A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression

Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine.publishedVersio

Adverse effects of repeated subanesthetic doses of subcutaneous esketamine in treatment-resistant depression

A cetamina é uma droga anestésica com poderes dissociativos usada principalmente para anestesia e alívio da dor. Seu efeito farmacológico se dá sobre os receptores N­Metil­D aspartato (NMDA) no cérebro, que estão envolvidos na regulação do humor, cognição e percepção da dor. A ação da cetamina sobre os receptores NMDA leva a um aumento na liberação do neurotransmissor glutamato, o que desencadeia uma cascata de reações bioquímicas que, em última instância, resulta nos efeitos antidepressivos, analgésicos e pode produzir uma série de efeitos psicológicos e físicos, incluindo alívio da dor, sedação e alucinações. Nos últimos anos, a cetamina tem mostrado potencial como um antidepressivo de ação rápida em baixas doses sob supervisão médica para pacientes com transtorno depressivo resistente ao tratamento (TRD). A cetamina é uma mistura racêmica de dois enantiômeros, a escetamina (enantiômero S) e a arcetamina (enantiômero R). Eles diferem em sua orientação tridimensional, o que significa que eles têm pequenas diferenças em suas propriedades farmacológicas. A principal diferença entre a (S)­ cetamina e a (R)­cetamina é sua potência e afinidade por diferentes receptores no cérebro. A (S)­cetamina é conhecida por ser mais potente e ter maior afinidade com o receptor NMDA, que é o principal alvo dos efeitos antidepressivos da cetamina. Acredita­se também que a (S)­cetamina tenha menos efeitos colaterais, tais como dissociação e alucinações, em comparação com a (R)­cetamina. Em geral, a (S)­cetamina mostrou­se mais eficaz no tratamento de depressão e distúrbios de humor, enquanto a (R)­cetamina pode ser mais útil para o controle da dor e anestesia. Em março de 2019, a US Food and Drug Administration (FDA) aprovou o uso da escetamina como spray nasal sob a marca Spravato para depressão resistente ao tratamento em combinação a terapia antidepressiva oral. Esta decisão veio após vários ensaios clínicos que demonstraram a eficácia da escetamina em reduzir rapidamente os sintomas da depressão, incluindo pensamentos suicidas, em pacientes que não haviam respondido a outros tratamentos convencionais focados na modulação do sistema monoaminérgico. Entretanto, devido a seu potencial de abuso e efeitos colaterais, tais como dissociação, sedação e aumento da pressão arterial, a escetamina só está disponível através de um programa restrito chamado REMS (Risk Evaluation and Mitigation Strategy). Os pacientes devem ser monitorados e tratados em um ambiente de saúde sob a supervisão de um profissional de saúde. A escetamina é uma medicação considerada segura e bem tolerada, mas como todos os medicamentos, ela pode causar eventos adversos. Os eventos adversos mais comuns relatados em ensaios clínicos para o tratamento da depressão incluem: dissociação (sentir­se desapegado de si mesmo ou do ambiente), tontura, náusea, cefaleia, sedação, vertigem (uma sensação de girar), visão embaçada, aumento da pressão arterial e vômitos. Os efeitos adversos são geralmente bem tolerados, seguros, autolimitados e dose dependentes. Podem ser modulados a depender da via de administração utilizada (via intravenosa­IV está associada a maior incidência de efeitos adversos em comparação a intranasal ou subcutânea). A via subcutânea (SC) possui biodisponibilidade semelhante a IV em 40 minutos de infusão, é segura, de fácil manuseio e baixo custo, sendo, portanto, uma alternativa para o uso na atenção pública de saúde primária. Os objetivos dessa tese são i) avaliar os efeitos colaterais de infusões subcutâneas repetidas de escetamina em pacientes com depressão resistente ao tratamento unipolar e bipolar e revisar dados da tolerabilidade e segurança do uso escetamina para tratamento da depressão resistente a tratamento na literatura, ii) avaliação da tolerabilidade e segurança de 394 infusões subcutâneas repetidas de escetamina para o tratamento de pacientes com diagnóstico de transtorno depressivo unipolar e episódio depressivo bipolar resistentes ao tratamento usual encaminhados para a Clínica de Cetamina do Programa de Doenças Afetivas (PRODAF) da Universidade Federal de São Paulo (UNIFESP) no período de abril de 2017 à dezembro de 2018. Medidas de segurança como avaliação de sinais vitais, nível de consciência, presença e quantificação de sintomas psicotomiméticos foram avaliados durante infusões com duração de 120 minutos. Doses de dextrocetamina variaram de 0,5mg/kg à 1mg/kg na concentração de 50mg/ml conforme resposta do paciente, iii) avaliar os efeitos psicotomiméticos e sedativos em infusões subcutâneas repetidas de escetamina em pacientes com depressão resistente ao tratamento unipolar e bipolar e revisar dados da tolerabilidade e segurança do uso escetamina para tratamento da depressão resistente através de uma análise retrospectiva de 394 injeções subcutâneas de escetamina dadas a 70 pacientes com TRD que foram administradas uma vez por semana durante um ensaio de seis semanas em conjunto com terapia antidepressiva oral; doses entre 0,5 a 1,0 mg/kg foram administradas de acordo com a resposta do paciente; os sintomas dissociativos foram avaliados usando a Escala Clinical­Administered Dissociative States (CADSS) 30 e 60 minutos após cada tratamento semanal (dia 1, 8, 15, 22, 29 e 36) iv) realizar uma revisão da literatura que explora a tolerabilidade e segurança cardiovascular, efeitos dissociativos do uso de escetamina no tratamento de transtornos depressivo resistente a tratamento. Os resultados obtidos foram que as injeções de escetamina subcutânea são seguras do ponto de vista cardiovascular e dissociativo. As mudanças na pressão arterial foram leves e bem toleradas para doses de até 1 mg/kg. A via SC é um método simples e seguro de administração de escetamina, mesmo para pacientes com comorbidades clínicas, incluindo obesidade, hipertensão, diabetes e dislipidemia. Entretanto, 14/70 pacientes experimentaram hipertensão transitória emergente (pressão arterial sistólica superior a 180 mmHg e/ou uma pressão diastólica superior a 110 mmHg ou mais). Portanto, recomendamos fortemente o monitoramento da pressão arterial durante 90 minutos após a dosagem de escetamina. Como a escetamina SC tem um custo baixo, dosagem menos freqüente (uma vez por semana) e é um procedimento mais simples quando comparado às infusões intravenosas, com impacto para a saúde pública. Com o tempo, a evolução dos escores CADSS demonstrou uma diferença média significativa de CADSS a 60 minutos após a injeção (p = 0,010) ao longo das seis infusões. Os escores médios do CADSS aos 60 min. nos dias 22, 29 e 36 foram semelhantes. Não houve diferenças entre os escores médios do CADSS 30 min após as injeções, nenhuma correlação clínica entre resposta e sintomas dissociativos, nenhuma correlação entre tempo e características demográficas e clínicas e nenhuma interação entre tempo e medicação combinada. Conclui­se que a escetamina subcutânea no tratamento da TRD é segura e bem tolerada mesmo na presença de comorbidades clínicas.Ketamine is an anesthetic drug with dissociative powers used mainly for anesthesia and pain relief. Its pharmacological effect is on the N-Methyl-D-aspartate (NMDA) receptors in the brain, which are involved in the regulation of mood, cognition, and pain perception. Ketamine's action on NMDA receptors leads to an increase in the release of the neurotransmitter glutamate, which triggers a cascade of biochemical reactions that ultimately results in the antidepressant, analgesic effects, and can produce a range of psychological and physical effects, including pain relief, sedation, and hallucinations. In recent years, ketamine has shown potential as a fast-acting antidepressant in low doses under medical supervision for patients with treatmentresistant depressive disorder (TRD). Ketamine is a racemic mixture of two enantiomers, scetamine (S enantiomer) and arcetamine (R enantiomer). They differ in their threedimensional orientation, which means that they have minor differences in their pharmacological properties. The main difference between (S)-ketamine and (R)-ketamine is their potency and affinity for different receptors in the brain. (S)-ketamine is known to be more potent and have a higher affinity for the NMDA receptor, which is the main target of ketamine's antidepressant effects. (S)-ketamine is also believed to have fewer side effects, such as dissociation and hallucinations, compared to (R)-ketamine. Overall, (S)- ketamine has been shown to be more effective in treating depression and mood disorders, while (R)-ketamine may be more useful for pain control and anesthesia. In March 2019, the US Food and Drug Administration (FDA) approved the use of ketamine as a nasal spray under the brand name Spravato for treatment-resistant depression in combination with oral antidepressant therapy. This decision came after several clinical trials demonstrated the effectiveness of ketamine in rapidly reducing symptoms of depression, including suicidal thoughts, in patients who had not responded to other conventional treatments focused on modulation of the monoaminergic system. However, due to its potential for abuse and side effects, such as dissociation, sedation, and increased blood pressure, ketamine is only available through a restricted program called REMS (Risk Evaluation and Mitigation Strategy). Patients must be monitored and treated in a healthcare setting under the supervision of a healthcare professional. Ketamine is a medication that is considered safe and well tolerated, but like all medications, it can cause adverse events. The most common adverse events reported in clinical trials for the treatment of depression include dissociation (feeling detached from oneself or one's environment), dizziness, nausea, headache, sedation, vertigo (a feeling of spinning), blurred vision, increased blood pressure, and vomiting. Adverse effects are generally well tolerated, safe, self-limited, and dose dependent. They can be modulated depending on the route of administration used (intravenous-IV route is associated with a higher incidence of adverse effects compared to intranasal or subcutaneous). The subcutaneous (SC) route has similar bioavailability to IV within 40 minutes of infusion, is safe, easy to handle, and low cost, and is therefore an alternative for use in public primary health care. The objectives of this thesis are i) to evaluate the side effects of repeated subcutaneous infusions of scetamine in patients with unipolar and bipolar treatment resistant depression and to review data on the tolerability and safety of using scetamine for treatment resistant depression in the literature, ii) evaluation of the tolerability and safety of 394 repeated subcutaneous infusions of ketamine for the treatment of patients diagnosed with unipolar depressive disorder and bipolar depressive episode resistant to usual treatment referred to the Ketamine Clinic of the Affective Diseases Program (PRODAF) of the Federal University of São Paulo (UNIFESP) in the period from April 2017 to December 2018. Safety measures such as vital sign assessment, level of consciousness, presence and quantification of psychotomimetic symptoms were evaluated during infusions lasting 120 minutes. Doses of dextrocetamine ranged from 0.5mg/kg to 1mg/kg at a concentration of 50mg/ml as per patient response, iii) evaluate the psychotomimetic and sedative effects in repeated subcutaneous infusions of esketamine in patients with unipolar and bipolar treatment resistant depression and review data on the tolerability and safety of using esketamine for treatment resistant depression in the literature through a retrospective analysis of 394 subcutaneous injections of esketamine given to 70 patients with TRD that were administered once a week during a six week trial in conjunction with oral antidepressant therapy; doses ranging from 0.5 to 1.0 mg/kg were administered according to patient response; dissociative symptoms were assessed using the Clinical- Administered Dissociative States (CADSS) 30 and 60 minutes after each weekly treatment (day 1, 8, 15, 22, 29 and 36) iv) to conduct a review of the literature exploring the tolerability and safety cardiovascular, dissociative effects of using ketamine in the treatment of treatment-resistant depressive disorder. The results obtained were that subcutaneous ketamine injections are safe from a cardiovascular and dissociative standpoint. Changes in blood pressure were mild and well tolerated for doses up to 1 mg/kg. The SC route is a simple and a safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced emergent transient hypertension (systolic blood pressure greater than 180 mmHg and/or a diastolic pressure greater than 110 mmHg or more). Therefore, we strongly recommend monitoring blood pressure for 90 minutes after dosing ketamine. Because SC ketamine has a low cost, less frequent dosing (once a week), and is a simpler procedure compared to IV infusions, it may have a public health impact. Over time, the evolution of CADSS scores demonstrated a significant mean difference in CADSS at 60 minutes after injection (p = 0.010) over the six infusions. The mean CADSS scores at 60 min on days 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics, and no interaction between time and combination medication. It is concluded that subcutaneous ketamine in the treatment of TRD is safe and well tolerated despite the presence of clinical comorbidities

Impact of Repeated Doses of Subcutaneous Esketamine on Acute Dissociative Symptoms in Treatment-Resistant Depression

Background: Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects. Methods: A retrospective analysis of 394 subcutaneous esketamine injections given to 70 patients with TRD that were administered once a week during a six-week trial in conjunction with oral antidepressant therapy. Doses between 0.5 to 1.0 mg/kg were administered according to the patient’s response. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS) 30 and 60 min after every weekly treatment (day 1, 8, 15, 22, 29 and 36). Results: Seventy patients received a total of 394 subcutaneous esketamine injections over six weeks. Over time, the evolution of CADSS scores demonstrated a significant mean difference of CADSS at 60 min post-injection (p = 0.010) throughout the six infusions. The mean CADSS scores at 60 min on day 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics and no interactions between time and combined medication. Conclusions: Our results suggest that repeated subcutaneous esketamine doses are safe and well-tolerated regarding their acute dissociative and psychotomimetic symptoms. Symptoms usually peak at 30 min and decrease at 60 min post-injection, returning to their pretreatment levels at 120 min. Dissociative symptoms do not correlate with antidepressant response

A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression

Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine