Acupuncture and Escitalopram for Treating Major Depression Clinical Study (AE-TMDCS): protocol for a factorial randomised controlled trial.

INTRODUCTION: Major depressive disorder (MDD), the second leading cause of disability globally, is considered to be associated with a consequent deterioration in the quality of life and can lead to a major economic burden on medical service and suicide-related costs. Previous research has shown that acupuncture may be beneficial for treating MDD. However, there is a lack of rigorous evidence from previous studies comparing acupuncture with antidepressant medications. This study aims to assess the therapeutic potential of acupuncture in the management of depressive disorders. METHODS AND ANALYSIS: A multicentre, randomised, participant-blind, sham-controlled, 2×2 factorial clinical trial, Acupuncture and Escitalopram for Treating Major Depression Clinical Study, aims to compare the efficacy of acupuncture versus escitalopram in treating depression. This study will be conducted at three hospitals in China, enrolling 260 patients with moderate-to-severe major depression, as defined by DSM-5 criteria and Hamilton Depression Rating Scale (HDRS-17) Scores above 17. Participants will be randomly assigned in equal proportions to one of four groups (acupuncture/escitalopram, sham acupuncture/escitalopram, acupuncture/placebo and sham acupuncture/placebo) and undergo 30 sessions across 10 weeks. The primary outcome is change in HDRS-17 Score and secondary outcomes include BDI, Clinical Global Impression, Generalised Anxiety Disorder-7 and Mini-Mental State Examination Scores, alongside potential biological markers. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the Ethics Committees of the Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine (2023-7th-HIRB-020), Shanghai Mental Health Centre (2022-86) and Shanghai Pudong New Area Hospital of Traditional Chinese Medicine (2023-003). Informed consent will be obtained from all participants. The study's findings are intended for publication in a scholarly journal. TRIAL REGISTRATION: NCT05901571.

Impact of trazodone once-a-day on quality of life and functional recovery in adults with major depressive disorder: A prospective, observational study.

BACKGROUND: Health-related quality of life (HRQL) is an important goal for patients with major depressive disorder (MDD), but whether antidepressants improve HRQL in these patients is unclear. Here, we describe the real-world effects of trazodone once-a-day (TzOAD) and selective serotonin reuptake inhibitor (SSRI) treatments on HRQL and functioning in adults with MDD. METHODS: This 8-week prospective, observational, open-label, multicenter study was conducted in adults with moderate or severe MDD for whom TzOAD or SSRI were prescribed as monotherapy. The primary outcome was life enjoyment and satisfaction assessed via the patient-reported Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) from baseline to week 8. Secondary outcomes included change in Q-LES-Q-SF from baseline to weeks 1 and 2; severity of depressive symptoms using the Montgomery Åsberg Depression Rating Scale (MADRS) and sleep disturbance via the PROMIS SF-SD 8b questionnaire at weeks 1, 2, and 8; and overall functioning via the Sheehan Disability Scale (SDS), hedonic capacity using the Snaith-Hamilton Pleasure Scale (SHAPS), and cognitive dysfunction using the Perceived Deficits Questionnaire (PDQ-5) at baseline and week 8. RESULTS: The study included 208 adults with MDD (mean [SD] age = 50.2 [14.3] years; 68.6% female; 98.4% White). Life enjoyment and satisfaction improved from baseline to week 8 for both treatment groups: Q-LES-Q-SF mean (SD) scores were 27.5 (20.4) for the SSRI group and 39.0 (22.1) for the TzOAD group. Depressive symptoms and sleep disturbances also reduced from baseline to week 8: MADRS (SSRI, -15.7 [8.3]; TzOAD, -21.0 [9.8]); PROMIS SF-SD 8b (SSRI, -9.9 [12.6]; TzOAD, -22.0 [12.6]). Mean change scores in Q-LES-Q-SF, MADRS, and PROMIS SF-SD 8b improved as early as week 1 in both groups. Mean scores also improved from baseline to week 8 on SDS (SSRI, -9.2 [7.4]; TzOAD, -14.3 [7.5]), SHAPS (SSRI, -6.6 [4.3]; TzOAD, -8.3 [4.4]), and PDQ-5 (SSRI, -5.8 [4.5]; TzOAD, -7.7 [5.0]). CONCLUSIONS: In adults with MDD who received TzOAD or SSRIs, overall and individual HQRL domains improved rapidly and in parallel with improvements in depressive symptoms, with a slightly greater improvement observed in the TzOAD group.

Profiling the combination of bupropion and dextromethorphan as a treatment option for major depressive disorder.

INTRODUCTION: Major Depressive Disorder (MDD) is a common mental health disorder marked by sadness, hopelessness, and anhedonia. Various therapies exist, but their effectiveness is limited. Dextromethorphan hydrobromide combined with bupropion hydrochloride (Auvelity®) is a recently approved alternative for treating this condition in adults. AREAS COVERED: This review summarizes the neurobiology of major depression and delves into the pharmacology, efficacy, safety, and tolerability of dextromethorphan plus bupropion in adult patients. It is based on observational studies, clinical trials, and other secondary studies obtained through systematic literature searches. EXPERT OPINION: The combination of bupropion and dextromethorphan as a new pharmacotherapy for mental health is an interesting addition to the treatment options that can be used for MDD. The combination can be used in a range of scenarios, including as a first line therapy, as a second option when a patient has failed to achieve remission with a serotonin targeting agent, and for treatment resistant depression. Further research for other indications, including addiction disorders, may provide exciting results. Although a new combination, clinicians will be very familiar with both agents, increasing their acceptability. This pharmacotherapy also may bring increased impetus for discovering other combinations that may have beneficial synergistic effects.

Rethinking the role of trazodone in the different depressive dimensions.

INTRODUCTION: The efficacy of trazodone for several psychopathologic dimensions of depression has been shown in the literature. Trazodone has been widely used in some clinical contexts (e.g. for insomnia and depression in the elderly). However, the role of trazodone in several aspects of depression is not well known. AREA COVERED: Eight experts from academic and medical centers across Italy met to identify the difficulties and barriers faced in daily clinical practice in the assessment and management of major depressive disorder and how the use of trazodone could address some unmet needs. The objective of the expert meetings and the present document was to increase knowledge of particular areas of treatment with trazodone. EXPERT OPINION: Evidence of the role of trazodone in patients affected by major depressive disorder with anxiety symptoms, insomnia, agitation, cognitive deficits, alcohol use disorders, physical comorbidities, and suicide risk has been identified, showing the effectiveness of trazodone in different presentations of major depressive disorder. The main characteristics of patients with depression for whom trazodone seems to be most effective have been identified, providing clinicians with information on possible uses of this drug in such population of patients.

Targeting self-care adherence for glycaemic control in multimorbid type 2 diabetes mellitus with depression using bupropion: a protocol for cross-over randomised controlled trial.

INTRODUCTION: Diabetes and depression are among the 10 biggest health burdens globally. They often coexist and exhibit a strong bidirectional relationship. Depression leads to decreased adherence to self-care activities. This impacts glycaemic control and worsens type 2 diabetes mellitus (T2D). Both conditions have a synergistic effect and lead to greater complications, hospitalisations, healthcare expenditure and a worse quality of life. There is no consensus on managing people with comorbid T2D and depression. Bupropion is an efficacious antidepressant with many properties suitable for T2D with depression, including a favourable metabolic profile, persistent weight loss and improvement in sexual dysfunction. We will assess the efficacy and safety of add-on bupropion compared with standard care in people with T2D and mild depression. This study can give valuable insights into managing the multimorbidity of T2D and depression. This can help mitigate the health, social and economic burden of both these diseases. RESEARCH DESIGN AND METHODS: This cross-over randomised controlled trial will recruit people with T2D (for 5 years or more) with mild depression. They will be randomised to add-on bupropion and standard care. After 3 months of treatment, there will be a washout period of 1 month (without add-on bupropion while standard treatment will continue). Following this, the two arms will be swapped. Participants will be assessed for glycosylated haemoglobin, adherence to diabetes self-care activities, lipid profile, urine albumin-to-creatinine ratio, autonomic function, sexual function, quality of life and adverse events. ETHICS AND DISSEMINATION: The Institutional Ethics Committee at All India Institute of Medical Sciences, Jodhpur has approved this study (AIIMS/IEC/2022/4172, 19 September 2022). We plan to disseminate the research findings via closed group discussions at the site of study, scientific conferences, peer-reviewed published manuscripts and social media. TRIAL REGISTRATION NUMBER: CTRI/2022/10/046411.

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.

The effect of paroxetine on heart rate variability in patients with major depressive disorder: A systematic review and meta-analysis.

INTRODUCTION: The impacts of antidepressant pharmacotherapies on cardiovascular risk are unclear. We completed a systematic review with meta-analysis to assess the effect of paroxetine on heart rate variability (HRV) in patients with major depressive disorder (MDD). METHODS: The searches were accomplished via EMBASE, MEDLINE/PubMed (using the National Library of Medicine), Cochrane Library, CINAHL, Scopus, and Web of Science databases. We included non-blind, single, or double-blind randomized control trials in patients older than 18 diagnosed with MDD. Paroxetine needs to be enforced as a chronic therapeutic medication. We included individual studies that investigated resting HRV. RESULTS: We documented 402 studies, only following screening and eligibility phases; only six were included (five studies in the meta-analysis). No significant change was noticed for the SDNN index: subtotal = 8.23 [CI: -2.17, 18.63], p = 0.12, I2 = 54 % (very low quality of evidence). A significant change was distinguished for the LF index: subtotal = 0.74 [CI: 0.33, 1.15], p = 0.0004, I2 = 0 % (low quality of evidence). A significant alteration was perceived for the HF index: subtotal = 0.33 [CI: 0.06, 0.6], p = 0.02, I2 = 0 % (low quality of evidence). CONCLUSION: Meta-analysis demonstrated that paroxetine could advance HRV in MDD patients. Nevertheless, our supposition is founded only on statistical analysis and the very low quality of evidence breakdown reinforces the necessity for further studies to confirm or reject this theory.

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.