) and an increased/unchanged value of TP (p=0.029) and MTT (p=0.010) were associated with longer survival. Three D-CEUS parameters (AUC, TP, Pw) were significantly associated with PFS. CONCLUSIONS: D-CEUS provides a reliable and early measure of efficacy for anti-angiogenic therapies and could be an excellent tool for selecting patients who will benefit from treatment.

A case of variant angina in a patient under chronic treatment with sorafenib.

BACKGROUND: A 63-year-old man with an unresectable multifocal hepatocellular carcinoma (HCC) presented with upper abdominal discomfort, nausea and vomiting. We report a case of variant angina in a patient affected by unresectable HCC under chronic treatment with sorafenib. Spontaneous spasm occurred during cardiac catheterization and was revealed during coronary angiogram with the unusual feature of a retrograde transient filling of a contralateral branch. INVESTIGATIONS: Electrocardiogram, cardiac catheterization, chest X-ray, emergency ECG. DIAGNOSIS: Variant angina induced by sorafenib treatment mimicking infero-posterior ST-elevation myocardial infarction (STEMI). MANAGEMENT: High-dose calcium-antagonists and nitrates were initially given intravenously and then orally. Sorafenib therapy was then resumed without further symptoms. Restaging of the cancer revealed unexpected local recurrence and the patient died 1 month after receiving palliative care. We contend that the effects of sorafenib treatment were primarily responsible for the major cardiovascular event observed in this case, and it is important for clinicians to be aware of this possible severe complication of sorafenib therapy.

Acute hepatitis caused by a natural lipid-lowering product: when "alternative" medicine is no "alternative" at all.

BACKGROUND/AIMS: The general public's growing mistrust of the pharmaceutical industry and its perception of the lack of adverse effects of "natural" therapy have lead to the increasing use of "alternative drugs" for hypercholesterolemia. METHODS: A sixty-three year old woman presented with severe hypertransaminasemia that had developed progressively over a few weeks. For six months she had been taking Equisterol, an over-the-counter lipid-lowering product containing guggulsterol and red yeast rice extract. The product had been prescribed for hypercholesterolemia because the patient had developed hepatotoxicity while on lovastatin. RESULTS: Liver biopsy revealed severe lobular necroinflammatory changes with an eosinophilic infiltrate. The episode was regarded as an adverse drug reaction after exclusion of other possible causes of acute liver disease and the prompt normalization of liver function tests after Equisterol had been discontinued. Red yeast rice extract's cholesterol-lowering properties are largely due to fungal metabolites known as monacolins, one of which--monacolin K--is identical to lovastatin. CONCLUSIONS: The choice of an alternative medicine approach in this case subjected the patient to "re-challenge" with the official medicine agent that had previously caused mild hepatotoxicity. Physicians should keep in mind that "alternative" medicine is not always the safest alternative and sometimes it is not even "alternative."