Newer Treatments for Mood and Anxiety Disorders.

For more than 20 years, the mainstay of pharmacologic treatment for depression and anxiety disorders has been serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors. There are newer medications, many with novel mechanisms of action, that have come to market; however, first-line treatments remain the same. There are now more robust data on the use of various augmentation agents in the treatment of major depressive disorder providing better recommendations for use by the primary care provider. Data to support the use of psychedelic-assisted psychotherapy in the treatment of mood and anxiety disorders are not robust enough to recommend generalized use at this time.

Sequenced Treatment Effectiveness for Posttraumatic Stress (STEPS) Trial: A protocol for a pragmatic comparative effectiveness trial with baseline results.

BACKGROUND: There have only been two efficacy trials reporting a head-to-head comparison of medications and psychotherapy for PTSD, and neither was conducted in primary care. Therefore, this protocol paper describes a pragmatic trial that compares outcomes of primary care patients randomized to initially receive a brief trauma-focused psychotherapy or a choice of three antidepressants. In addition, because there are few trials examining the effectiveness of subsequent treatments for patients not responding to the initial treatment, this pragmatic trial also compares the outcomes of those switching or augmenting treatments. METHOD: Patients screening positive for PTSD (n = 700) were recruited from the primary care clinics of 7 Federally Qualified Health Centers (FQHC) and 8 Department of Veterans Affairs (VA) Medical Centers and randomized in the ratio 1:1:2 to one of three treatment sequences: 1) selective serotonin reuptake inhibitor (SSRI) followed by augmentation with Written Exposure Therapy (WET), 2) SSRI followed by a switch to serotonin-norepinephrine reuptake inhibitor (SNRI), or 3) WET followed by a switch to SSRI. Participants complete surveys at baseline, 4 months, and 8 months. The primary outcome is PTSD symptom severity as measured by the PTSD Checklist (PCL-5). RESULTS: Average PCL-5 scores (M = 52.8, SD = 11.1) indicated considerable severity. The most common bothersome traumatic event for VA enrollees was combat (47.8%), and for FQHC enrollees was other (28.2%), followed by sexual assault (23.4%), and child abuse (19.8%). Only 22.4% were taking an antidepressant at baseline. CONCLUSION: Results will help healthcare systems and clinicians make decisions about which treatments to offer to patients.

Efficacy of Duloxetine With Arthrocentesis in the Management of TMJ Internal Derangement.

Temporomandibular joint (TMJ) arthrocentesis is one of the most commonly used non-invasive surgical interventions in the treatment of refractory pain and dysfunction associated with internal derangement. Several adjunctive therapies have been used in combination with arthrocentesis in an attempt to increase its efficacy and long-term maintenance. Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor which is used in different chronic pain conditions. This study aimed to assess the efficacy of duloxetine in combination with arthrocentesis compared with arthrocentesis alone. Twenty-eight patients with chronic TMJ pain were included and randomly allocated into 2 groups (control and study groups). The control group included patients who underwent TMJ arthrocentesis only, and the study group included patients who underwent arthrocentesis followed by giving duloxetine (30 mg) orally twice daily for 3 months. Pain, maximum mouth opening, and level of anxiety and depression were assessed preoperatively and followed at regular intervals of 1 week, 1 month, 3 months, and 6 months postoperatively. Pain was significantly reduced in both groups at all postoperative intervals and was significantly lower in the study group than the control group at 6 months. Maximum mouth opening increased significantly in both groups, but the difference between them was not significant. Level of anxiety and depression was significantly decreased in both groups, with no statistically significant difference between them. The results of this study indicate that duloxetine in combination with arthrocentesis may provide effective and long-term pain control; however, its use is associated with a higher risk of adverse events.

Suspected duloxetine-induced restless legs syndrome phenotypic variant: a case report.

BACKGROUND: Restless arms syndrome (RAS) is the most common variant of restless legs syndrome (RLS), which is easy to be ignored in clinical practice due to the lack of specific diagnostic criteria. When effective therapeutic agents induced RAS and symptoms persisted after briefly observation, clinicians will face the challenge of weighing efficacy against side effects. CASE PRESENTATION: A 67-year-old woman was admitted to a geriatric psychiatric ward with depression. Upon admission, the escitalopram dose was reduced from 15 mg to 10 mg per day, and the duloxetine dose was increased from 60 mg to 80 mg per day. The next night before bedtime, she developed itching and creeping sensations deep inside bilateral shoulders and arms, with the urge to move, worsening at rest, and alleviation after hammering. The symptoms persisted when escitalopram was discontinued. A history of RLS was confirmed. Treatment with 40 mg of duloxetine and 0.125 mg of pramipexole significantly improved depression, and the paresthesia disappeared, with no recurrence occurring 6 months after discharge. DISCUSSION AND CONCLUSIONS: This case suggests that psychiatrists should pay attention to RLS variants when increasing doses of duloxetine. Long-term improvement can be achieved through dosage reduction combined with dopaminergic drugs instead of immediate discontinuation.

The effect of earthquake on fibromyalgia: a comparison of patients on medication and without medication.

INTRODUCTION / OBJECTIVES: Stressful events like earthquakes might worsen the symptoms of fibromyalgia, although the influence of medications on these consequences is yet uncertain. The objective of this study was to examine the influence of an earthquake on the symptoms of fibromyalgia and evaluate the impacts of medications used to treat fibromyalgia on the clinical picture. METHOD: Ninety-five fibromyalgia patients were enrolled in a comparative study and divided into two groups: medication and non-medication. Three subcategories of medication groups were established: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and gabapentinoid drugs (GDs). Before and after the earthquake, clinical evaluations were conducted using the Fibromyalgia Impact Questionnaire (FIQ), Hospital Anxiety and Depression Scale (HADS), and Jenkins Sleep Rating Scale (JSS). Statistical analyses were conducted to compare the scores before and after the earthquake and evaluate the differences between the groups. RESULTS: Statistically significant increases were observed in FIQ, HADS-anxiety, HADS-depression, and JSS scores in the medication and non-medication groups before and after the earthquake comparisons (p < 0.05). Non-medication group reported significantly higher post-earthquake changes in FIQ, HADS-anxiety, HADS-depression, and JSS compared to the medication group (p < 0.05). While HADS-anxiety, HADS-depression, and JSS changes after the earthquake differed according to the drug subgroups (p < 0.05), no statistically significant difference was observed in FIQ values (p > 0.05). The highest scores were detected in the GD subgroup. CONCLUSIONS: This study highlights the substantial impact of earthquakes on fibromyalgia patients. Medication use may assist in reducing the detrimental effects of stresses like earthquakes on fibromyalgia symptomatology. Future research with larger sample sizes and more extended follow-up periods is needed to explain these findings and optimize treatment regimens for fibromyalgia patients experiencing significant stressors.

Psychopharmacological treatment in patients planned for hip or knee replacement.

Psychopharmacological treatment may be an independent risk factor for increased length of stay and readmission after hip and knee replacement. Thus, temporary perioperative discontinuation may be beneficial. However, little is known regarding the treatments, and not all are feasible to discontinue. Therefore, the aim of this study was to describe the treatments in terms of type, dose, duration, indication and initiating physician to assess the feasibility of temporary perioperative discontinuation. We included 482 patients planned for hip or knee replacement in psychopharmacological treatment for psychiatric disorders from 2021 to 2023 at five orthopaedic departments in Denmark. Most patients were treated with antidepressants (89%); most frequently, either selective serotonin reuptake inhibitors (SSRIs; 48%) or serotonin-norepinephrine reuptake inhibitors (SNRIs; 21%). The majority received monotherapy (70%); most frequently, an SSRI (36%) or an SNRI (12%). Most antidepressants were initiated by general practitioners (71%), and the treatments had lasted for more than a year (87%). The doses of SSRIs/SNRIs were moderate, and the most frequent indication for antidepressants was depression (77%). These results imply that temporary perioperative SSRI/SNRI discontinuation may be feasible in hip and knee replacement patients and support a future randomized controlled trial investigating the potential benefits of temporary discontinuation.

Identifying data-driven subtypes of major depressive disorder with electronic health records.

BACKGROUND: Efforts to reduce the heterogeneity of major depressive disorder (MDD) by identifying subtypes have not yet facilitated treatment personalization or investigation of biology, so novel approaches merit consideration. METHODS: We utilized electronic health records drawn from 2 academic medical centers and affiliated health systems in Massachusetts to identify data-driven subtypes of MDD, characterizing sociodemographic features, comorbid diagnoses, and treatment patterns. We applied Latent Dirichlet Allocation (LDA) to summarize diagnostic codes followed by agglomerative clustering to define patient subgroups. RESULTS: Among 136,371 patients (95,034 women [70 %]; 41,337 men [30 %]; mean [SD] age, 47.0 [14.0] years), the 15 putative MDD subtypes were characterized by comorbidities and distinct patterns in medication use. There was substantial variation in rates of selective serotonin reuptake inhibitor (SSRI) use (from a low of 62 % to a high of 78 %) and selective norepinephrine reuptake inhibitor (SNRI) use (from 4 % to 21 %). LIMITATIONS: Electronic health records lack reliable symptom-level data, so we cannot examine the extent to which subtypes might differ in clinical presentation or symptom dimensions. CONCLUSION: These data-driven subtypes, drawing on representative clinical cohorts, merit further investigation for their utility in identifying more homogeneous patient populations for basic as well as clinical investigation.

Efficacy and safety of aticaprant, a kappa receptor antagonist, adjunctive to oral SSRI/SNRI antidepressant in major depressive disorder: results of a phase 2 randomized, double-blind, placebo-controlled study.

This was a double-blind, randomized, phase 2 study of adults (18-64 years) with DSM-5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥25) despite an adequate course with ongoing antidepressant for ≥6 weeks to ≤12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n = 85, placebo n = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: -2.1 [-1.09], 1-sided p = 0.044; effect size (ES) 0.23; fITT -3.1 [2.21], 1-sided p = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith-Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.

Central Neuromodulators in Irritable Bowel Syndrome: Why, How, and When.

Irritable bowel syndrome (IBS) is responsive to treatments using central neuromodulators. Central neuromodulators work by enhancing the synaptic transmission of 5-hydroxytryptamine, noradrenalin, and dopamine, achieving a slower regulation or desensitization of their postsynaptic receptors. Central neuromodulators act on receptors along the brain-gut axis, so they are useful in treating psychiatric comorbidities, modifying gut motility, improving central downregulation of visceral signals, and enhancing neurogenesis in patients with IBS. Choosing a central neuromodulator for treating IBS should be according to the pharmacological properties and predominant symptoms. The first-line treatment for pain management in IBS is using tricyclic antidepressants. An alternative for pain management is the serotonin and noradrenaline reuptake inhibitors. Selective serotonin reuptake inhibitors are useful when symptoms of anxiety and hypervigilance are dominant but are not helpful for treating abdominal pain. The predominant bowel habit is helpful when choosing a neuromodulator to treat IBS; selective serotonin reuptake inhibitors help constipation, not pain, but may cause diarrhea; tricyclic antidepressants help diarrhea but may cause constipation. A clinical response may occur in 6-8 weeks, but long-term treatment (usually 6-12 months) is required after the initial response to prevent relapse. Augmentation therapy may be beneficial when the therapeutic effect of the first agent is incomplete or associated with side effects. It is recommended to reduce the dose of the first agent and add a second complementary treatment. This may include an atypical antipsychotic or brain-gut behavioral treatment. When tapering central neuromodulators, the dose should be reduced slowly over 4 weeks but may take longer when discontinuation effects occur.

Hyponatremia-associated hospital visits are not reduced by early electrolyte testing in older adults starting antidepressants.

BACKGROUND: Clinical practice guidelines recommend early serum electrolyte monitoring when starting antidepressants in older adults due to the increased risk of hyponatremia. It is unclear whether this monitoring improves outcomes. METHODS: Population-based, retrospective cohort study of Ontario adults aged ≥66 years who initiated therapy with a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI) between April 1, 2013, and January 31, 2020. The index date was the date of the first such prescription, and the exposure of interest was serum electrolyte measurement during the subsequent 7 days. The primary outcome was any emergency department or hospital admission with hyponatremia within 8-60 days of antidepressant initiation. Poisson regression models compared individuals who had versus did not have their serum electrolytes tested in the week following SSRI/SNRI initiation, weighting by propensity score-based overlap weights. RESULTS: Among the 420,085 patients aged ≥66 years initiating treatment with an SSRI/SNRI, 26,808 (6.4%) had serum electrolytes measured in the subsequent 7 days and 6109 (1.5%) subsequently presented to hospital with hyponatremia. The time from drug initiation to hospitalization varied (median 29, interquartile range [IQR] 17-44 days), and the median sodium concentration measured in the community (136, IQR 133-138 mmol/L) was marginally higher than those at the time of hospitalization (132, IQR 130-134 mmol/L). Patients who underwent electrolyte testing in the week following SSRI/SNRI treatment were more likely to attend an emergency department (ED) or hospital with hyponatremia within 8-60 days relative to those who did not (relative risk = 2.31, 95% confidence interval: 2.16-2.46). CONCLUSIONS: Testing serum electrolytes in the week after starting an SSRI/SNRI is not associated with a reduced risk of a hospital visit with hyponatremia. These findings do not support current guidelines recommending routine electrolyte monitoring.

Trajectory and magnitude of response in adults with anxiety disorders: a Bayesian hierarchical modeling meta-analysis of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and benzodiazepines.

BACKGROUND: How the trajectory of response to medication (and placebo response) varies among selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and across anxiety disorders is unknown. METHODS: We performed a meta-analysis using weekly symptom severity data from randomized, parallel-group, placebo-controlled trials of SSRIs, SNRIs, and benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in anxiety using Bayesian hierarchical models. RESULTS: Across 122 trials (N=15,760), SSRIs, SNRIs, and benzodiazepines produced significant improvement in anxiety compared to placebo. Benzodiazepines produced faster improvement by the first week of treatment (p < 0.001). By week 8, the response for benzodiazepines and SSRIs (p = 0.103) and SNRIs (p = 0.911) did not differ nor did SSRIs and SNRIs differ (p = 0.057), although for patients with generalized anxiety disorder (GAD), the benzodiazepines produced greater improvement than SNRIs at week 8 (difference - 12.42, CrI: -25.05 to -0.78, p = 0.037). Medication response was similar across anxiety disorders except for benzodiazepines, which produced greater improvement over the first 4 weeks compared to SSRIs and SNRIs in panic disorder. For SSRIs and SNRIs, women improved more than men, and for benzodiazepines, older patients improved more compared to younger patients. Finally, placebo response plateaued by week 4 of treatment, and, at week 8, social anxiety disorder trials had lower placebo response compared to other anxiety disorders. CONCLUSIONS: Benzodiazepines show early improvement compared to SSRIs and SNRIs. However, by week 8, all treatments yield similar results. Patient characteristics influence the improvement trajectory and magnitude, suggesting potential for personalized medication selection.

Serotonin norepinephrine reuptake inhibitors in managing neuropathic pain following spinal and non-spinal surgery: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: While serotonin norepinephrine reuptake inhibitors (SNRIs) offer promise in managing Post-surgical neuropathic pain (PSNP), uncertainties remain. This study aims to evaluate the effectiveness and adverse events of SNRIs in managing PSNP. METHODS: Systematic searches of PubMed, Embase, and Cochrane databases up to January 1st 2023 identified randomized controlled trials (RCTs) comparing SNRIs to placebo for PSNP. The primary outcome measures were pain at rest and adverse events post-surgery. Subgroup analyses were conducted based on surgical type and specific SNRIs. RESULTS: A total of 19 RCTs, encompassing 1440 participants (719 in the SNRI group vs 721 in the placebo group), met the inclusion criteria and were included. The pooled results demonstrated that pain scores were significantly lower in patients treated with SNRIs at 2 hours (MD:-0.26; 95%CI: -0.47 to -0.04; p=0.02), 6 hours (MD:-0.68; 95%CI: -1.01 to -0.34; p<0.0001), 24 hours (MD:-0.54; 95%CI: -0.99 to -0.09; p=0.02), and 48 hours (MD:-0.66; 95%CI: -1.23 to -0.10; p=0.02) post-surgery. In terms of adverse events, dizziness (OR:2.53; 95%CI: 1.34-4.78; p=0.004) and dry mouth (OR:2.21; 95%CI: 1.25-3.92; p=0.007) were significantly higher in the SNRIs group. Subgroup analysis showed that SNRI was found to significantly lower the 24-hour pain score after spinal surgery (MD:-0.45; 95%CI: -0.84 to -0.05; p=0.03). Duloxetine (MD:-0.63; 95%CI: -1.15 to -0.11; p=0.02) had a significant effect in lowering the 24-hour pain score at rest compared to placebo, whereas venlafaxine did not. CONCLUSIONS: SNRIs yielded considerable pain score reductions across multiple post-surgical intervals, although accompanied by an increased incidence of dizziness and dry mouth.

Association of antidepressant and benzodiazepine use, and anticholinergic burden with cognitive performance in schizophrenia.

Schizophrenia is characterized by cognitive impairment affecting everyday functioning. Earlier research has hypothesized that antidepressants may associate with better cognitive functioning, but results are mixed. This study explored the association between antidepressant use and cognitive performance in terms of reaction time and visual learning in a clinical sample. In addition, we examined benzodiazepine use and anticholinergic burden. Study participants were drawn from the SUPER-Finland cohort, collected among patients with psychotic illnesses in 2016-2018 throughout Finland (n = 10,410). The analysis included adults with a schizophrenia diagnosis (F20) and results from a cognitive assessment (n = 3365). Information about medications and psychosocial factors were gathered through questionnaire and interview. Cognitive performance was assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB) with two subtests measuring reaction time and visual learning. Almost 36 % of participants used at least one antidepressant. The use of antidepressants in general was not associated with performance in the reaction time and visual learning tasks. However, the use of SNRI antidepressants was associated with a faster reaction time. Benzodiazepine use and a higher anticholinergic burden were associated with poorer performance in both tests. The results strengthen earlier findings that there is no association between antidepressant use in general and cognitive performance in schizophrenia. However, the association of SNRI medications with a faster reaction time warrants further research. Moreover, the results suggest that more attention should be paid to the anticholinergic burden of the medications used by patients with schizophrenia, as well as avoiding continuous benzodiazepine use.

Monitoramento do horizonte tecnológico: Medicamentos para o tratamento do transtorno depressivo maior / Monitoring the technological horizon: Drugs for the treatment of major depressive disorder

A DOENÇA: O transtorno depressivo maior (TDM) é considerado um grave problema de saúde pública que afeta mais de 264 milhões de pessoas em todo o mundo (1). No Brasil, a prevalência nacional da depressão estimada pelo Global Burden of Disease 2017 foi de 3,3% e esta condição está entre as quatro principais causas de invalidez, afetando a produtividade e qualidade de vida dos pacientes. Nas populações vulneráveis como os idosos, esse número é significativamente maior, uma revisão sistemática publicada em 2019 estimou uma prevalência de 21,9% em idosos brasileiros residentes na comunidade. Segundo projeções da Organização Mundial da Saúde (OMS) para 2030, a depressão ocuparia o primeiro lugar entre as principais doenças incapacitantes. TRATAMENTO RECOMENDADO: Atualmente não existem Protocolos Clínicos e Diretrizes Terapêuticas (PCDT) do Ministério da Saúde, bem como avaliações da Conitec sobre esse tema. O tratamento da TDM depende da gravidade da doença, nos indivíduos com depressão grave, em que há risco de suicídio, o encaminhamento para o especialista deve ser imediato e a hospitalização pode ser um recurso necessário. Nos casos moderados, em geral, se sugere a combinação de psicoterapia e medicamentos antidepressivos, sendo que diversas classes são consideradas opções terapêuticas, como Inibidores seletivos da recaptação da serotonina; Inibidores seletivos da recaptação da noradrenalina; Antidepressivos atípicos; Moduladores da serotonina; Antidepressivos tricíclicos; Inibidores da monoaminoxidase. ESTRATÉGIA DE BUSCA: Uma busca no repositório de protocolos de estudos clínicos ClinicalTrials.gov foi realizada com o objetivo de localizar os medicamentos em fase de pesquisa clínica e/ou recentemente aprovados para TDM. Foram excluídos medicamentos com registro na Anvisa superior a dois anos para a indicação de depressão maior, assim como procedimentos, produtos da medicina tradicional chinesa, vitaminas e testes diagnósticos. MEDICAMENTOS APROVADOS RECENTEMENTE: ESCETAMINA SPRAY NASAL: A escetamina, o enantiômero "S" da cetamina racêmica, é um antagonista não seletivo, não competitivo do receptor N-metil-D-aspartato (NMDA), que atua como um modulador do receptor de glutamato, o que parece aumentar a sinalização entre as células, restaurando a função normal nas regiões cerebrais. Embora a ligação da escetamina ao receptor NMDA aumente o glutamato do sistema nervoso central (SNC), o mecanismo de ação exato como antidepressivo permanece incerto. Esse medicamento possui registro nas agências norte-americana e europeia (FDA e EMA) e, em dezembro de 2020, foi aprovado pela Anvisa para tratamento do TDM em pacientes com ideação suicida e de depressão resistente ao tratamento. Depressão resistente ao tratamento: MEDICAMENTOS EM FASE DE PESQUISA CLÍNICA: RAPASTINEL: O rapastinel (GLYX-13) é um anticorpo monoclonal com apresentação para administração endovenosa, que atua como agonista parcial funcional do receptor de N-metil-D-aspartato (NMDA) com ação no sistema glutamatérgico. INFORMAÇÕES ADICIONAIS: Atualmente existem diferentes tecnologias sendo estudadas para o tratamento de TDM, sendo que neste informe, foram descritas as tecnologias que estão em um horizonte mais próximo para aprovação por agências regulatórias ou foram aprovadas pela Anvisa recentemente. A escetamina spray nasal e brexpiprazol foram aprovados pela Anvisa em 2020, com o objetivo de avaliar a incorporação dessas tecnologias no mundo, uma busca foi realizada em novembro de 2021 nos websites das agências de ATS do Reino Unido, Canadá e Austrália. CONSIDERAÇÕES FINAIS O TDM: é um grave problema de saúde pública por afetar milhões de pessoas em todo o mundo. Apesar de haver muitos estudos em andamento para o tratamento dessa condição clínica, em geral os resultados dos estudos demonstraram que não há diferença significativa na eficácia dos medicamentos quando comparados ao placebo. O rapastinel, que recebeu designação Breakthough Therapy pela FDA em 2016, caracterizando-o como medicamento inovador para uma necessidade médica não atendida e que teria prioridade para avaliação na FDA, apresentou resultados promissores para estudo de fase 2, entretanto eles não foram confirmados nos ECR fase 3, duplo-cego, controlados por placebo, tanto em monoterapia como tratamento adjuvante para TDM. O medicamento REL-1017 (ou d-metadona), também é um inibidor do receptor NMDA e recebeu designação FastTrack pela FDA em 2017 para o tratamento adjuvante de TDM. Apesar dos dados do estudo de fase 2 mostrarem resultados promissores, o estudo de fase 3 ainda está em andamento. Também, esperam-se os dados das diversas pesquisas fase 3, realizadas em diferentes cenários (adjuvante ou monoterapia, por exemplo), e que avaliaram o medicamento SAGE-217, um modulador do receptor GABA que mostrou resultados positivos no estudo fase 2. O brexpiprazol foi aprovado pela Anvisa em 2020, indicado para o tratamento de depressão maior em adultos em associação a um antidepressivo, em caso de inefetividade da monoterapia com antidepressivo anterior. Os ensaios clínicos randomizados fase 3 avaliaram que o uso do medicamento reduziu o escore basal de MADRS na semana 6. O brexipiprazol para tratamento de depressão não foi avaliado por nenhuma agência de ATS até o momento. A escetamina spray nasal teve registro sanitário aprovado pela Anvisa em novembro de 2020 para pacientes com ideação suicida e de depressão resistente ao tratamento - a partir da avaliação da redução do escore basal de MADRS em 24h e após 28 dias. Mas esse medicamento não foi recomendado para incorporação pelas agências de ATS do Reino Unido e Canadá. Os medicamentos em desenvolvimento para depressão incluem populações específicas e frequentemente são usados em associação a outros antidepressivos. O tratamento da depressão grave e não responsiva a tratamentos prévios ainda é uma necessidade médica não atendida, assim como tratamentos específicos para populações vulneráveis como idosos. Também é importante destacar que todos os resultados descritos neste documento são dados precoces e devem ser avaliados com cautela. Dessa maneira, considerando os estudos de fase 3 citados neste documento, conclui-se que ainda são poucas as opções promissoras em estudo para um horizonte de curto a médio prazo.

Generaliseerunud ärevushäire ja paanikahäire (agorafoobiaga või ilma) käsitlus perearstiabis / Management of generalized anxiety disorder and panic disorder (with or without agoraphobia) in family practice

The update of the treatment manual "Management of generalized anxiety disorder and panic disorder (with or without agoraphobia) in family medicine" was initiated because more than five years had passed since the publication of the original manual in 2014. The procedure for updating treatment manuals is written in the "Estonian manual for the preparation of treatment manuals" (2020). At the first meeting, the working group of the treatment guideline reviewed the questions raised during the preparation of the original guideline and found that some clinical questions concerning the pharmacological treatment of generalized anxiety disorder may have added evidence over time, which may change the originally given recommendation. They also wanted to review the recommendations regarding healthcare management given in the original guide. Based on the audit of the Estonian Health Insurance Fund (1) published in 2018, it was revealed that the diagnosis, treatment and monitoring of anxiety disorders varies in Estonia. One of the observations was the incomplete completion of treatment documentation, which made it difficult to assess and understand the justification of various actions and the doctor's thinking in the treatment of a patient with an anxiety disorder. The audit showed that most of the patients were prescribed treatment at the initial visit: a third were recommended psychotherapy, a third were prescribed antidepressant treatment, and a third were treated with a benzodiazepine. However, recommendations on self-help techniques are mostly not shared. The auditors recommended developing evidence-based material on self-help techniques that can be given to the patient (with him). The audit also noted that sufficient opportunities must be ensured to refer patients to psychotherapy. Mental health nurses are needed, who would help monitor and support patients. In order to ensure the best treatment for the patient, it is important that the family doctor can easily consult with a psychiatrist during the treatment process. The purpose of updating the treatment manual was to ensure contemporary evidence-based treatment of patients with anxiety disorders in family medicine care in Estonia. When updating the guide, the focus was on the (re)opened questions of the working group and the bottlenecks in the treatment of patients with anxiety disorders revealed by the audit.

Ravijuhendi "Generaliseerunud ärevushäire ja paanikahäire (agorafoobiaga või ilma) käsitlus perearstiabis" ajakohastamine algatati, kuna algse juhendi ilmu- misest 2014. aastal oli möödunud üle viie aasta. Ravijuhendite uuendamise kord on kirjas "Eesti ravijuhendite koostamise käsiraamatus" (2020). Ravijuhendi töörühm vaatas esimesel koosolekul läbi algse juhendi koostamisel esitatud küsi- mused ja leidis, et mõningate generaliseerunud ärevushäire farmakoloogilist ravi puudutavate kliiniliste küsimuste kohta võib aja jooksul olla lisandunud tõen- dusmaterjali, mis võib algselt antud soovitust muuta. Samuti sooviti üle vaadata algses juhendis antud tervishoiukorraldust puudutavad soovitused. 2018. aastal ilmunud Eesti Haigekassa auditi (1) põhjal selgus, et ärevushäirete diagnoosimine, ravi ja jälgimine Eestis varieerub. Üks tähelepanekuid oli puudu- lik ravidokumentatsiooni täitmine, mistõttu oli raske hinnata ja aru saada eri tege- vuste põhjendatusest ja arsti mõttekäigust ärevushäirega patsiendi käsitluses. Au- dit näitas, et esmasel visiidil määrati enamikule patsientidest ravi: kolmandikule soovitati psühhoteraapiat, kolmandikule määrati antidepressantravi ja kolmandik sai raviks bensodiasepiini. Soovitusi eneseabivõtete kohta enamasti aga ei jaga- tud. Auditeerijad soovitasid välja töötada tõenduspõhise materjali eneseabivõte- te kohta, mille saab patsiendile (kaasa) anda. Veel märgiti auditis, et patsientide psühhoteraapiale suunamiseks tuleb tagada piisavad võimalused. Juurde on vaja vaimse tervise õdesid, kes aitaksid patsiente jälgida ja toetaksid neid. Patsiendile parima ravi tagamiseks on oluline, et raviprotsessis saaks perearst vajadusel hõlp- sasti psühhiaatriga konsulteerida. Ravijuhendi ajakohastamise eesmärk oli tagada ärevushäirega patsientide nüü- disaegne tõenduspõhine käsitlus perearstiabis Eestis. Juhendi ajakohastamisel keskenduti töörühma (taas)avatud küsimustele ja auditist selgunud ärevushäirega patsiendi käsitluse kitsaskohtadele.

Sibutramina para o tratamento dos pacientes com obesidade / Sibutramine for the treatment of patients with obesity

DEMANDANTE:Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde (SCTIE/MS) e Associação Brasileira para o Estudo da Obesidade e Síndrome Metabólica (Abeso) Pergunta - A sibutramina é eficaz e segura no tratamento de pacientes adultos com obesidade, refratária ao tratamento não farmacológico e que não apresentem doença cardiovascular? TECNOLOGIA : Cloridrato de sibutramina monoidratado. EVIDÊNCIAS CIENTÍFICAS: No relatório elaborado pela SCTIE/MS foram incluídos 14 estudos, sendo três revisões sistemáticas, dez ensaios clínicos randomizados e uma coorte. As três revisões sistemáticas foram avaliadas como alto risco de viés. Os ensaios clínicos incluídos foram avaliados pela ferramenta do risco de viés da Cochrane, sendo a maioria classificados como alto risco ou risco incerto, enquanto a coorte teve baixo risco, de acordo com as respectivas ferramentas de avaliação. Na análise crítica do Dossiê Técnico elaborado pela Abeso foram incluídas 14 publicações, sendo dez ensaios clínicos randomizados e três estudos de coorte. De toda a evidência apresentada por ambos os demandantes, a sibutramina se mostrou eficaz na redução do peso com significância clínica, do índice de massa corporal e da circunferência abdominal, principalmente frente ao placebo e a curto e médio prazo. A longo prazo, há evidências que apontam para um reganho de peso e uma baixa persistência. Na maioria dos estudos, a sibutramina foi utilizada concomitantemente à recomendação de mudança de hábitos alimentares e comportamentais. Os principais eventos adversos relacionados com o uso da sibutramina foram boca seca, constipação e insônia. Aumento da pressão arterial e de batimentos cardíacos também foram relatados, mas em um quantitativo menor. Tanto os ensaios clínicos randomizados quanto os estudos de coorte incluídos na análise crítica apresentaram alto risco ou risco incerto de viés. AVALIAÇÃO ECONÔMICA: No relatório elaborado pela SCTIE/MS, a ACE foi construída utilizando dados do SIGTAP referentes aos custos estimados com tratamento convencional oferecido aos pacientes adultos obesos. O custo anual da sibutramina por paciente foi calculado considerando a média do custo dos tratamentos nas diferentes posologias, totalizando um custo médio anual de R$ 532,10. Não foram encontrados no SIGTAP procedimentos relacionados ao tratamento convencional, dieta e exercício físico, assim, estes custos foram considerados como nulos. O desfecho de efetividade considerado na avaliação foi a proporção de pacientes que alcançou a perda de pelo menos 10% do peso corpóreo (perda de peso clinicamente significante), obtida por meio da meta-análise de proporção dos estudos incluídos na revisão de Rucker et al., 2007 e no estudo de Halpern et al., 2002. Assim, a razão de custo-efetividade incremental foi de R$ R$ 3.130,00 para que um paciente alcance uma redução de pelo menos 10% no peso corpóreo, em relação ao tratamento convencional. No Dossiê Técnico elaborado pela Abeso, a razão de custo-efetividade incremental se mostrou favorável ao uso da sibutramina frente ao tratamento não farmacológico disponível no SUS (uma economia de R$ 602,35). Após a análise de sensibilidade, o tratamento da obesidade com sibutramina durante 12 meses permaneceu sendo uma estratégia dominante em 44,97% das simulações (menor custo e maior efetividade). Porém, no Dossiê Técnico, as incertezas e as limitações nos parâmetros e premissas adotados nestas avaliações, somados a impossibilidade de conferência e a reprodução dos cálculos utilizados, podem estar sub ou superestimando a estimativa obtida. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: No relatório elaborado pela SCTIE/MS, para estimar o custo do tratamento foram consideradas as apresentações farmacêuticas registradas na ANVISA, cápsulas de 10 e 15 mg. Os custos assumidos nessa análise foram restritos aos de aquisição do medicamento. Como não foram encontrados dados na literatura sobre a porcentagem de indivíduos que utilizam a posologia de 10 e 15 mg por dia, optou-se por fazer seis cenários, um no qual todos os indivíduos utilizavam a posologia de 10 mg por dia, outro em que todos os participantes utilizavam 15 mg/dia e mais um em que metade dos participantes utilizava a posologia de 10 mg. Finalmente, outros três, nos quais cada um excluía algum tipo de população com contraindicação (pacientes com doenças cardiovasculares, com diabetes e hipertensão arterial e com hipertensão descontrolada). A análise foi realizada para um horizonte temporal de cinco anos, assumindo-se um market share inicial de 30% para a sibutramina, com incrementos anuais no mesmo valor, chegando a 50% no quinto ano. Com isso, nestes seis cenários, a estimativa de impacto orçamentário decorrente da incorporação da sibutramina estaria entre R$ 3,3 a R$ 4,3 bilhões no primeiro ano de incorporação e de R$ 22,7 a R$ 29,6 bilhões em cinco anos de incorporação. Após a utilização do menor preço de compra pública praticado em um período de seis meses no ano corrente, de dados mais recentes da população elegível e mantendo as demais premissas dos cenários anteriores, a estimativa de impacto orçamentário decorrente da incorporação da sibutramina estaria entre R$ 1,4 a R$ 1,7 bilhões no primeiro ano de incorporação e de R$ 9,3 a R$ 11,8 bilhões em cinco anos. Outros três cenários propostos, mantendo o preço e a população total atualizada, excluindo os pacientes que realizaram cirurgias de redução de estômago, pacientes sem perda de peso significativa, taxa de persistência e difusão de mercado de 100%, além de considerar somente pacientes sem doenças cardiovasculares (exceto hipertensão) ou pacientes sem diabetes e hipertensão arterial ou pacientes sem hipertensão arterial descontrolada, os valores foram: R$ 6,4, R$ 5,6 e R$ 5,8 bilhões, respectivamente. No Dossiê Técnico elaborado pela Abeso, o impacto orçamentário em cinco anos variou de R$ 542,3 a R$ 902,5 milhões, considerando diferentes valores de efetividade. Variando a taxa de difusão e o maior e o menor valor de efetividade, os valores podem chegar a R$ 1,8 bilhões. Considerando os valores de eficácia da sibutramina, a redução na incidência dos casos de diabetes e descontando o valor da sibutramina, o impacto orçamentário variou de uma economia de R$ 769,5 milhões a R$ 2,9 bilhões. Contudo, no Dossiê Técnico da Abeso, as incertezas e as limitações nos parâmetros e premissas adotados na avaliação de impacto orçamentário, somados à impossibilidade de conferência e reprodução de alguns cálculos utilizados em sua elaboração, também podem estar sub ou superestimando a estimativa obtida, comprometendo a compreensão das consequências financeiras oriundas de uma provável incorporação da sibutramina no SUS. CONSIDERAÇÕES GERAIS: As evidências disponíveis sugerem que o tratamento com sibutramina para a redução do peso representa ganhos clinicamente relevantes para pacientes com obesidade. No entanto, fatores como a baixa qualidade metodológica dos estudos, a tendência de reganho de peso ao longo do tempo e de publicação de resultados positivos, um número considerável de eventos adversos e a persistência de uso que ainda gera dúvidas, agregam incertezas quanto ao benefício atribuído à sibutramina. Embora disponível no Brasil, a sibutramina não possui mais autorização para comercialização em muitos países. CONSULTA PÚBLICA: Foram recebidas 1421 contribuições, sendo 38 técnico-científicas e 1383 contribuições de experiência e opinião. A maioria discordou totalmente com a recomendação da Conitec, sendo os principais argumentos a eficácia e a segurança da sibutramina, a condição incapacitante da obesidade e que agrega riscos para outras comorbidades e a ausência de alternativas no SUS para o tratamento farmacológico destes pacientes. A Abeso e a Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) participaram da consulta pública e as suas considerações foram devidamente apreciadas e comentadas. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 86ª reunião ordinária, deliberaram por recomendar a não incorporação da sibutramina para o tratamento dos pacientes com obesidade. Foi assinado o Registro de Deliberação nº 513/2020. DECISÃO: não incorporar a sibutramina para o tratamento dos pacientes com obesidade, no âmbito do Sistema Único de Saúde - SUS, conforme a Portaria nº 15, publicada no Diário Oficial da União nº 78, seção 1, página 221, em 24 de abril de 2020.

Assessment of sleep quality of patients with panic disorder and generalized anxiety disorder during remission: a case-control study

Abstract Background Sleep disorders are common in psychiatric diseases. Panic disorder (PD) and generalized anxiety disorder (GAD) are two major anxiety disorders that are associated with sleep disorders. Objective We hypothesized that poor sleep quality continues in PD and GAD during remission. Therefore, in this study we aimed to compare the sleep quality of patients with PD and GAD to that of healthy controls. Methods The study included patients with PD (n = 42) and GAD (n = 40) who had been in remission for at least 3 months and healthy control volunteers (n = 45). The patients were administered the Pittsburgh Sleep Quality Index (PSQI), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI). Results The total PSQI scores of the GAD group were significantly increased in comparison to those of the PD (p = 0.009) and control (p < 0.001) groups. The rate of poor sleep quality in GAD during remission (77.5%) was greater than that of the PD (47.6%) and control (51.1%) groups (p = 0.011). Discussion GAD is a chronic and recurrent disease. In this study, it was found that the deterioration in sleep quality of patients with GAD may continue during remission. In the follow-up and treatment of patients, it is appropriate to question about sleep symptoms and to plan interventions according to these symptoms.

Eficacia y seguridad de tapentadol en comparación con terapia de soporte en pacientes con dolor neuropático crónico severo, refractario o intolerante a tratamiento convencional físico y farmacológico / Efficacy and safety of tapentadol compared to supportive therapy in patients with chronic severe neuropathic pain, refractory or intolerant to conventional physical and pharmacological treatment

El dolor neuropático puede definirse como un dolor que aparece debido a uma lesión o enfermedad del sistema somatosensorial, por lo que, consiste en um conjunto de síntomas y no en un diagnóstico per se. La prevalencia de dolor neuropático se encuentra entre 7 % y 10 % a nivel global. Las personas manifiestan presentar alodinia, hiperalgesia, anestesia dolorosa y alteración positiva o negativa de la sensibilidad. Para el tratamiento del dolor neuropático crónico severo, refractario o intolerante a tratamiento convencional físico y farmacológico, incluyendo opioides débiles (tramadol) y fuertes (oxicodona y morfina), EsSalud sólo cuenta con terapias de soporte invasivas, como las infiltraciones locales, bloqueos nerviosos, estimulaciones eléctricas, entre otras opciones. Sin embargo, dada la poca evidencia de su eficacia y su agresividad, las terapias de soporte invasivas se consideran el último escalón (cuarto escalón) en el manejo del dolor según la escalera analgésica de la Organización Mundial de la Salud (OMS), por lo que, se plantea el uso de tapentadol como una alternativa farmacológica, más

Randomized controlled trials of serotonin-norepinephrine reuptake inhibitor in treating major depressive disorder in children and adolescents: a meta-analysis of efficacy and acceptability

New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs), were introduced in the late 1980s; however, few comprehensive studies have compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD) in young patients. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to January 2015. Only clinical trials that randomly assigned one SNRI or placebo to patients aged 7 to 18 years who met the diagnostic criteria for major depressive disorder were included. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Primary efficacy was determined by pooling the risk ratios (RRs) of treatment response and remission. Acceptability was determined by pooling the RRs of dropouts for all reasons and for adverse effects as well as suicide-risk outcomes. Five trials with a total of 973 patients were included. SNRIs were not significantly more effective than placebo for treatment response but were for remission. The comparison of patients taking SNRIs that dropped out for all reasons and those taking placebo did not reach statistical significance. Significantly more patients taking SNRIs dropped out for adverse effects than those taking placebo. No significant difference was found in suicide-related risk outcomes. SNRI therapy does not display a superior efficacy and is not better tolerated compared to placebo in these young patients. However, duloxetine has a potential beneficial effect for depression in young populations, showing a need for further research.