Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression.

BACKGROUND AND OBJECTIVE: Affective disorders account for most cases of suicide. The pharmacological arsenal to treat suicidality is limited and available agents take too long to take effect. A large body of evidence shows optimal results of ketamine for treating depression, but the evidence concerning suicidality has not been fully described. We report the first real-world study of severely depressed patients presenting with suicide ideation who were treated with repeated administration of subcutaneous esketamine. METHODS: We analyzed data from 70 acutely depressed subjects diagnosed with resistant major depressive disorder or bipolar depression. Subjects were administered subcutaneous esketamine once a week for 6 weeks. The primary efficacy endpoint, the change from baseline to 24-h post-administration 6 in the item 10 Montgomery-Åsberg Depression Rating Scale score, was analyzed using a mixed-effects repeated-measures model. RESULTS: There were significant effects for time on item 10 Montgomery-Åsberg Depression Rating Scale scores (p < 0.0001) but not for a time × diagnosis interaction (p = 0.164) from baseline to the end of the study. Efficacy of esketamine did not differ between groups (major depressive disorder vs bipolar depression) at any timepoint. Statistical significance on suicidality scores was observed from 24 h after the first administration (p < 0.001), and a further reduction was observed with repeated administrations. Esketamine was safe and well tolerated. Mean heart rate remained stable during the administrations and the blood pressure increase was self-limited. CONCLUSIONS: Repeated subcutaneous esketamine administration had significant anti-suicidality effects in both major depressive disorder and bipolar groups, with a rapid onset of action and a good tolerability profile. Large randomized controlled trials are warranted to confirm these preliminary findings.

The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.

INTRODUCTION: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC). MATERIAL AND METHODS: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection. RESULTS: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%. CONCLUSIONS: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC.

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.

Repeated subcutaneous esketamine for treatment-resistant depression: Impact of the degree of treatment resistance and anxiety comorbidity.

BACKGROUND: A large number of studies indicate that subanesthetic doses of ketamine induce a fast antidepressant effect. Limited studies have investigated the subcutaneous (SC) route, and it remains unclear for whom this treatment is most suitable. AIMS: The aim of this study was to examine the effect on depressive symptoms of repeated subanesthetic doses of SC esketamine in unipolar and bipolar treatment-resistant depression (TRD) and clinical predictors of response. METHODS: A retrospective analysis of 70 patients who received six SC esketamine doses weekly as an adjunctive treatment was carried out. Doses started at 0.5 mg/kg and it could be titrated up to 1 mg/kg, according to response. The primary outcome was reduction in depressive symptoms. Statistical analysis to investigate clinical predictors of effectiveness included logistic regression analysis using a dependent variable of a 50% reduction in rating scale scores at the end of treatment. Comparisons between groups were made through analysis of variance and treatment effects. RESULTS: At baseline, our sample presented with severe treatment resistance in 65.7%, as assessed by the Maudsley Staging Method (MSM), and 47.1% had anxiety disorder comorbidity. The response rate was 50%. A better outcome was predicted by mild and moderate MSM scores (OR = 3.162, p = 0.041) and anxiety disorder comorbidity (OR = 3.149, p = 0.028). CONCLUSIONS: Our results suggest that higher levels of treatment resistance may be associated with a poor response to SC esketamine. Unlike traditional pharmacotherapies, it might benefit those with poor prognosis such as patients with depression and comorbid anxiety. Therefore, future research could investigate whether esketamine should receive a more prominent place in the treatment algorithm for TRD.

Comparative effectiveness of esketamine in the treatment of anhedonia in bipolar and unipolar depression.

BACKGROUND: Anhedonia is a symptom associated with poorer outcomes in depression treatment, including resistance to treatment, higher functional impact and suicidality. Few drugs are known to adequately treat anhedonia in both unipolar and bipolar depression. The NMDA antagonist ketamine has been demonstrated to be effective in rapidly ameliorating anhedonia in depressive episodes. The main aim of present study is to evaluate the anti-anhedonic effect of esketamine, the S-enantiomer of ketamine recently approved for treatment-resistant depression, in unipolar and bipolar depression. METHODS: 70 patients with unipolar or bipolar depression were treated with 6 weekly subcutaneous esketamine infusions (0.5-1mg/kg). Anhedonia was measured through MADRS item 8 before and 24h after each infusion. RESULTS: A significant reduction in anhedonia severity was observed (p<0.0001) after 6 infusions. The effect was statistically significant 24h after the first infusion (p<0.001) in both unipolar and bipolar groups and increased with repeated infusions. Anti-anhedonic effect of esketamine did not differ between groups. LIMITATIONS: This is an open-label, real-world study. Lack of blinding and of a placebo arm may limit the interpretation of findings. CONCLUSION: Although preliminary, present findings suggest that repeated subcutaneous esketamine infusions are effective for the treatment of anhedonia in both unipolar and bipolar depressed patients. These results need to be confirmed through replication in larger double-blinded controlled trials.

The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.

INTRODUCTION: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC). MATERIAL AND METHODS: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection. RESULTS: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%. CONCLUSIONS: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC.

Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression.

INTRODUCTION AND OBJECTIVES: The impact of multiple subcutaneous (s.c.) esketamine injections on the blood pressure (BP) and heart rate (HR) of patients with unipolar and bipolar treatment-resistant depression (TRD) is poorly understood. This study aimed to assess the cardiovascular safety of multiple s.c. doses of esketamine in patients with TRD. METHODS: Seventy TRD patients received 394 weekly s.c. esketamine injections in conjunction with oral antidepressant therapy for up to six weeks. Weekly esketamine doses were 0.5, 0.75 or 1.0 mg/kg according to each patient's response to treatment. Participants were monitored before each treatment and every 15 minutes thereafter for 120 minutes. We assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measurements for the entire treatment course. RESULTS: BP increased after the first s.c. esketamine injection, reaching maximum mean SBP/DBP levels of 4.87/5.54 mmHg within 30-45 minutes. At the end of monitoring, 120 minutes post dose, vital signs returned to pretreatment levels. We did not detect significant differences in BP between doses of 0.5, 0.75, and 1 mg/kg esketamine. Mean HR did not differ significantly between doses or before and after s.c. esketamine injection. CONCLUSIONS: The BP changes observed with repeated s.c. esketamine injections were mild and well tolerated for doses up to 1 mg/kg. The s.c. route is a simple and safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced treatment-emergent transient hypertension (SBP >180 mmHg and/or a DBP >110 mmHg). Therefore, we strongly recommend monitoring BP for 90 minutes after esketamine dosing. Since s.c. esketamine is cheap, requires less frequent dosing (once a week), and is a simpler procedure compared to intravenous infusions, it might have an impact on public health.

Factors associated with attrition rate in a supportive care service for substance using pregnant women in Brazil.

BACKGROUND AND OBJECTIVES: Retaining substance using women in antenatal care remains a major challenge. This study explored factors associated with attrition rate among women with substance use problems attending a supportive care service during pregnancy and soon after the birth of the infant. METHODS: Records of 166 women's antenatal consultations were analyzed. RESULTS: Attrition rate was high (75/166, 45.2%), and was associated with women having no schooling/primary schooling only, no family contact, having child(ren), crack-cocaine use, poly drug use, and substance use problems by the expected child's father. DISCUSSION AND CONCLUSIONS: Attrition may be the outcome of socio-demographic, family, individual, and substance use issues not fully addressed in prenatal interventions. SCIENTIFIC SIGNIFICANCE: Identification of who are at risk for dropping out affords services with an opportunity to prevent its occurrence. (Am J Addict 2017;26:676-679).

[Clinical and demographical aspects of alcohol and drug dependent physicians]. / Perfil clínico e demográfico de médicos com dependência química.

UNLABELLED: The misuse of alcohol and drugs among physicians is a common cause of malpractice, absenteeism and complaints to the Medical Councils. This problem demands more attention, because it entails risks to the population and to the physicians themselves. AIMS: To describe the clinical and demographic profile of a sample of physicians in treatment for alcohol and drug dependence also to evaluate psychiatric comorbidity and consumption-related consequences. METHODS: Data was collected from a sample of 198 physicians attending outpatient treatment by a questionnaire specifically designed for this study. RESULTS: Most of the subjects were men (87.8%), married (60.1%), with a mean age of 39.4 years (S.D. =10.7). Sixty-six per cent had already been in inpatient treatment for alcohol and drug misuse. Sixty-nine per cent were specialists practicing mainly: internal medicine, anaesthesiology and surgery. Psychiatric comorbidity was diagnosed in 27.7% for DSM-IV Axis I and in 6% for DSM-V Axis II. With regard to drugs the most frequent pattern was use of alcohol and drugs (36.8%), followed by exclusive use of alcohol (34.3%) and exclusive use of drugs (28.3%). It was observed that the mean interval between the identification of misuse of substances and the seeking of treatment was of 3.7 years. Thirty per cent tried to achieve treatment by themselves. The social and legal problems observed were: unemployment in the previous year (1/3 of the sample), marital problems and divorce (52%), car accidents (42%), legal problems (19%). 84.8% presented professional problems and 8.5% had problems within the Medical Councils. CONCLUSION: The researchers suggest supportive and preventive attitudes for this matter.

Perfil clínico e demográfico de médicos com dependência química / Clinical and demographical aspects of alcohol and drug dependent physicians

OBJETIVO: Traçar o perfil clínico e demográfico de uma amostra de médicos em tratamento por dependência química, avaliar comorbidades psiquiátricas e conseqüências associadas ao consumo. MÉTODOS: Foram coletados dados de 198 médicos em tratamento ambulatorial por uso nocivo e dependência química, através de questionário elaborado pelos autores. RESULTADOS: A maioria de indivíduos foi do sexo masculino (87,8 por cento), casados (60,1 por cento), com idade média de 39,4 anos (desvio padrão=10,7 anos). Sessenta e seis por cento já tinham sido internados por causa do uso de álcool e/ou drogas. Setenta e nove por cento possuía residência médica e as especialidades mais envolvidas foram: clínica médica, anestesiologia e cirurgia. Comorbidade psiquiátrica foi diagnosticada em 27,7 por cento (Eixo I do DSM-IV)¹ e em 6 por cento (Eixo II do DSM-IV)¹. Quanto às substâncias consumidas, o mais freqüente foi uso associado de álcool e drogas (36,8 por cento), seguido por uso isolado de álcool (34,3 por cento) e uso isolado de drogas (28,3 por cento). Observou-se o intervalo de 3,7 anos em média entre a identificação do uso problemático de substâncias e a procura de tratamento. Quanto à busca por tratamento, 30,3 por cento o fizeram voluntariamente. Quanto aos problemas sociais e legais observou-se: desemprego no ano anterior em quase 1/3 da amostra; problemas no casamento ou separação (52 por cento), envolvimento em acidentes automobilísticos (42 por cento), problemas jurídicos (19 por cento), problemas profissionais (84,8 por cento) e 8,5 por cento tiveram problemas junto aos Conselhos Regionais de Medicina. CONCLUSÃO: Os autores recomendam medidas assistenciais e preventivas para o problema.

O que acontece com os pacientes dependentes de alcool e drogas que desaparecem das primeiras consultas? / What happens to alcohol and drug users who disappear from the first clinical appointments?

O elevado índice de abandono de tratamento de dependentes químicos motivou a realizaçäo deste trabalho. O estudo foi feito num centro de atendimento universitário em Säo Paulo. Foram entrevistados 69 pacientes ou familiares após pelo menos três meses da interrupçäo do tratamento. As informaçöes obtidas foram: dados sociodemográficos, criminalidade, procura de outros tratamentos, consumo de álcool, drogas e tabaco, morte e razöes para a näo-aderência ao tratamento. A amostra era constituída em sua maioria de homens jovens, solteiros, fumamntes, de baixo grau de escolaridade. A maioria dos pacientes näo procurou tratamento e continuou usando álcool e drogas após a consulta perdida. Dos 69 pacientes, três haviam morrido no período analisado, envolvidos com tráfico de drogas. As primeiras razöes apontadas para a näo-aderência ao tratamento foram motivos práticos, excesso de otimismo em si mesmo e atitude negativa em relaçäo ao tratamento

O que acontece com os pacientes dependentes de alcool e drogas que desaparecem da primeiras consultas?

O elevado indice de abandono de tratamento de dependentes quimicos motivou a realizacao deste trabalho. O estudo foi feito num centro de atendimento universitario em Sao Paulo. Foram entrevistados 69 pacientes ou familiares apos pelo menos tres meses de interrupcao do tratamento. As informacoes obtidas foram: dados sociodemograficos, criminalidade, procura de outros tratamentos, consumo de alcool, droga e tabaco, morte e razoes para a nao-aderencia ao tratamento. A amostra era constituida em sua maioria de homens jovens, solteiros, fumantes, de baixo grau de escolaridade. A maioria dos pacientes nao procurou tratamento e continuou usando alcool e drogas apos a consulta perdida. Dos 69 pacientes, tres haviam morrido no periodo analisado, envolvidos com trafico de drogas. As principais razoes apontadas para a nao-aderencia ao tratamento foram motivos praticos, excesso de otimismo em si mesmo e atitude negativa em relacao ao tratamento.