Neurobiological and pharmacological arguments for customization of cognitive behavioral psychotherapy in the treatment of major depressive disorder.

INTRODUCTION: Depression represents a public health issue because it significantly increases the risk of disabilities and premature mortality, decreases the quality of life, and increases the costs of care. The incomplete remissions favor the aggravation of neurobiological dysfunctions and pathogenesis of severe somatic comorbidities. The etiopathogenic mechanisms of depression are complex and involve multisystemic risk factors (genetic, neuroanatomic, neurobiochemical, neuroendocrine and psychosocial). Cognitive behavioral therapy (CBT) is used in all the stages of depression, as independent therapeutic method or as support of pharmacotherapy. PATIENTS, MATERIALS AND METHODS: This study has evaluated the therapeutic response of depression in M (medication) group with 136 patients under pharmacotherapy, compared with P (psychotherapy and medication) group with 137 patients treated simultaneously with medication and CBT, and the factors that can improve therapeutic management. RESULTS: Patients with depression had predominantly a reactive onset, recurrent evolution of at least four episodes, and frequent somatic comorbidities. After treatment, a significant improvement of depressive symptomatology was recorded especially in M group (72.06%), compared to P group (88.32%), p<0.01, as well as a significant difference in regaining functional skills (69.12% - M group, 93.43% - P group; p<0.001). The therapeutic response was significantly correlated with age (p<0.01), social-economical involvement and education level. CONCLUSIONS: CBT demonstrated efficiency in the treatment of major depressive disorder in association with pharmacotherapy. The therapeutic approach should rely on the pathogenic biological models that would highlight the prediction indicators for the therapeutic response and for the evolution of depression, as well as considering the psychological profile of each patient.

Impairment of the cardiac ejection fraction by blocking dopamine D2 receptors induced by long-acting injectable antipsychotic treatment.

INTRODUCTION: Atypical antipsychotics have numerous benefits compared to conventional ones in respect to the possible adverse effects. However, like the other ones, they may induce direct cardiovascular alterations, probably through the apoptotic effect of dopamine receptor D2 (DRD2) blockade. The main objective of the study was to assess the cardiac ejection fraction (EF) using transthoracic speckle tracking echocardiography (TSTE) in patients treated with long-acting injectable (LAI) atypical antipsychotics. PATIENTS, MATERIALS AND METHODS: This cross-sectional study was conducted on 123 patients with schizophrenia or schizoaffective disorder divided in four samples according to their treatment: Aripiprazole, Olanzapine, Paliperidone and Risperidone. We analyzed socio-demographic data, the intensity of psychiatric symptoms, the duration of psychosis and of LAI treatment, and the cardiac EF measured with TSTE. RESULTS: We found no statistically significant differences between the four antipsychotics regarding the values of the EF. Nevertheless, we observed a trend indicating that patients treated with an antipsychotic associated with a lower affinity for the DRD2, such as Olanzapine, have higher EF values than patients treated with antipsychotics with a stronger binding to the DRD2, such as Paliperidone and Risperidone. Patients receiving Aripiprazole, which has the strongest affinity for the DRD2 from all four antipsychotics but is also a partial DRD2 agonist, display higher EF values than those on Paliperidone and Risperidone. CONCLUSIONS: Antipsychotics with a lower affinity for the DRD2 or a partial agonism for it may be associated with higher EF. Cardiac monitoring should be performed periodically in patients on LAI antipsychotic therapy.

Mild TBI in the elderly - risk factor for rapid cognitive impairment in Alzheimer's disease.

In recent decades, traumatic brain injury (TBI) has become one of the most important health problems worldwide and is a major cause of morbidity, mortality and economic losses. Mild traumatic brain injury (mTBI) is less considered, with clinical underestimation leading to an epidemiological underevaluation of its incidence. Many of the signs and symptoms induced by mTBI are difficult to highlight clinically, especially those related to cognitive, behavioral, or emotional impairment. The complexity of the biological mechanisms induced by mTBI in the elderly determines synchronous pathogenic actions in which the vascular, inflammatory and neurodegenerative elements are intertwined. It is difficult to highlight a major pathogenic factor, since they act simultaneously, multimodally, in a real pathogenic cascade. The identification of mTBI and cerebral vascular changes by neuroimaging techniques, transcranial Doppler (TCD) or biological markers, suggests a potential prophylactic intervention by using neuroprotective factors as early as possible. Proper prophylaxis measures with neurotrophic treatment, rebalancing the gamma-aminobutyric acid (GABA)∕glutamate balance and combating the chronic inflammatory process, can become important pharmacological therapeutic targets.

SARS-CoV-2 infection in patients with serious mental illness and possible benefits of prophylaxis with Memantine and Amantadine.

Patients with serious mental illness are a high-risk category of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with schizophrenia are not participatory and have increased mortality and morbidity, patients with dementia cannot be cared for while depression, anxiety, bipolar tubing are associated with low immune status. Social stress is amplified by social isolation, amplifying depression and the mechanisms of decreased immunity. Hygiene measures and prophylactic behavior are impossible to put into practice in conditions of chronic mental illness. In coronavirus disease 2019 (COVID-19), the risk for severe development is associated with the presence of comorbidities and immune system deficiency. Prothrombotic status, cytokine storm and alveolar destruction are mechanisms that aggravate the evolution of patients, especially in the context in which they have dysfunction of the autonomic system. The activity of proinflammatory cytokines is accentuated by hyperglutamatergia, which potentiates oxidative stress and triggers the mechanisms of neural apoptosis by stimulating microglial activation. Activation of M1-type microglia has an important role in pathogenesis of major psychiatric disorders, such as major depression, schizophrenia or bipolar disorder, and may associate hippocampal atrophy and disconnection of cognitive structures. Memantine and Amantadine, N-methyl-D-aspartate (NMDA) glutamate receptor inhibitors, have demonstrated, through their pharmacological profile, psychotropic effects but also antiviral properties. In the conditions of the COVID-19 pandemic, based on these arguments, we suggest that they can be associated with the therapy with the basic psychotropics, Memantine or Amantadine, for the control of neuropsychiatric symptoms but also as adjuvants with antiviral action.

Current understanding of psycho-neurobiology in depressive disorders with suicidal thoughts - translational models.

Epidemiological data confirm the rising incidence of depression associated with suicidal ideation and cardiovascular comorbidities of coronary type. In contradiction with the large number of antidepressant drugs, the therapeutic results are not satisfactory, with numerous existing incomplete remissions characterized by maintained cellular dysfunctionalities that amplify the cognitive deterioration and the risk of several somatic comorbidities. The surprising fact is the relatively high number of deaths in this type of patients due to acute coronary disease (myocardial infarction - MI). The vulnerability of hippocampal and frontal cortex cerebral structures is presented as obtained on animal model consecutive to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and on theoretical model where the hypothalamic disconnectivity determines the activation in the sympathetic autonomic nervous system, leading to heart disorders: high blood pressure, left ventricular hypertrophy and coronary illness. Identifying the association of psychological risk factors, patients fitting in a model of psychosomatic dominant personality traits, where the main risk factors are represented by inflexibility, guilt and self-accusation feelings, associated with increase of biological indicators (proinflammatory factors, endothelial dysfunction and cytokine aggressiveness) and neuroimaging indicators (frontal, temporal, hippocampal atrophy, ventriculomegaly, cerebellum atrophy). Changes identified post-mortem in the arterioles from the frontal cortex were found also in the coronary vessels, suggesting a symmetric evolution The highlighted personality factors are responsible for the decrease of adherence and compliance both in the psychiatric and the cardiologic treatment, the patient being exposed to behavioral risks regarding life style and nutrition, factors that increase the risk for acute coronary accident. The psycho-neurobiological inspired theoretical models argument the importance of a differentiated and customized approach of the patients with depressive disorder and suicidal ideation, and they can be the base for initiating strategies for prevention of unfavorable evolution and risk of death by MI.

Efficacy of Tianeptine 25-50 mg in Elderly Patients With Recurrent Major Depressive Disorder: An 8-Week Placebo- and Escitalopram-Controlled Study.

OBJECTIVE: The present placebo-controlled study evaluated the efficacy and safety of 8 weeks of treatment with tianeptine 25-50 mg/d in elderly patients suffering from major depressive disorder (MDD) according to DSM-IV-TR. Escitalopram 5-10 mg/d was used as an active comparator. METHODS: Elderly outpatients aged at least 65 years with a primary diagnosis of moderate to severe episode of recurrent MDD were recruited by psychiatrists in 44 clinical centers in 10 countries from October 2013 to January 2016. Patients were randomly assigned to receive tianeptine (n = 105), placebo (n = 107), or escitalopram (n = 99) for 8 weeks. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS17) total score. RESULTS: Tianeptine improved depressive symptoms, as evaluated by the HDRS17 total score in terms of absolute change from baseline (week 0) to week 8 (placebo-tianeptine difference [SE] of 3.84 [0.85] points, P < .001, using a last-observation-carried-forward approach) and response to treatment (tianeptine: 46.7%; placebo: 34.0%, estimate [SE] = 12.70% [6.70], P = .06). A sensitivity analysis using a mixed model for repeated measures confirmed the main results on HDRS total s​core. The placebo-tianeptine difference (SE) was 0.66 (0.15) for Clinical Global Impressions-Severity of Illness (95% CI, 0.37 to 0.96; P < .001) and 0.57 (0.14) for Clinical Global Impressions- Improvement (95% CI, 0.30 to 0.83; P < .001). Positive results were also obtained with the active control escitalopram (HDRS17 total score placebo-escitalopram difference of 4.09 ± 0.86 points, P < .001), therefore validating the sensitivity of the studied population. Tianeptine was well tolerated, with only minimal differences in tolerability from placebo. CONCLUSIONS: The present study provides robust evidence that an 8-week treatment period with tianeptine 25-50 mg is efficacious and well tolerated in depressed patients aged 65 years or older. TRIAL REGISTRATION: EudraCT identifier: 2012-005612-26​.

Neurobiological arguments for a pathogenic multifactorial disconnective model of cognitive disorders from Alzheimer's disease in elderly people.

Incidence of Alzheimer's disease (AD) in people over 75 years is much higher, and the progression of cognitive deficit become faster, leading to a decrease of quality of life for patients and their families. In this context, it is proposed a multifactorial pathogenic model of disconnected cognitive circuits, which is combined with genetic and vascular-cerebral vulnerability elements, allowing an aggressive progression of neurodegenerative factors, favoring onset of dementia. Data from research studies on animal model (rat) highlighted central role of cerebral cholinergic deficit (which is amplified by cerebral ischemia) on the background of apolipoprotein E4 (ApoE4) genotype, favoring multifactorial disconnected mechanisms, by excess of beta-amyloid (ß-A) or increase of vascular dysfunction. Depressive disorder, social stress and traumatic brain injury are favoring the excess in production of ß-A. Hippocampal structure disconnects the cognitive circuits, and from a neuropsychological point of view can be many patterns, which are correlated with neuroimaging (hippocampal atrophy, cerebral siderosis, white matter hyperintensity, ventriculomegaly) or biological (hyperhomocysteinemia) factors. Identifying the pathogenic model of multifactorial disconnectivity in the rapid evolution of cognitive deficit in patients with AD may create the premises for an early diagnosis and treatment, based on the biological, neuropsychological and clinical elements.

The microvascular alterations in frontal cortex during treatment with antipsychotics: a post-mortem study.

INTRODUCTION: Schizophrenia is the most severe psychiatric illness, with a biological support in the brain. There is evidence that the adequate dopamine balance in the frontal cortex is associated with a better outcome of the disorder, while the alteration of dopamine mechanism at this level may affect the vascular system leading to secondary neuronal alterations. Our study was conducted post-mortem and its objective was to identify the alterations in the neuronal architecture, in the integrity of the microvascular unit in the frontal cortex of patients treated with potent and excessive D2-blocking antipsychotics. MATERIALS AND METHODS: We studied post-mortem sections of the frontal cortex of three patients (two women and one man) diagnosed with schizophrenia or schizophrenia-spectrum disorders and treated with antipsychotics for the last 24 months. The slides were prepared according to the classical histopathological protocols. RESULTS: Various alterations were found at the neural and vascular levels in the frontal cortex. The most significant was the neural loss as the result of severe changes in the microvessels (diameter reduction, hyaline and collagen deposits, edema, pinocytosis and vacuolization). DISCUSSION: The evidences shown in our study highlight the fact that antipsychotics with potent antagonist action on D2 receptors may affect the neurovascular unit and small vessels in frontal cortex by altering the balance vasoconstriction-vasodilatation, thus reducing the blood flow and metabolism and generating structural microvascular changes proportional with the level of apoptosis at this level. The functional integrity of the dopaminergic system in frontal cortex depends on the vascular support and the capabilities of the neurovascular unit and any dysfunction increases the neuronal loss with clinically significant changes. CONCLUSIONS: The pathological data of our study raises the hypothesis for the pathogenic stages at the level of microvessels in the frontal cortex of the patients with schizophrenia or schizophrenia-spectrum disorders treated with D2-blocking antipsychotics: a stage with functional, reversible alterations that may be correlated with the impairments of working memory and presence of extrapyramidal symptoms and a lesional, irreversible stage with significant deterioration of cognition and global functioning. Further studies are needed to verify this hypothesis.