Efficacy and safety of adding fluoxetine to the treatment regimen of hospitalized patients with non-critical COVID-19 pneumonia: A double-blind randomized, placebo-controlled clinical trial.

INTRODUCTION: Selective serotonin reuptake inhibitors are considered the drugs, whose effectiveness in viral pandemics has been studied. The aim of this study was to evaluate of adding fluoxetine to the treatment regimen of patients with COVID-19 pneumonia. METHODS: This study was a double-blind randomized placebo controlled clinical trial .36 patients in the fluoxetine and 36 patients in the placebo group were enrolled. Patients in the intervention group were first treated with fluoxetine 10 mg for 4 days and then the dose of 20 mg was continued for 4 weeks. Data analysis was conducted using SPSS V. 22.0. RESULTS: There was no statistically significant difference between the two groups in terms of clinical symptoms at the beginning of the study and also the score of anxiety and depression, oxygen saturation at the time of hospitalization, mid-hospitalization and discharge periods. The need for mechanical ventilator support (p = 1.00), the need for admission in the intensive care unit (ICU) (p = 1.00), rate for mortality (p = 1.00), and discharge with relative recovery (p = 1.00) were not significantly different between the two groups. The distribution of CRP within the study groups showed a significant decrease during different time periods (p = 0.001), and although there was no statistically significant difference between the two groups on the first day (p = 1.00) and at discharge (p = 0.585), mid-hospital CRP showed a significant decrease in the fluoxetine group (p = 0.032). CONCLUSION: Fluoxetine resulted in a faster reduction of patients' inflammation without association with depression and anxiety.

Changes of Mental State and Serum Prolactin Levels in Patients with Schizophrenia and Depression after Receiving the Combination Therapy of Amisulpride and Chloroprothixol Tablets.

OBJECTIVE: To investigate the changes in mental state and serum prolactin levels in patients with schizophrenia and depression after receiving the combination therapy of amisulpride and chloroprothixol tablets. METHODS: A total of 148 schizophrenic patients with depression were randomly divided into control group (N = 73) and study group (N = 75). The control group was treated with clopidothiol, and the study group was treated with amisulpride. Symptom scores, sleep quality, adverse reactions, therapeutic effects, prolactin, and progesterone levels, HAMD, PANSS, and PSP scores were compared between the two groups. RESULTS: The symptom scores of both groups were significantly reduced, but when compared to the control group, the symptom scores of the research group were significantly reduced more significantly (P < 0.05); serum GDNF levels of both groups were significantly increased, while serum NSE, IL-1, and MBP levels were significantly reduced (P < 0.05). However, the research group altered more substantially (P < 0.05) than the control group; the overall PSQI score of the research group was lower (P < 0.05) than the control group; and the incidence of adverse responses in the control and study groups was 12.3 percent and 4.0 percent. The research group had a lower rate of adverse responses (P < 0.05) than the control group, and the effective treatment of the control and research groups was 82.2 percent and 98.7%, respectively. The research group had a lower rate of adverse reactions (P < 0.05) than the control group, while the control and research groups' successful treatment rates were 82.2 percent and 98.7%, respectively. When compared to the control group, the research group had a greater treatment efficiency (P < 0.05); blood prolactin and progesterone levels were considerably lowered in both groups, but the reductions in the research group were more evident (P < 0.05). Both groups had considerably lower HAMD and PANSS scores, and both had significantly higher PSP scores, although the difference in the research group was more evident (P < 0.05). CONCLUSION: For people with schizophrenia and depression, a combination of amisulpride and chloroprothixol pills has a considerable effect. It can help patients with their clinical symptoms and sleep quality while also lowering their serum prolactin levels, which is favorable to their illness recovery. As a result, the combined treatment of amisulpride and chloroprothixol pills deserves to be promoted and used.

Differences in Cerebral Distribution between Imipramine and Paroxetine via Membrane Transporters at the Rat Blood-Brain Barrier.

PURPOSE: The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats. METHODS: In vivo influx and efflux transport of imipramine and paroxetine across the BBB were tested using integration plot analysis and a combination of brain efflux index and brain slice uptake studies, respectively. Conditionally immortalized rat brain capillary endothelial cells, TR-BBB13 cells, were utilized to characterize imipramine and paroxetine transport at the BBB in vitro. RESULTS: The in vivo influx clearance of [3H]imipramine and [3H]paroxetine in rats was determined to be 0.322 mL/(min·g brain) and 0.313 mL/(min·g brain), respectively. The efflux clearance of [3H]imipramine and [3H]paroxetine was 0.380 mL/(min·g brain) and 0.126 mL/(min·g brain), respectively. These results suggest that the net flux of paroxetine, but not imipramine, at the BBB in vivo was dominated by transport to the brain from the circulating blood. The uptake of imipramine and paroxetine by TR-BBB13 cells exhibited time- and temperature-dependence and one-saturable kinetics with a Km of 37.6 µM and 89.2 µM, respectively. In vitro uptake analyses of extracellular ion dependency and the effect of substrates/inhibitors for organic cation transporters and transport systems revealed minor contributions to known transporters and transport systems and the difference in transport properties in the BBB between imipramine and paroxetine. CONCLUSIONS: Our study showed the comprehensive outcomes of imipramine and paroxetine transport at the BBB, implying that molecular mechanism(s) distinct from previously reported transporters and transport systems are involved in the transport.

Metformin and fluoxetine improve depressive-like behavior in a murine model of Parkinsons disease through the modulation of neuroinflammation, neurogenesis and neuroplasticity.

Thereabout 30-40% of patients with Parkinson's Disease (PD) also have depression contributing to the loss of quality of life. Among the patients who treat depression, about 50% do not show significant improvement due to the limited efficacy of the treatment. So far, there are no effective disease-modifying treatments that can impede its progression. The current clinical approach is based on symptom management. Nonetheless, the reuse of drugs with excellent safety profiles represents an attractive alternative strategy for treating of different clinical aspects of PD. In this study, we evaluated the effects of metformin separately and associated with fluoxetine on depressive like-behavior and motor alterations in experimental Parkinson's disease. C57BL6 mice were induced with rotenone (2.5 mg/kg/day) for 20 days and treated with metformin (200 mg/kg/day) and fluoxetine (10 mg/kg/day) from the 5th day of induction. The animals were submitted to Sucrose Preference, Tail Suspension, and rotarod tests. Hippocampus, prefrontal cortex, and substantia nigra were dissected for molecular and morphological analysis. Metformin and fluoxetine prevented depressive-like behavior and improved motor impairment and increased TH nigral positive cells. Metformin and fluoxetine also reduced IBA-1 and GFAP positive cells in the hippocampus. Moreover, metformin reduced the phospho-NF-kB, IL-1ß in the prefrontal cortex and iNOS levels in the hippocampus. Both metformin and fluoxetine increased neurogenesis by increasing KI67, but only the combined treatment increased neuronal survival by NeuN positive cells in the hippocampus. In addition, fluoxetine reduced cell death, decreasing caspase-3 and PARP-1 levels. Lastly, metformin potentiated the effect of fluoxetine on neuroplasticity by increasing BDNF positive cells. Metformin has antidepressant and antiparkinsonian potential due to anti-inflammatory neurogenic, and neuroplasticity-inducing effects when combined with fluoxetine.

Impact of a High-Fat Meal and Sprinkled Administration on the Bioavailability and Pharmacokinetics of Viloxazine Extended-Release Capsules (QelbreeTM) in Healthy Adult Subjects.

BACKGROUND AND OBJECTIVES: Viloxazine extended-release (viloxazine ER) capsules (QelbreeTM) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Here, we determined whether the pharmacokinetics of viloxazine are impacted by consuming the capsule contents sprinkled on applesauce rather than an intact capsule, and the effect of a high-fat meal on the pharmacokinetics of viloxazine ER. METHODS: This was a randomized, open-label, crossover, three-treatment, three-period study in healthy adults using orally administered single-dose viloxazine ER 200 mg capsules. Subjects consumed: (1) an intact capsule after a 10-h fast (control condition); (2) the capsule contents sprinkled on one tablespoon of applesauce; and (3) an intact capsule with a standard high-fat meal. Blood samples were collected for 48 h post-dosing. Relative bioavailability analyses were performed to assess the impact of each test condition against the control condition (intact capsule, fasting). The absence of an impact was indicated if the 90% confidence interval (CI) for the least-squares geometric mean ratio (LSGMR) of maximal concentration (Cmax), the area under the concentration-time curve from time 0 to the last measurable concentration time (AUClast), and the area under the concentration-time curve from time 0 to infinity (AUCinf) were within the predetermined no-difference limits of 80-125%. RESULTS: Out of 27 enrolled subjects, 25 were included in the pharmacokinetic analysis. The LSGMR (90% CI) for viloxazine ER sprinkled vs. intact were 90.10% (83.35-97.40) for Cmax, 93.71% (89.09-98.57) for AUClast, and 95.37% (89.80-101.28) for AUCinf. The LSGMR (90% CI) for viloxazine ER consumed in the fed state vs. fasting state were 90.86% (84.05-98.21) for Cmax, 89.68% (85.26-94.33) for AUClast, and 92.35% (86.96-98.07) for AUCinf. The 90% CIs of the LSGMRs were within the predetermined no-difference limits of 80-125%. Viloxazine ER was well tolerated, with most adverse events reported as mild. CONCLUSIONS: These data suggest that viloxazine ER can be consumed sprinkled on applesauce or as intact capsules with or without meals without significantly changing its pharmacokinetics.

P-glycoprotein mediates the pharmacokinetic interaction of olanzapine with fluoxetine in rats.

Clinical trials of olanzapine combined with fluoxetine (Olanzapine/Fluoxetine Combination, OFC) in the treatment of refractory depression have shown significant efficacy, but the drug-drug interaction (DDI) between them remains unclear. In this report, the pharmacokinetic interaction between olanzapine and fluoxetine was studied in wild-type (WT) and Mdr1a/b gene knockout (KO) rats. By analyzing the pharmacokinetics and tissue distribution of olanzapine in single dose and combination, the potential DDI mediated by P-gp was explored. The results showed that in WT rats, the combination of fluoxetine increased the peak concentration (Cmax, 44.1 ± 5.1 ng/mL in the combination group vs 9.0 ± 1.5 ng/mL in the monotherapy group) and the exposure (AUC0-t, 235.8 ± 22.7 h × ng/mL in the combination group vs 47.5 ± 8.4 h × ng/mL in monotherapy group) of olanzapine, and decreased the clearance (CL, 8119.0 ± 677.9 mL/h/kg in the combination group vs 49,469.0 ± 10,306.0 mL/h/kg in monotherapy group). At the same time, fluoxetine significantly increased the in vivo exposure of olanzapine in brain, liver, kidney and ileum of WT rats, indicating the occurrence of DDI. The same phenomenon was observed in Caco-2 cells in vitro as well. However, in KO rats, there was no significant difference in pharmacokinetic parameters between the monotherapy group and the combination group. In conclusion, P-gp plays an important role in the pharmacokinetic interaction between olanzapine and fluoxetine in rats. This study may provide a reference for the clinical safety of olanzapine combined with fluoxetine.

Autophagy Induction and Accumulation of Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Adult C57BL/6 Mice Subjected to Adolescent Fluoxetine Treatment.

BACKGROUND: Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer's disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. OBJECTIVE: Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure on these pathways, using mice as a model system. METHODS: We subjected C57BL/6 adolescent male mice to FLX (20 mg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. RESULTS: Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortexConclusion: Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life.

Escitalopram enhances synchrony of brain responses during emotional narratives in patients with major depressive disorder.

One-week treatment with escitalopram decreases amygdala responses to fearful facial expressions in depressed patients, but it remains unknown whether it also modulates processing of complex and freely processed emotional stimuli resembling daily life emotional situations. Inter-subject correlation (ISC) offers a means to track brain activity during complex, dynamic stimuli in a model-free manner. Twenty-nine treatment-seeking patients with major depressive disorder were randomized in a double-blind study design to receive either escitalopram or placebo for one week, after which functional magnetic resonance imaging (fMRI) was performed. During fMRI the participants listened to spoken emotional narratives. Level of ISC between the escitalopram and the placebo group was compared across all the narratives and separately for the episodes with positive and negative valence. Across all the narratives, the escitalopram group had higher ISC in the default mode network of the brain as well as in the fronto-temporal narrative processing regions, whereas lower ISC was seen in the middle temporal cortex, hippocampus and occipital cortex. Escitalopram increased ISC during positive parts of the narratives in the precuneus, medial prefrontal cortex, anterior cingulate and fronto-insular cortex, whereas there was no significant synchronization in brain responses to positive vs negative events in the placebo group. Increased ISC may imply improved emotional synchronization with others, particularly during observation of positive events. Further studies are needed to test whether this contributes to the later therapeutic effect of escitalopram.

Clinical features of Barré-Lièou syndrome and efficacy of trazodone for its treatment: A retrospective single center study.

Barré-Lièou syndrome (BLS) is a manifestation of various autonomic and secondary symptoms including muscle stiffness, tinnitus, dizziness, and pain in various body parts. Although considered to be caused by hyperactivation of the autonomic nervous system due to trauma, there is currently no firmly established etiology or evidence on the treatment and clinical features of BLS. We retrospectively examined the clinical features of BLS and evaluated the efficacy of trazodone (TZD) for its treatment. We conducted a retrospective analysis of the data of 20 consecutive cases with suspected BLS who were treated in our hospital between 2016 and 2019. BLS symptoms were rated on a 10-point scale, and two groups were defined, that is, a mild-BLS group (BLS scores, 1-5) and a severe-BLS group (BLS scores, 6-10). Univariate analysis of patient factors was performed. The BLS score was 6.0 ± 1.7, and the maximum TZD dose was 80 ± 34 mg/day; nine patients (45%) were TZD free, and no TZD side effects were observed, while all patients had a good clinical outcome. There were significant differences between the mild-BLS and severe-BLS groups in the period from injury to diagnosis (p = 0.015), chest/back pain (p < 0.001), constipation (p = 0.001), and maximum TZD dose (p = 0.008). BLS involves posttraumatic autonomic symptoms accompanied by depression and insomnia. The sympathetic hypersensitivity theory could explain its etiology. TZD could effectively and safely treat BLS, and early diagnosis and treatment can contribute toward good clinical outcomes. Enhanced recognition and understanding of this disease are warranted.

Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression.

PURPOSE: The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression. METHODS: Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included. FINDINGS: A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater. CONCLUSIONS: Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.

Neuronal activity regulated pentraxin (narp) and GluA4 subunit of AMPA receptor may be targets for fluoxetine modulation.

Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.

CYP2D6*10 polymorphism and the enantioselective O-desmethylation of S-(+)- and R-(-)-venlafaxine in Japanese psychiatric patients.

According to previous studies, R-(-)-venlafaxine (VEN) has higher enantioselectivity than S-(+)-VEN, and the plasma concentration of R-(-)-VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady-state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O-desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S-(+)-VEN were approximately 1.9-fold higher than those of R-(-)-VEN. The plasma concentrations of S-(+)-VEN and R-(-)-VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S-(+)-VEN and R-(-)-VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R-(-)-ODV/R-(-)-VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R-(-)-VEN and S-(+)-VEN. Further studies are needed to examine how these findings affect clinical practice.

Evidence of hypoglycemic anhedonia and modulation by bupropion in rats.

BACKGROUND: Disorders characterized by dysfunction of glucose metabolism are often comorbid with depression. The current study investigated whether a hypoglycemic state caused by 2-deoxy-d-glucose (2-DG) can result in anhedonic behaviors responsive to stimulation of monoamine activity. METHODS: In experiment 1, male Sprague-Dawley rats were tested for maintenance of intra-oral self-administration (IOSA) of a sweet solution after pre-treatment with 300 or 500 mg/kg 2-DG, a blocker of glucose metabolism. Experiment 2 determined whether exposure to an environment previously paired with the effects of 2-DG (0, 200 or 300 mg/kg) can influence IOSA, and whether 2-DG can modify taste reactivity to same sweet solution. Finally, experiment 3 examined whether 0 or 30 mg/kg bupropion, a monoamine-reuptake blocker, would attenuate the effect of 300 mg/kg 2-DG on IOSA and taste reactivity. RESULTS: It was found that 2-DG produced a sustained decrease in IOSA when animals were tested drug-free. This decrease in IOSA did not appear linked to place conditioning or to alterations in taste reactivity, and it was partially normalized by pre-treatment with bupropion. CONCLUSIONS: Taken together, these results in rats suggest that rapid hypoglycemia can induce an anhedonic state characterized by impaired consummatory responses to nutritional incentive stimuli and that can be alleviated by the antidepressant bupropion.

Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial. OBJECTIVES: To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults. SEARCH METHODS: In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI. MAIN RESULTS: We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest. AUTHORS' CONCLUSIONS: We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.

Intermittent repeated stress but not ketamine changes mice response to antidepressants.

Discovery of the rapid antidepressant effect of ketamine has been considered one of the most important advances in major depressive disorder treatment. Several studies report a significant benefit to patients that lasts up to 19 days after treatment. However, concerns arise from the long-term use of ketamine, thus a safe and effective strategy for maintaining its antidepressant effect is still necessary. To this end, our work assessed the effects of imipramine and fluoxetine after repeated ketamine treatment in male mice. Ketamine (30 mg/kg/day for 14 days) induced an anti-immobility effect in the forced swimming (FS) paradigm, detected 1 and 3 days after treatment. Seven days after the last ketamine injection, mice received imipramine (20 mg/kg) or fluoxetine (30 mg/kg). Imipramine and fluoxetine did not change mice's immobility time, regardless of the pre-treatment (saline or ketamine). Since both drugs' anti-immobility effect was demonstrated in the classical FS test, we can assume that repeated exposure to intermittent stress inhibited the antidepressant drugs' anti-immobility effects. Moreover, pre-exposure to ketamine did not counteract stress-induced changes in mice response to antidepressants. Since exposure to forced swim and i.p. injections are stressful to rodents, each stressor's contribution to the blunted response to antidepressants was investigated. Our data demonstrated that both stressors (FS and i.p. injections) influenced the reported effect. In summary, our results showed that exposure to intermittent repeated stress inhibited the anti-immobility effect of imipramine and fluoxetine in mice and corroborated findings demonstrating that exposure to stress can blunt patients' response to antidepressants.

Environmental level of the antidepressant venlafaxine induces behavioral disorders through cortisol in zebrafish larvae (Danio rerio).

Psychoactive drugs discharged into the environment have different effects on the behavior of vertebrates. The objective of this study was to evaluate the effect of venlafaxine on the behavior of zebrafish, and whether melatonin could reverse the induction of venlafaxine. In this study, a series of venlafaxine concentrations (1 µg/L, 10 µg/L, 100 µg/L) was used to treat zebrafish embryos from 2 hours post-fertilization (hpf) to 5dpf. We found that venlafaxine (1 µg/L) can stimulate the growth of the head area, eye area, and body length of zebrafish. The light-dark test showed that venlafaxine (1 µg/L) could increase the activity of zebrafish larvae. What's more, venlafaxine (1 µg/L) upregulated the expression of steroid regulatory factors including steroidogenic acute regulatory protein (star), cytochrome P450 family member 11A1 (cyp11a1) and 11 ß hydroxylase (cyp11b1) by cAMP-pCREB pathway, affecting the function of the steroidogenic cells, which might be involved in the increased cortisol levels in zebrafish larvae. Whereas, melatonin (230 µg/L) restored the altered locomotion behavior induced by venlafaxine and recovered the altered gene expression. Our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts behavior and may compromise the adaptive responses to the environment in zebrafish larvae.

AMPA receptors mediate the pro-cognitive effects of electrical and optogenetic stimulation of the medial prefrontal cortex in antidepressant non-responsive Wistar-Kyoto rats.

BACKGROUND: The chronic mild stress (CMS) procedure is a widely used animal model of depression, and its application in Wistar-Kyoto (WKY) rats has been validated as a model of antidepressant-refractory depression. While not responding to chronic treatment with antidepressant drugs, WKY rats do respond to acute deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC). In antidepressant-responsive strains there is evidence suggesting a role for AMPA subtype of glutamate receptor in the action mechanism of both antidepressants and DBS. METHODS: Animals were subjected to CMS for 6 to 8 weeks; sucrose intake was monitored weekly and novel object recognition (NOR) test was conducted following recovery from CMS. Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. The AMPA receptor antagonist NBQX was administered, at identical sites in mPFC, immediately following the exposure trial in the NOR. RESULTS: Sucrose intake and NOR were suppressed by CMS, and restored by VEN in Wistars and by DBS, OGS, or CX-516 in WKY. However, OGS of the ventral hippocampal afferents to mPFC was ineffective. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. CONCLUSIONS: These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats.

Nonresponse to high-dose bupropion for depression in a patient carrying CYP2B6*6 and CYP2C19*17 variants: a case report.

We report the case of a patient with major depression treated with high-dose bupropion due to prior detected subtherapeutic blood concentrations at standard dosing. Pharmacogenetic panel testing identified the patient as a carrier of the CYP2B6*6 allele, which has been associated with reduced bupropion metabolism and decreased concentrations of the pharmacologically active metabolite hydroxybupropion. Interestingly, we also found the patient to be homozygous for the CYP2C19*17 allele, predicting an ultra rapid metabolizer phenotype. We propose a combined effect of the detected CYP2C19 and CYP2B6 genetic variants on bupropion metabolism. This case underlines the potential benefit of pre-emptive pharmacogenotyping but also the yet still fragmentary evidence making precise pharmacogenotype guided antidepressant selection and dosing challenging.

Coprescribed Benzodiazepines in Older Adults Receiving Antidepressants for Anxiety and Depressive Disorders: Association With Treatment Outcomes.

OBJECTIVE: There is a paucity of data on the effects of coprescribed benzodiazepines on treatment response variability and adherence to antidepressant pharmacotherapy for depression and anxiety in late life. The objective of this transdiagnostic analysis was to examine the effect of benzodiazepines on treatment outcomes in older patients with generalized anxiety disorder (GAD) or major depressive disorder (MDD). METHODS: Secondary analyses of data from 2 clinical trials of antidepressant pharmacotherapy for GAD (escitalopram vs placebo, 2006-2009) or MDD (open treatment with venlafaxine, 2009-2014) were conducted. Participants included 640 adults aged 60+ years with DSM-IV-defined GAD (n = 177) or MDD (n = 463). Benzodiazepine data were collected at baseline. Adherence and treatment response were assessed over 12 weeks. The analysis addressed whether coprescribed benzodiazepines are associated with treatment response, antidepressant medication adherence, dropout, final dose of antidepressant medication, and report of antidepressant-related adverse effects. RESULTS: Participants with GAD and coprescribed benzodiazepines were treated with a lower mean dosage of escitalopram and were less likely to complete the trial; there was no difference in adherence or treatment response. Participants with MDD and coprescribed benzodiazepines were less likely to tolerate a therapeutic dose of venlafaxine and reported more medication-related adverse effects; there was no difference in adherence, dropout, or treatment response. CONCLUSIONS: Coprescription of benzodiazepines was associated with increased dropout in older patients with GAD and more medication-related adverse effects in older patients with MDD. However, with the systematic clinical attention offered in a clinical trial, they do not impede treatment response. Clinicians should be aware that a coprescribed benzodiazepine may be a marker of a more challenging treatment course. Trial Registration: Data analyzed were from studies with ClinicalTrials.gov identifiers NCT00892047 and NCT00105586.