Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Physical exercise and major depressive disorder in adults: systematic review and meta-analysis.

The objective of this study was to assess the benefits and potential risks associated with different physical exercise modalities for managing symptoms in adults with major depressive disorder who were not receiving second-generation antidepressants or cognitive behavioral therapy. A systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted. The search included multiple databases: Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycInfo, Web of Science, Clinical Trials repository, gray literature, and manual search. No language restrictions were applied. Eligible studies involved RCTs of adults with major depressive disorder who were not on antidepressants or receiving psychological therapy, comparing various exercise modalities with second-generation antidepressants or cognitive behavioral therapy, body-mind exercise, or no exercise interventions. Nine RCTs involving 678 adults were analyzed. The pooled results indicated a small clinical effect favoring exercise in reducing depressive symptoms, although the difference was not statistically significant (SMD = 0.27, 95% CI [- 0.58, 0.04], P = 0.09). Subgroup analyses suggested that intervention duration, frequency, intensity, supervision, age, overweight/obesity status, and diagnosis of depression could influence treatment outcomes. A sensitivity analysis was conducted for studies with controls without exercise interventions and a low risk of bias in the domains related to the randomization process and deviations from the intended interventions. The results showed that there are no statistically significant differences when interventions are compared with medication and body-mind exercise (p = 0.12, I2 = 78%). Furthermore, the analysis showed a moderate effect size favoring exercise, but no statistically significant difference between groups (p = 0.05), with high heterogeneity (I2 = 85%). The evidence quality was generally low to very low, and methodological limitations compromised the certainty of the findings. Adverse events associated with exercise were manageable. The study emphasizes the need for well-designed RCTs to provide clearer insights into the potential benefits of exercise in managing major depressive disorder symptoms. Caution is warranted in interpreting these results due to the limitations of the included studies.Systematic review registration: PROSPERO CRD42022356741.

Moving from serotonin to serotonin-norepinephrine enhancement with increasing venlafaxine dose: clinical implications and strategies for a successful outcome in major depressive disorder.

INTRODUCTION: Mental health disorders, especially depressive and anxiety disorders, are associated with substantial health-related burden. While the second-generation antidepressants are widely accepted as first-line pharmacological treatment for major depressive disorder (MDD), patient response to such treatment is variable, with more than half failing to achieve complete remission, and residual symptoms are frequently present. AREAS COVERED: Here, the pharmacodynamics of venlafaxine XR are reviewed in relation to its role as both a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine-reuptake inhibitor (SNRI), and we look at how these pharmacodynamic properties can be harnessed to guide clinical practice, asking the question 'is it possible to develop a symptom-cluster-based approach to the treatment of MDD with comorbid anxiety utilizing venlafaxine XR?.' Additionally, three illustrative clinical cases provide practical examples of the utility of venlafaxine-XR in real-world clinical practice. The place of venlafaxine XR in managing fatigue/low energy, a frequent residual symptom in MDD, is explored using pooled data from clinical trials of venlafaxine XR. EXPERT OPINION: Venlafaxine XR should be considered as a first-line treatment for MDD with or without comorbid anxiety, and there are clear pharmacodynamic signals supporting a symptom cluster-based treatment paradigm for venlafaxine XR.

[Treatment of mental disorders caused or triggered by somatic and neurological diseases with the use of the multimodal antidepressant trazodone]. / Terapiya psikhicheskikh rasstroistv, obuslovlennykh libo provotsirovannykh somaticheskoi i nevrologicheskoi patologiei, s primeneniem mul'timodal'nogo antidepressanta trazodon.

The purpose of this narrative review is to relate current data on the molecular mechanisms of action of trazodone with its clinical effects and applicability in mental disorders caused or triggered by somatic and neurological disease, according to available publications. In the article, the prospects for the use of the multimodal antidepressant trazodone are discussed in accordance with therapeutic targets. The latter are discussed in accordance with the typology of the mentioned above psychosomatic disorders. Trazodone is an antidepressant acting primarily due to the blockade of postsynaptic serotonin 5H2A- and 5H2C-receptors, as well as the blockade of serotonin reuptake, but also has affinity for a number of additional receptors. The drug has a favorable safety profile and a wide range of beneficial effects: antidepressive, somnolent, anxiolytic, anti-dysphoric and somatotropic. This makes it possible to influence a wide range of therapeutic targets in the structure of mental disorders caused or triggered by somatic and neurological diseases, carrying out safe and effective psychopharmacotherapy.

A comprehensive review and meta-analysis of neurological side effects related to second-generation antidepressants in individuals with major depressive disorder.

Second-generation antidepressants (SGADs) often cause neurological side effects (SEs). This meta-analysis seeks to quantify the short-term rates of neurological SEs related to routinely used second-generation antidepressants used to treat major depressive disorder (MDD). A search of the PubMed, EMBASE,Cochrane Library databases and Web of Science was done to uncover double-blind, randomized, placebo-controlled studies evaluating the effectiveness of frequently used SGADs medicines in people with MDD. Qualifying studies were required to concentrate on the use of SGADs routinely used in MDD and to uncover data on treatment-emergent neurological SEs occurring within 12 weeks of therapy. Overall, 143 RCT studies containing 188 treatment arms were included in the meta-analyses. Most SGADs increased the risk of neurological SEs compared to placebo. The least tolerated antidepressants on the neurological tract were desvenlafaxine (OR=1.98; CI 0.85-4.65; p-value=0.12) and venlafaxine (OR=1.15; CI 0.96-1.38; p-value=0.13). Agomelatine, bupropion and vortioxetine exhibited reduced neurological SEs, showing diminished risk in insomnia (OR=0.56; CI 0.36-0.88; p-value=0.01), somnolence (OR=0.46; CI 0.27-0.79; p-value=0.01), vision blurred (OR=0.43; CI 0.19-0.96; p-value=0.04), respectively. Most SGADs did not or just marginally increased the risk of headache compared to placebo. In conclusion, frequently used SGADs demonstrated distinct patterns of neurological SEs, which physicians should consider when prescribing antidepressants to promote treatment adherence and favorable outcomes in patients with MDD.

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.

Pharmacologic Treatment of Depression.

The prevalence of depression and the use of antidepressant medications have risen steadily in the United States over the past three decades. Antidepressants are the most commonly prescribed medications for U.S. adults 20 to 59 years of age. Second-generation antidepressants (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin modulators, atypical antidepressants) are first-line therapy for depression. Psychotherapy, including cognitive behavior therapy and other types of individual and group therapy, is also a first-line treatment. The combination of medication and psychotherapy is preferred for severe depression. Treatment history, comorbidities, costs, and risk of adverse effects should be considered when choosing an antidepressant medication. Although many patients use antidepressants indefinitely, few studies have examined safety and effectiveness beyond two years. There is an increased risk of relapse or recurrence of depressive symptoms when an antidepressant is discontinued, compared with continued use. Gradually tapering the dosage while concurrently providing cognitive behavior therapy can decrease this risk. High-quality evidence on antidepressant use in pregnancy is lacking. Depression and use of antidepressants are both associated with preterm birth.

Cost-Effectiveness of First- and Second-Step Treatment Strategies for Major Depressive Disorder : A Rapid Review.

BACKGROUND: Major depressive disorder (MDD) is the most prevalent, disabling form of depression, with a high economic effect. PURPOSE: To assess evidence on cost-effectiveness of pharmacologic and nonpharmacologic interventions as first- and second-step treatments in patients with MDD. DATA SOURCES: Multiple electronic databases limited to English language were searched (1 January 2015 to 29 November 2022). STUDY SELECTION: Two investigators independently screened the literature. Seven economic modeling studies fulfilled the eligibility criteria. DATA EXTRACTION: Data abstraction by a single investigator was confirmed by a second; 2 investigators independently rated risk of bias. One investigator determined certainty of evidence, and another checked for plausibility. DATA SYNTHESIS: Seven modeling studies met the eligibility criteria. In a U.S. setting over a 5-year time horizon, cognitive behavioral therapy (CBT) was cost-effective compared with second-generation antidepressants (SGAs) as a first-step treatment from the societal and health care sector perspectives. However, the certainty of evidence is low, and the findings should be interpreted cautiously. For second-step treatment, only switch strategies between SGAs were assessed. The evidence is insufficient to draw any conclusions. LIMITATIONS: Methodologically heterogeneous studies, which compared only CBT and some SGAs, were included. No evidence on other psychotherapies or complementary and alternative treatments as first-step treatment or augmentation strategies as second-step treatment was available. CONCLUSION: Although CBT may be cost-effective compared with SGAs as a first-step treatment at a 5-year time horizon from the societal and health care sector perspectives, the certainty of evidence is low, and the findings need to be interpreted cautiously. For other comparisons, the evidence was entirely missing or insufficient to draw conclusions. PRIMARY FUNDING SOURCE: American College of Physicians.

Manejo farmacológico del episodio depresivo bipolar en adolescentes: actualización bibliográfica / Pharmacological management of bipolar depressive episode in adolescents: bibliographic update

El manejo farmacológico del episodio depresivo en contexto del trastorno bipolar constituye un desafío para el clínico tanto en psiquiatría adultos como infantoadolescente. El presente trabajo tiene por objetivo actualizar y sintetizar la evidencia disponible respecto al manejo farmacológico para la depresión bipolar en población pediátrica. Metodología: Se realizó una búsqueda de las publicaciones de los últimos 5 años en bases de datos. Resultados: La evidencia muestra como primera línea el uso de antipsicóticos de segunda generación por sobre los estabilizadores del ánimo en este grupo etario; demostrando lurasidona y lanzapina/fluoxetina eficacia similares. Lurasidona es una opción con mejor perfil de seguridad por asociarse a menos efectos adversos y mejor adherencia. El uso de antidepresivos debe considerarse dentro de los pasos iniciales del manejo, asociado a un antipsicótico de segunda generación. Conclusiones: Se destaca la importancia de la sospecha, evaluación y diagnóstico adecuado para guiar la decisión de manejo integral. A pesar de los riesgos y consideraciones existentes, es importante considerar el uso en primera línea de antipsicóticos de segunda generación y de antidepresivos en el manejo de un cuadro depresivo en contexto de la enfermedad bipolar. La escasez de estudios en el tratamiento farmacológico de la depresión bipolar en general y especialmente en población pediátrica limita la generalización y extrapolación de los resultados a la realidad local.

The pharmacological management of the depressive episode in the context of bipolar disorder constitutes a challenge for the clinician both in adult and child-adolescent population. The objective of this paper is to update and synthesize the available evidence regarding the pharmacological management of bipolar depression in the pediatric population. Methodology: A search of the publications of the last 5 years in databases was carried out. Results: The evidence shows the use of second generation antipsychotics over mood stabilizers as the first line in this age group; demonstrating similar efficacy. Results: The evidence shows the use of second generation antipsychotics over mood stabilizers as the first line in this age group; demonstrating similar efficacy lurasidone and lanzapine/fluoxetine. Lurasidone is an option with a better safety profile as it is associated with fewer adverse effects and better adherence. The use of antidepressants should be considered within the initial steps of management, associated with a second generation antipsychotic. Conclusions: The importance of suspicion, evaluation and adequate diagnosis to guide the decision of comprehensive management is highlighted. Despite the existing risks and considerations, it is important to consider the first-line use of second-generation antipsychotics and antidepressants in the management of a depressive episode in the context of bipolar illness. The scarcity of studies on the pharmacological treatment of bipolar depression in general and especially in the pediatric population limits the generalization and extrapolation of the results to the local reality.

Global cognitive effects of second-generation antidepressants in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.

The second-generation antidepressants (SGAs) are used widely in patients with Alzheimer's disease (AD) for the treatment of mood disorder, sleep disturbance and psychiatric symptoms. Several evidences from AD mice confirmed that antidepressants could delaying cognitive decline. However, the conclusions varied in randomized controlled trials (RCTs) based on patients. This meta-analysis summarizes the cognitive impact of SGAs on AD patients with different neuropsychiatric symptoms (NPS). Results show there is no effect on cognition and depression between SGAs treatment and controls, and this remains in subgroups analyses of duration of medication (<12 weeks or ≥12 weeks), drug classes (SSRIs or non-SSRIs), combination with anti-dementia medication, various NPS, and degree of AD. The available evidence provides no support for the efficacy of SGAs for cognition and depression of AD patients. The implications of the findings and their mechanism relevance are also discussed in this paper.

The effect of second-generation antidepressant treatment on the attention and mental processing speed of patients with major depressive disorder: A meta-analysis study with structural equation models.

Major depressive disorder (MDD) has been linked to attention and mental processing speed deficits that can be improved after pharmacological treatment. However, it is unclear whether a class of antidepressants is more effective than others to ameliorate these deficits in MDD. Additionally, the possible effects of clinical and demographic variables on improving MDD attention and processing speed deficits after antidepressant treatment are unknown. We aimed to study the possible neuropsychological effects of second-generation antidepressant classes on the attention and processing speed of MDD patients and the potential influences of clinical and demographic variables as moderators of these effects using a meta-analytic approach. Twenty-five papers were included in our study. A structural equation model meta-analysis was performed. The improvement of attention and processing speed after pharmacological treatment is clinically relevant but incomplete. Selective serotonin reuptake inhibitors (SSRIs) and dual inhibitors are the drugs causing the greatest improvement in the processing speed of MDD patients. Antidepressant class is an important variable linked to processing speed improvement after MDD treatment. However, the degree of improvement in both cognitive functions is strongly influenced by some clinical and demographic variables of depressed patients, such are age and education of the MDD patients, the duration of the antidepressant treatment, and the depression status of the patients.

Which patients with bipolar depression receive antidepressant augmentation? Results from an observational multicenter study.

BACKGROUND: To identify demographic and clinical characteristics of bipolar depressed patients who require antidepressant (AD) augmentation, and to evaluate the short- and long-term effectiveness and safety of this therapeutic strategy. METHODS: One hundred twenty-two bipolar depressed patients were consecutively recruited, 71.7% of them received mood stabilizers (MS)/second-generation antipsychotics (SGA) with AD-augmentation and 28.3% did not. Patients were evaluated at baseline, and after 12 weeks and 15 months of treatment. RESULTS: The AD-augmentation was significantly higher in patients with bipolar II compared with bipolar I diagnosis. Patients with MS/SGA + AD had often a seasonal pattern, depressive polarity onset, depressive index episode with anxious features, a low number of previous psychotic and (hypo)manic episodes and of switch. They had a low irritable premorbid temperament, a low risk of suicide attempts, and a low number of manic symptoms at baseline. After 12 weeks of treatment, 82% of patients receiving ADs improved, 58% responded and 51% remitted, 3.8% had suicidal thoughts or projects, 6.1% had (hypo)manic switch, and 4.1% needed hospitalization. During the following 12 months, 92% of them remitted from index episode, 25.5% did not relapse, and 11% needed hospitalization. Although at the start advantaged, patients with AD-augmentation, compared with those without AD-augmentation, did not significantly differ on any outcome as well on adverse events in the short- and long-term treatment. CONCLUSION: Our findings indicate that ADs, combined with MS and/or SGA, are short and long term effective and safe in a specific subgroup for bipolar depressed patients.

Efficacy of Fluoxetine for Post-Ischemic Stroke Depression in Tanzania.

OBJECTIVE: Post-stroke fluoxetine trials are primarily conducted in high-income countries. We characterize post-ischemic stroke depression in fluoxetine-treated and -untreated study participants in urban Tanzania. METHODS: Adults (>18 years old) within 14 days of CT-confirmed acute ischemic stroke onset were enrolled at Muhimbili National Hospital, Tanzania. The fluoxetine-treated group took 20mg fluoxetine daily for 90 days in a phase II trial and were compared to fluoxetine-untreated historical controls. The primary outcome was depression at 90 days, measured by the Patient Health Questionnaire-9 (PHQ-9). PHQ-9 scores were compared between fluoxetine-treated and -untreated groups. A score >=9 points was considered to reflect depression. A multivariable linear regression model assessed associations with post-stroke PHQ-9 scores. RESULTS: Of the fluoxetine-treated (n=27) and -untreated (n=32) participants, the average age was 56.8 years old (39% women, 100% Black/African). The average presentation NIHSS score was 12.1 points and modified Rankin Scale (mRS) score was 3.5. The average mRS score at 90-day follow-up was 2.3. There was no significant difference between 90-day PHQ-9 scores in the fluoxetine-treated (mean=4.1 points, standard deviation=3.2; 11% depression) and untreated (mean=4.4, standard deviation=4.8; 19% depression) groups, p=.69. In the multivariable analysis, older age (ß=0.08, p=.03) and higher NIHSS score (ß=0.15, p=.04), but neither fluoxetine (ß=0.57, p=.59) nor sex (ß=-0.51, p=.63), were significantly associated with more depressive symptoms. CONCLUSIONS: Our findings parallel results from trials from higher income settings that fluoxetine does not significantly improve post-ischemic stroke depression, although our sample size was small. More work is needed to depict the longitudinal nature and treatment of post-stroke depression in Sub-Saharan Africa.

Changes of functional connectivity of the subgenual anterior cingulate cortex and precuneus after cognitive behavioral therapy combined with fluoxetine in young depressed patients with suicide attempt.

This single-center, randomized, single-blind, parallel-controlled study aimed to analyze the changes in resting-state functional connectivity (RSFC) in young patients with a suicide attempt caused by depression before and after cognitive-behavioral therapy (CBT) combined with fluoxetine or fluoxetine alone by functional magnetic resonance imaging (fMRI). Before treatment, functional connectivity of the right subgenual anterior cingulate cortex (R-sgACC), left subgenual anterior cingulate cortex (L-sgACC) and right precuneus (R-PCu) was lower in depressed patients with a suicide attempt than that of healthy controls. After treatment, compared with the fluoxetine group, functional connectivity between the R-sgACC and left posterior cerebellar lobe in the CBT group was increased, while this group also showed increased RSFC between the L-sgACC and right anterior cingulate cortex/ medial prefrontal cortex. On the contrary, the functional connectivity between the R-PCu and right parietal lobe was reduced (P < 0.001). It was also found there were some changes in different brain regions in pre- and post-treatment within both the CBT and MG group. The functional connectivity of the R-sgACC and the left posterior cerebellum lobe was negatively correlated with the SSI score. The functional connectivity of the R-PCu and right middle frontal cortex was negatively correlated with the HAMD score before treatment. After treatment, functional connectivity between the R-PCu and right superior frontal gyrus was positively correlated with the SSI scores in the CBT group. After 8 weeks of combined CBT, the strength of the functional connectivity in the bilateral sgACC and bilateral PCu was significantly changed.

Efficacy and safety of 24-week pramipexole augmentation in patients with treatment resistant depression. A retrospective cohort study.

Pramipexole is a dopamine agonist with potential antidepressant, neuroprotective, antioxidant and anti-inflammatory activity. In the present study we investigated the 24 weeks effect and safety of traditional AD augmentation with pramipexole for treatment-resistant depression. The study includes 116 patients, 37 (32%) with bipolar disorders and 79 (68%) with major depressive disorder, who failed to respond to at least 2 ADs trials of different classes and that were treated with AD augmented with pramipexole. Mood stabilizers and/or second-generation antipsychotics were added in patients with bipolar or mixed depression. Exclusion criteria were psychotic depression, rapid cycling bipolar course and previous unsuccessful treatment with pramipexole. After 24 weeks of pramipexole augmentation (median max dose 1.05 mg/day, IQR 0.72-1.08) 74.1% of patients responded (≥50% reduction of baseline Hamilton Depression Rating Scale21 total score) and 66.4% remitted (Hamilton Depression Rating Scale21 total score < 7). Global Assessment of Functioning score significantly increase from 53 (50-60) at baseline to 80 (71-81) at 24 weeks (Wilcoxon signed rank test = 8.174, p < 0.001]. Ten patients (8.6%) dropped out (8 due to side effects and 2 for lack of efficacy) and 1 experienced an induced hypomanic switch. No patient committed a suicide attempt, had suicidal ideation, needed hospitalization, reported lethargy, gambling, hypersexuality and compulsive shopping. The limitations of the study are the observational design, the lack of a control group, the inclusion of outpatients only, the unblinded outcomes assessment, and the flexibility of the add-on schedule. The findings of the present study showed that off-label use of pramipexole as augmentation of traditional AD is an effective and safe 24 weeks treatment of resistant unipolar and bipolar depression. These results need confirmation from randomized clinical trials on larger samples.

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.

Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder.

BACKGROUND: Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). METHODS: This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. RESULTS: All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. CONCLUSION: These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.