Mechanisms Involved in the Link between Depression, Antidepressant Treatment, and Associated Weight Change.

Major depressive disorder is a severe mood disorder associated with a marked decrease in quality of life and social functioning, accompanied by a risk of suicidal behavior. Therefore, seeking out and adhering to effective treatment is of great personal and society-wide importance. Weight changes associated with antidepressant therapy are often cited as the reason for treatment withdrawal and thus are an important topic of interest. There indeed exists a significant mechanistic overlap between depression, antidepressant treatment, and the regulation of appetite and body weight. The suggested pathomechanisms include the abnormal functioning of the homeostatic (mostly humoral) and hedonic (mostly dopaminergic) circuits of appetite regulation, as well as causing neuromorphological and neurophysiological changes underlying the development of depressive disorder. However, this issue is still extensively discussed. This review aims to summarize mechanisms linked to depression and antidepressant therapy in the context of weight change.

Cardiac Autonomic Balance Is Altered during the Acute Stress Response in Adolescent Major Depression-Effect of Sex.

Autonomic nervous system (ANS) abnormalities are associated with major depressive disorder (MDD) already at adolescent age. The majority of studies so far evaluated parasympathetic and sympathetic branches of ANS individually, although composite indices including cardiac autonomic balance (CAB) and cardiac autonomic regulation (CAR) seem to measure ANS functioning more comprehensively and thus could provide better psychopathologies' predictors. We aimed to study CAB and CAR derived from high-frequency bands of heart rate variability and left ventricular ejection time during complex stress response (rest-Go/NoGo task-recovery) in MDD adolescents with respect to sex. We examined 85 MDD adolescents (52 girls, age: 15.7 ± 0.14 yrs.) and 80 age- and sex-matched controls. The MDD group showed significantly reduced CAB compared to controls at rest, in response to the Go/NoGo task, and in the recovery phase. Moreover, while depressed boys showed significantly lower CAB at rest and in response to the Go/NoGo task compared to control boys, depressed girls showed no significant differences in evaluated parameters compared to control girls. This study for the first time evaluated CAB and CAR indices in drug-naïve first-episode diagnosed MDD adolescents during complex stress responses, indicating an altered cardiac autonomic pattern (i.e., reciprocal sympathetic dominance associated with parasympathetic underactivity), which was predominant for depressed boys.

Peripheral Inflammatory Markers in Autism Spectrum Disorder and Attention Deficit/Hyperactivity Disorder at Adolescent Age.

Autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) are associated with immune dysregulation. We aimed to estimate the pro- and anti-inflammatory activity/balance in ASD and ADHD patients at a little-studied adolescent age with respect to sex. We evaluated 20 ASD patients (5 girls, average age: 12.4 ± 1.9 y), 20 ADHD patients (5 girls, average age: 13.4 ± 1.8 y), and 20 age- and gender-matched controls (average age: 13.2 ± 1.9 y). The evaluated parameters included (1) white blood cells (WBCs), neutrophils, monocytes, lymphocytes, platelets, platelet distribution width (PDW), mean platelet volume, and derived ratios, as well as (2) cytokines-interferon-gamma, interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, and IL-10, tumor necrosis factor-alpha (TNF-α), and derived profiles and ratios. ASD adolescents showed higher levels of WBC, monocytes, IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, and IL-10, macrophages (M)1 profile, and anti-inflammatory profile than the controls, with ASD males showing higher monocytes, IL-6 and IL-10, anti-inflammatory profile, and a lower T-helper (Th)1/Th2+T-regulatory cell ratio than control males. The ADHD adolescents showed higher levels of PDW, IL-1ß and IL-6, TNF-α, M1 profile, proinflammatory profile, and pro-/anti-inflammatory ratio than the controls, with ADHD females showing a higher TNF-α and pro-/anti-inflammatory ratio than the control females and ADHD males showing higher levels of IL-1ß and IL-6, TNF-α, and M1 profile than the control males. Immune dysregulation appeared to be different for both neurodevelopmental disorders in adolescence.

Evaluation of Inflammatory Response System (IRS) and Compensatory Immune Response System (CIRS) in Adolescent Major Depression.

Purpose: Nowadays, the role of two tightly interconnected systems, the inflammatory response system (IRS) and the compensatory immune response system (CIRS) in depression, is increasingly discussed. Various studies indicate pro-inflammatory activity in adolescent depression; however, there is an almost complete lack of findings about IRS and CIRS balance. Thus, we aimed to assess different IRS and CIRS indices, profiles, and IRS/CIRS ratios in drug-naïve MDD patients at adolescent age, with respect to sex. Patients and Methods: One hundred MDD adolescents (40 boys, average age: 15.4±1.2 yrs.) and 60 controls (28 boys, average age: 15.3±1.5 yrs.) were examined. Evaluated parameters were 1. plasma levels of interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, interferon gamma, tumor necrosis factor alpha (TNF-α), soluble receptor of IL-6 (sIL-6R), soluble receptors of TNF-α (sTNF-R1, sTNF-R2); 2. profiles: IL-6 trans-signaling, M1 macrophage signaling, helper T lymphocytes (Th) 1 profile, regulatory T lymphocytes (Treg)+Th2, allIRS, and allCIRS; 3. IRS vs CIRS activity ratios: TNF-α/TNF-R1, TNF-α/TNF-R2, TNF-α/sTNF-Rs (ie sTNF-R1+sTNF-R2), Th1/Th2, Th1/Treg, Th1/Th2+Treg, M1/Th2, M1/Treg, M1/Treg+Th2, allIRS/allCIRS. Results: MDD patients showed increased IL-4, IL-10, TNF-α, sIL-6R, Treg+Th2, allIRS, allCIRS, and TNF-α/sTNF-Rs, and decreased Th1/Th2+Treg. MDD females showed increased IL-10 and TNF-α compared to control females. MDD males showed increased IL-4, IL-10, sIL-6R, Treg+Th2, and TNF-α/TNF-R1 compared to control males. Increased sTNF-R1 was found in MDD males compared to MDD females. Positive correlations were found between CDI score and sIL-6R and IL-10 in the total group and between CDI score and IL-10 in adolescent males. Conclusion: Our study for the first time extensively evaluated IRS and CIRS interactions revealing enhanced pro-inflammatory TNF-α signaling and IL-6 trans-signaling in association with increased IL-10- and IL-4-mediated anti-inflammatory activity in first-episode depression at the adolescent age. Moreover, results reflect the sex-specific simultaneous activation of IRS and CIRS pathways in adolescent depression.

Major depressive disorder at adolescent age is associated with impaired cardiovascular autonomic regulation and vasculature functioning.

Cardiovascular adverse complications represent a risk factor for increased cardiovascular morbidity and mortality in patients with major depressive disorder (MDD). However, there is little knowledge of adolescent MDD. We aimed to study complex cardiovascular autonomic regulation and early atherosclerotic damage with a focus on an analysis of heart rate variability (HRV), blood pressure variability (BPV), systolic time intervals, and measures of early atherosclerotic changes in adolescent MDD. Ninety depressive adolescents (34 boys, age 15.8 ± 1.3 yrs.) and 90 age-/gender-matched controls were examined. Evaluated parameters: HRV - time and spectral parameters, BPV - mean, systolic, and diastolic blood pressure, spectral systolic parameters; haemodynamic indices - stroke volume, cardiac output, total peripheral resistance, systolic time intervals - left ventricular ejection time, pre-ejection period; atherosclerotic indices - ankle-brachial index (ABI), pulse wave velocity, brachial-ankle pulse wave velocity, cardio-ankle vascular index; growth factors - epidermal growth factor (EGF), vascular endothelial growth factor associated with monocyte chemoattractant protein-1. Our results showed that the MDD group had significantly reduced HRV and higher BPV measures, shortened systolic time intervals, lower ABI, and higher EGF compared to controls. Concluding, our study revealed that adolescent MDD is associated with cardiovascular dysregulation and early vasculature dysfunction as preclinical markers of higher risk for cardiovascular morbidity, thus adolescence seems to represent an important age period for early diagnosis and prevention of later MDD-linked cardiovascular diseases manifesting in adulthood.

The Plasma Levels of 3-Hydroxybutyrate, Dityrosine, and Other Markers of Oxidative Stress and Energy Metabolism in Major Depressive Disorder.

Major depressive disorder (MDD) is a serious mental disease with a pathophysiology that is not yet fully clarified. An increasing number of studies show an association of MDD with energy metabolism alteration and the presence of oxidative stress. We aimed to evaluate plasma levels of 3-hydroxybutyrate (3HB), NADH, myeloperoxidase, and dityrosine (di-Tyr) in adolescent and adult patients with MDD, compare them with healthy age-matched controls, and assess the effect of antidepressant treatment during hospitalisation on these levels. In our study, plasmatic levels of 3HB were elevated in both adolescents (by 55%; p = 0.0004) and adults (by 88%; p < 0.0001) with MDD compared to controls. Levels of dityrosine were increased in MDD adults (by 19%; p = 0.0092) but not adolescents. We have not found any significant effect of antidepressants on the selected parameters during the short observation period. Our study supports the findings suggesting altered energy metabolism in MDD and demonstrates its presence independently of the age of the patients.

Simultaneous determination of fluoxetine, venlafaxine, vortioxetine and their active metabolites in human plasma by LC-MS/MS using one-step sample preparation procedure.

The aim of antidepressant therapy is to induce remission and prevent relapses of major depressive disorder with minimum adverse effects during the treatment. Due to high variability in metabolism, therapeutic drug monitoring is recommended as a useful tool for individualisation of the therapy. For this purpose, we have developed simple and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for quantification of fluoxetine (FLX), venlafaxine (VEN), vortioxetine (VTX) and their active metabolites norfluoxetine (NFLX) and O-desmethylvenlafaxine (ODV). After one-step extraction procedure using OSTRO plate, analytes were separated by gradient elution on Acquity UPLC BEH C18 (50 × 2.1 mm, 1.7 µm) column with runtime 4.2 min. The detection was done on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode with transitions at m/z 310.23 → 148.20 for FLX, m/z 296.23 → 134.20 for NFLX, m/z 278.31 → 121.13 for VEN, m/z 264.31 → 107.14 for ODV and m/z 299.19 → 150.05 for VTX using a positive electrospray ionisation interface. The method was successfully validated according to the European Medicine Agency guideline for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effect, extraction recovery, carryover, dilution integrity and stability over a concentration range of 1-300 ng/mL for FLX, NFLX, VEN, ODV and 0.2-100 ng/mL VTX. Extraction recovery for each analyte was > 80 %, and no significant matrix effects were observed. The developed method was employed for quantification of antidepressants in clinical samples from patients treated with either FLX, VEN, or VTX.

Arterial stiffness and haemodynamic regulation in adolescent anorexia nervosa versus obesity.

Cardiovascular complications contribute to higher morbidity and mortality in patients with anorexia nervosa. We aimed to study biomarkers of cardiovascular risk in anorexic, normal-weight, and obese adolescents with focus on complex cardiovascular autonomic regulation and early arteriosclerotic damage. We examined 20 adolescent girls with anorexia nervosa, 20 obese girls, and 20 healthy normal-weight controls. Collected data: body composition analysis, 5 min recordings of R-R intervals and beat-to-beat blood pressure (BP), and arterial stiffness evaluated using cardio-ankle vascular index (CAVI). Evaluated parameters: beat-to-beat heart rate and BP variability, haemodynamic parameters (total peripheral resistance (TPR) cardiac output), CAVI, and anthropometric indices, including novel body roundness index (BRI). Adolescents with anorexia nervosa had increased CAVI associated with lower arterial constriction indexed by low-frequency band of BP variability compared with normal-weight peers (p = 0.03, p = 0.04, respectively) and obese adolescents (p < 0.01, p = 0.01, respectively). After normalization of CAVI and TPR by BRI, the relationship between CAVI and TPR was significant for all groups with the highest slope in the anorexia nervosa group (R2 = 0.724, p < 0.01). This is the first study revealing early arteriosclerotic damage in anorexic girls with increased CAVI. Complex analysis of cardiovascular autonomic regulation, and early arteriosclerotic, hemodynamic, and anthropometric changes in spectrum anorexia nervosa, normal weight, and obesity could help to understand the mechanisms of increased cardiovascular risk in malnutrition. Novelty Girls with anorexia nervosa showed signs of early arteriosclerotic damage indexed by CAVI. Insufficient sympathetic cardiovascular control was found already in adolescents with anorexia nervosa. The effect of body composition on CAVI was best predicted by novel body roundness index.

Complex cardiac vagal regulation to mental and physiological stress in adolescent major depression.

BACKGROUND: Cardiovagal control is known to be reduced in major depressive disorder (MDD), however, the neurocardiac reflex control to distinct types of stressors is still unclear. We aimed to study parasympathetically mediated cardiac reflex functioning in response to mental and physiological stressors using heart rate variability (HRV) linear and nonlinear analysis in adolescent MDD. METHODS: We examined 60 adolescents (40 girls) with MDD (age 14.9 ±â€¯0.3 years) and 60 age and gender-matched controls. ECG was continuously recorded during stress protocol: baseline, Go/NoGo test, recovery, supine position, and orthostasis. Evaluated HRV linear and nonlinear indices: RR interval, pNN50, rMSSD, HF-HRV, Poincaré plot (SD1), symbolic dynamics 2UV%. Cardiovagal reactivity expressed as percentual change (%) was calculated in response to both stressors. RESULTS: In each phase of stress protocol, the MDD group had significantly reduced HRV parameters compared to controls, except for symbolic dynamics index 2UV% in supine position. The reactivity of HRV indices was significantly greater in response to orthostasis in MDD compared to controls. No significant differences were found in response to Go/NoGo test. LIMITATIONS: The smoking status and the menstrual cycle phase potentially affecting the HRV parameters were not monitored. Future research is needed to expand a sample size with respect to sex and to study neurocardiac response to other different stressors in MDD. CONCLUSIONS: This study revealed reduced resting cardiovagal regulation and greater vagal withdrawal indicating abnormal neurocardiac reflex functioning to physiological stressor (orthostasis) in adolescent MDD patients. Nonlinear HRV analysis was sensitive to detect cardiac-linked regulatory differences in adolescent depression.

QTc prolongation after ADHD medication.

OBJECTIVE: Multicenter studies have shown that cardiovascular risks of ADHD medication are extremely low. However, QTc length has been shown to be increased in smaller samples of patients or case reports after stimulant and atomoxetine medication. Based on recent studies of genetic polymorphisms associated with drug-induced QTc prolongation and polymorphisms linkage to regional populations, we hypothesized that the drug-induced QTc prolongation could be a factor of particular polymorphisms linked to specific regional populations undistinguished in multicenter studies. METHODS: We included 69 patients from a region of central Slovakia, 36 patients were taking atomoxetine and 33 patients methylphenidate. QTc, heart rate, potassium levels and BMI were examined before and after 8 weeks of treatment. Therapeutic effect was measured by ADHD-RS-IV. RESULTS: We found QTc prolongation after 8 weeks of treatment both with atomoxetine and methylphenidate that was neither followed by the significant changes in BMI and potassium levels nor the significant increase of heart rate. CONCLUSION: This is the first study revealing QTc prolongation in the group of ADHD children from the same region after 8-week treatment with atomoxetine and methylphenidate, indicating the potential discrete abnormalities in cardiac functioning associated with polymorphisms in genes of dopaminergic and noradrenergic system.

Symbolic dynamics of heart rate variability - a promising tool to investigate cardiac sympathovagal control in attention deficit/hyperactivity disorder (ADHD)?

We aimed to evaluate complex cardiac sympathovagal control in attention deficit/hyperactivity disorder (ADHD) by using heart rate variability (HRV) nonlinear analysis - symbolic dynamics. We examined 29 boys with untreated ADHD and 25 healthy boys (age 8-13 years). ADHD symptoms were evaluated by ADHD-RS-IV scale. ECG was recorded in 3 positions: baseline supine position, orthostasis, and clinostasis. Symbolic dynamics indices were used for the assessment of complex cardiac sympathovagal regulation: normalised complexity index (NCI), normalised unpredictability index (NUPI), and pattern classification measures (0V%, 1V%, 2LV%, 2UV%). The results showed that HRV complexity was significantly reduced at rest (NUPI) and during standing position (NCI, NUPI) in ADHD group compared to controls. Cardiac-linked sympathetic index 0V% was significantly higher during all posture positions and cardiovagal index 2LV% was significantly lower to standing in boys suffering from ADHD. Importantly, ADHD symptom inattention positively correlated with 0V%, and negatively correlated with NCI, NUPI. Concluding, symbolic dynamics revealed impaired complex neurocardiac control characterised by potential cardiac beta-adrenergic overactivity and vagal deficiency at rest and to posture changes in boys suffering from ADHD that is correlated with inattention. We suggest that symbolic dynamics indices could represent promising cardiac biomarkers in ADHD.

Anxiety reduction on atomoxetine and methylphenidate medication in children with ADHD.

BACKGROUND: Atomoxetine and methylphenidate are widely used to treat attention-deficit-hyperactivity disorder (ADHD) with similar effectiveness after 8 weeks of treatment, when atomoxetine has reached its a full effect. Both drugs have also been shown to have an effect on comorbid anxiety. To the best of our knowledge, no study has compared their effect on the dynamics of anxiety symptom reduction. The aim of this study was to compare the medication effect on core and comorbid anxiety symptom dynamics in children with ADHD. METHODS: Sixty-nine patients participated in the study: 36 patients were taking atomoxetine and 33 patients, methylphenidate. Therapeutic effect on core symptoms of ADHD was measured on the ADHD-rating scale IV, and symptoms of anxiety were measured using the Conners Parent Rating Scale (CPRS). Symptoms were measured prior to and every 2 weeks during 8 weeks of treatment. RESULTS: There was a significant decrease in CPRS anxiety subscale score in both medication groups. Anxiety subscale score was significantly lower in the atomoxetine group in the fourth week, and lasted through to 8 weeks of medication. CONCLUSION: Both atomoxetine and methylphenidate reduced the symptoms of ADHD and anxiety. Atomoxetine was more effective in anxiety symptom reduction from the fourth week of treatment.

The Effect of Methylphenidate on Neurological Soft Signs in ADHD.

OBJECTIVE: Neurological soft signs are very common in children with the attention deficit hyperactivity disorder (ADHD), and the first line medication of this disorder is methylphenidate. The aim of the study was to assess the effect of methylphenidate on the neurological soft signs in children and adolescents suffering from ADHD depending on the dose of methylphenidate. METHODS: Thirty five patients with ADHD were investigated by the ADHD RS-IV parent version questionnaire and the Revised Neurological Examination for Subtle Signs before treatment adjustment and after four weeks of methylphenidate medication. The changes in hyperactivity symptomatology, neurological soft signs during therapy and the influence of the methylphenidate dose were statistically analyzed. RESULTS: A significant decrease in hyperactivity symptomatology was found after one month of methylphenidate medication (p=0.0001) and significant decrease in neurological soft signs was demonstrated in 21 from a total of 26 items (p<0.05). Correlation analysis showed no relationship between the dose of methylphenidate and the improvement of neurological soft signs. Similarly, the improvement of ADHD symptomatology had not correlation with the improvement of neurological soft signs. CONCLUSION: The study demonstrated the positive effect of methylphenidate on neurological soft signs in which improvement occurred independently of the dose, indicating that their progress may be due to methylphenidate treatment of any dose. The unrelated effect of methylphenidate on the attention deficit hyperactivity disorder and neurological soft signs suggest that methylphenidate might be useful in the therapy of clumsy child syndrome and in ADHD treatment of non-responders.