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Introduction: There are few published empirical data on the effects of COVID-19 on mental health, and until now, there is no large international study. ----- Material and methods: During the COVID-19 pandemic, an online questionnaire gathered data from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively. ----- Statistical analysis: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses and Factorial Analysis of Variance (ANOVA) tested relations among variables. ----- Results: Probable depression was detected in 17.80% and distress in 16.71%. A significant percentage reported a deterioration in mental state, family dynamics and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (31.82% vs. 13.07%). At least half of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop depression was associated with history of Bipolar disorder and self-harm/attempts (RR = 5.88). Suicidality was not increased in persons without a history of any mental disorder. Based on these results a model was developed. ----- Conclusions: The final model revealed multiple vulnerabilities and an interplay leading from simple anxiety to probable depression and suicidality through distress. This could be of practical utility since many of these factors are modifiable. Future research and interventions should specifically focus on them.

BACKGROUND: Schizophrenia is associated with immune-inflammatory and oxidative stress mechanisms leading to activation of the tryptophan catabolite (TRYCAT) pathway, which ultimately together with dysfunctional N-methyl-D-aspartate receptors (NMDAR) may cause neuroprogression and all symptom clusters of this mental disorder. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). By the enzymatic action of IDO, tryptophan is converted to quinolinic acid, a potent neurotoxin, related to NMDA receptors activation. Conversely, TDO enzymatic activity is related to the synthesis of kynurenic acid, an NMDA and nicotine alpha7 receptors antagonist. While IDO is expressed in microglial cells, astrocytes express TDO. The activation of TRYCAT pathway is being related to schizophrenia symptoms such as cognitive decline. 1-Methyl-D-tryptophan (MDT) is an IDO inhibitor. MDT is being tested as an immunomodulatory strategy for cancer treatment. Melatonin, another immunomodulatory drug is metabolized by IDO while inhibiting TDO. In the present preclinical study, we evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice, a validated pharmacological animal model of schizophrenia. METHODS: Male Swiss mice were administered MDT (20 or 40 mg/kg, intraperitoneal) or melatonin (15 mg/kg, per os). We tested oxidative alterations by the evaluations of myeloperoxidase activity (MPO), reduced glutathione (GSH) and lipid peroxidation as well as inflammatory changes, by the measures of interleukin (IL)-4 and IL-6 in brain areas related to schizophrenia neurobiology namely, prefrontal cortex (PFC), hippocampus and striatum. Risperidone was used as standard antipsychotic. RESULTS: Our results showed that ketamine triggered positive- (PPI deficits and hyperlocomotion), cognitive- (working memory deficits) and negative-like (social interaction deficits) symptoms of schizophrenia. These symptoms were accompanied by increased MPO activity, decreased GSH and increased lipid peroxidation in all brain areas tested and by increments in hippocampal IL-4 and IL-6 levels. MDT and melatonin reversed all ketamine-induced behavioral alterations, while the antipsychotic risperidone did not reverse working memory deficits. MDT and melatonin reversed the alterations in MPO activity and GSH levels. Lipid peroxidation was reversed only by melatonin and risperidone. Risperidone was not able to reverse MPO alterations in the PFC and striatum. The immunomodulatory drugs and risperidone reversed the brain alterations in IL-4 and IL-6. The hippocampus and striatum of ketamine+melatonin-treated animals had marked low levels of IL-6. CONCLUSIONS: In conclusion, we observed that ketamine repeated administration besides triggering behavioral and brain oxidative alterations related to schizophrenia also induces neuroimmune changes such as increased MPO activity and increments in IL-4 and IL-6 levels. The IDO inhibitor, MDT and melatonin reversed ketamine-induced behavioral, pro-oxidant and neuroimmune alterations. These experiments open new avenues for the study of drugs targeting tryptophan metabolism in schizophrenia.

Obesity and depression are among the most pressing health problems in the contemporary world. Obesity and depression share a bidirectional relationship, whereby each condition increases the risk of the other. By in- ference, shared pathways may underpin the comorbidity between obesity and depression. Activation of cell- mediated immunity (CMI) is a key factor in the pathophysiology of depression. CMI cytokines, including IFN- γ , TNF α and IL-1 β , induce the catabolism of tryptophan (TRY) by stimulating indoleamine 2,3-dioxygenase (IDO) resulting in the synthesis of kynurenine (KYN) and other tryptophan catabolites (TRYCATs). In the CNS, TRYCATs have been related to oxidative damage, in fl ammation, mitochondrial dysfunction, cytotoxicity, ex- citotoxicity, neurotoxicity and lowered neuroplasticity. The pathophysiology of obesity is also associated with a state of aberrant in fl ammation that activates aryl hydrocarbon receptor (AHR), a pathway involved in the de- tection of intracellular or environmental changes as well as with increases in the production of TRYCATs, being KYN an agonists of AHR. Both AHR and TRYCATS are involved in obesity and related metabolic disorders. These changes in the TRYCAT pathway may contribute to the onset of neuropsychiatric symptoms in obesity. This paper reviews the role of immune activation, IDO stimulation and increased TRYCAT production in the pa- thophysiology of depression and obesity. Here we suggest that increased synthesis of detrimental TRYCATs is implicated in comorbid obesity and depression and is a new drug target to treat both diseases.