Exploring Esketamine's Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review.

The expansive spectrum of major depressive disorder (MDD) continues to pose challenges for psychiatrists to treat effectively. Oral antidepressant (OAD) medications that alter monoamine neurotransmitters, mainly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), have been the mainstay of therapy for decades. Although these drugs have been largely beneficial, a considerable subset of patients do not respond adequately to multiple conventional therapies administered for an appropriate length of time, leading to a diagnosis of treatment-resistant depression (TRD). Ketamine, a non-monoaminergic drug, has long been known for its beneficial effects on TRD when given intravenously (IV). Between 2019 and 2020, an intranasal formulation of the S (+) enantiomer of racemic ketamine, esketamine (ESK), was granted "breakthrough designation" by the FDA and approved for the indications of TRD and MDD patients exhibiting acute suicidal intent. The objective of this narrative review was to review the academic literature and collect clinical evidence that may corroborate intranasal ESK's effectiveness for its approved indications while addressing its safety and tolerability profile, adverse effects, and impact on cognition. An overview of the drug's origins, pharmacology, and standard treatment regimen are provided. The outcomes from double-blinded randomized control trials (DB-RCTs) of ESK are outlined to demonstrate the efficacy and safety data leading to its FDA approval, along with its long-term post-market safety outcomes. Comparative trials between ESK and ketamine are then evaluated to highlight ESK's consideration as a more practical alternative to ketamine in common clinical practice. The authors further discuss currently approved and developing therapies for TRD, propose future research directions, and identify the inherent limitations of the review and further research. To conduct the research required, three digital databases (PubMed, Medline, and ClinicalTrials.gov) were queried to search for key terms, including ketamine, esketamine, treatment-resistant depression, and biomarkers, using automation tools along with selective search engine results. After streamlining the results by title and abstract and removing duplicates, a total of 37 results were chosen, of which 18 are clinical trials. A reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score was the primary efficacy endpoint for most of these clinical trials. In conclusion, intranasal ESK, when used as an adjunct to market OADs, shows greater efficacy in treating TRD and MDD with suicidal intent compared to OADs and placebo alone and provides a more suitable alternative to IV ketamine. It is important to note that further research is required to fully understand the novel mechanism of action of ESK, as well as the establishment of a consensus definition of TRD, which may facilitate better detection and treatment protocols. More focused quantitative and qualitative ESK studies are needed, as well as those pertaining to its use in patients with co-existing mental illnesses.

High-frequency rTMS modulates emotional behaviors and structural plasticity in layers II/III and V of the mPFC.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique, and it has been increasingly used as a nonpharmacological intervention for the treatment of various neurological and neuropsychiatric diseases, including depression. In humans, rTMS over the prefrontal cortex is used to induce modulation of the neural circuitry that regulates emotions, cognition, and depressive symptoms. However, the underlying mechanisms are still unknown. In this study, we investigated the effects of a short (5-day) treatment with high-frequency (HF) rTMS (15 Hz) on emotional behavior and prefrontal cortex morphological plasticity in mice. Mice that had undergone HF-rTMS showed an anti-depressant-like activity as evidenced by decreased immobility time in both the Tail Suspension Test and the Forced Swim Test along with increased spine density in both layer II/III and layer V apical and basal dendrites. Furthermore, dendritic complexity assessed by Sholl analysis revealed increased arborization in the apical portions of both layers, but no modifications in the basal dendrites branching. Overall, these results indicate that the antidepressant-like activity of HF-rTMS is paralleled by structural remodeling in the medial prefrontal cortex.

The brain-gut axis in gastrointestinal cancers.

Recent developments have given more credence into the brain-gut-microbiota axis and its role in the development of tumor genesis. The microbiota have multiple functions including maintenance of the epithelial barrier, immune response, digestion, cortisol regulation, and control of neurotransmitters and their metabolism [e.g., serotonin, dopamine, noradrenaline and gamma-Aminobutyric Acid (GABA)]. Changes in gut microbiota can interfere with homeostasis leading to dysbiosis microbiota, which is linked to colorectal cancer. Microbiota composition can cause pronounced effect on medical interventions including medications, chemotherapy, and radiation. Altered primary immune system is associated with microbiota disassociation and development of colorectal cancer. This article reviews the current research in brain-gut axis with focus on microbiota and its role in the development of gastrointestinal cancers. We conducted a literature review on PubMed, Cochrane, and Science direct using English language. We begin by reviewing the brain-gut axis and its function and then discuss its effect on the development of gastrointestinal cancers. We reviewed 70 manuscripts and found association between microbiota dysfunction and development of colorectal cancers predisposing to psychiatric manifestations. Lasting disturbances in the microbiota can lead to systemic inflammation with implications on disease development or treatment modifications. These disruptions of the intestinal flora can play an important role in the pathogenesis of cancers. Most psychological reactions to cancer are similar across cancer types but each cancer when examined individually has its own unique features associated with it. Correlation between fear of recurrence and the level of pathological distress is viewed as an indicator of overall adjustment to cancer survival.

Cytokine storm induced new onset depression in patients with COVID-19. A new look into the association between depression and cytokines -two case reports.

BACKGROUND: Depression appears to be a common complication in patients during and post-COVID-19 infection. Understanding the mechanism of action of cytokines such as interleukin-6, interleukin-10 and others in depression and in cytokine storm syndrome, the core component of COVID- 19, could shine a new light on future treatment options for both disorders. OBJECTIVE: This review demonstrates the role of interleukins in COVID-19 pathogenesis and their role in depression. RESULTS: We described cases we have treated as an example for the dual role interleukins have in COVID-19 infection and depression and reviewed approximately 70 articles focusing on the role of interleukins in cytokine storm syndrome and depression. CONCLUSION: This review highlights the key features of cytokines in both diseases. As the scientific community has more time to recover and process the effect of the current pandemic, we believe that additional research will pave the way to diverse pathways to treat depression in these patient and others.

Substance Use Disorders in Vulnerable Children.

Substance use remains a major challenge in adolescent health. The coexisting use of these substances often creates hurdles for accurate diagnosis of other comorbid psychiatric conditions. It is of critical importance that health care providers be aware of both the isolated presentation of substance use disorder and that with coexisting psychiatric illness in vulnerable children.

A Look at Genetic Linkage between Clozapine-induced Agranulocytosis, Malignant Hyperthermia, Neuroleptic Malignant Syndrome, and Statin-induced Myopathy.

Clozapine-induced agranulocytosis, malignant hyperthermia (MH), statin-induced myopathy, and neuroleptic malignant syndrome (NMS) are all serious drug reactions with significant overlap in terms of clinical symptomatology. The use of clozapine can lead to neutropenia, as well as the development of NMS; thus, it seemed logical to explore a possible common genetic background for the development of these two adverse effects. Furthermore, due to the overwhelming clinical resemblance between NMS, MH, and statin-induced myopathy, we decided specifically to search for a common genetic background in the development of these conditions. Methods: We searched the PubMed, OMIM, WikiGenes, Medline, and Google Scholar databases to identify articles pertinent to our subject published over the last 30 years. Articles were reviewed according to our inclusion/exclusion criteria, and irrelevant articles were excluded. Results and Conclusions: In our exploration for a common genetic background between clozapine-induced agranulocytosis, MH, NMS, and statin-induced myopathy, we identified the SLCO1B1 gene, which was common to three of these four conditions (MH, statin-induced myopathy, and clozapine-induced agranulocytosis). Although we did not find a gene common among NMS and the other conditions, the overlap of clinical symptoms between NMS, MH, and statin-induced myopathy did not allow us to rule out the possibility of a common factor, in terms of genetic predisposition, between these conditions. Future studies can aid to fill in the gaps of knowledge in terms of any genetic linkage between these three conditions and the mechanism of their associations.

A randomized controlled trial of buprenorphine taper duration among opioid-dependent adolescents and young adults.

BACKGROUND AND AIMS: Few randomized controlled trials have evaluated buprenorphine treatment interventions for opioid-dependent youth. Consequently, optimal administration strategies for this cohort are unclear. Our aim was to evaluate the relative efficacy of two different buprenorphine taper lengths in promoting abstinence from illicit opioids and treatment retention among opioid-dependent youth. DESIGN: A double-blind, placebo controlled, multicenter randomized controlled trial. SETTING: Two hospital-based research clinics (Manhattan and Brooklyn) in New York City, USA from 2005 to 2010. PARTICIPANTS: Volunteer sample of 53 primarily Caucasian participants between the ages of 16 and 24 (n = 11 under age 18) who met DSM-IV opioid dependence criteria. INTERVENTION: Participants were assigned randomly to either a 28-day buprenorphine taper (n = 28) or 56-day buprenorphine taper (n = 25) via a parallel-groups design during a 63-day period. Both groups received behavioral counseling and opioid abstinence incentives. Both taper conditions had a minimum of 1 week of placebo dosing at the end of the taper. MEASUREMENTS: The primary outcome was opioid abstinence measured as a percentage of scheduled urine toxicology tests documented to be negative for opioids. The secondary outcome was treatment retention, measured as number of days attended scheduled visits. FINDINGS: Intent-to-treat analyses revealed that participants who received a 56-day buprenorphine taper had a significantly higher percentage of opioid-negative scheduled urine tests compared with participants who received a 28-day buprenorphine taper [35 versus 17%, P = 0.039; Cohen's d = 0.57, 95% confidence interval (CI) = 0.02, 1.13]. Participants who received a 56-day buprenorphine taper were retained in treatment significantly longer than participants who received a 28-day buprenorphine taper (37.5 versus 26.4 days, P = 0.027; Cohen's d = 0.63, 95% CI = 0.06, 1.19). Daily attendance requirement was associated with decreased abstinence and shorter retention compared with a two to three times weekly attendance requirement, independent of taper duration. Follow-up data were insufficient to report. CONCLUSION: Longer (56-day) buprenorphine taper produces better opioid abstinence and retention outcomes than shorter (28-day) buprenorphine taper for opioid-dependent youth.

Mental health outcomes among vulnerable residents after Hurricane Sandy: implications for disaster research and planning.

OBJECTIVE: To evaluate mental health outcomes among New Jersey shore residents with health impairments and disabilities after Hurricane Sandy. DESIGN AND SETTING: Six months following Hurricane Sandy, a cross-sectional survey of 200 adults residing in beach communities directly exposed to the storm located in Monmouth County, NJ, was conducted. MAIN OUTCOME MEASURES: Post-traumatic stress disorder (PTSD), depression, mental health service use, and medication use. RESULTS: The average age of residents surveyed was 59 years (SD = 13.7) and 52.5 percent (95% CI = 45.5-59.4) reported recent hospitalizations, physical limitations, fair to poor health status, multiple chronic health conditions, or physical disabilities. A total of 14.5 percent (95% CI = 10.2-20.1) of residents screened positive for PTSD and 6.0 percent (95% CI = 3.1-10.2) met criteria for depression 6 months after Sandy. In addition, 20.5 percent (95% CI = 15.4-26.7) sought some type of professional counseling after Sandy and 30.5 percent (95% CI = 24.5-37.3) experienced PTSD symptoms, depression, sought professional mental health support, or used psychotropic medications. In multivariate analyses, the best predictors of mental health and service use were having sleep problems, suicidal thoughts, moderate or severe pain, and having high exposure hurricane-related events. Analyses also suggested that noncollege graduates were more likely to receive mental health services (OR = 3.10, p = 0.009), while women were less likely to have depression (OR = 0.12, p = 0.038). CONCLUSION: Having physical impairments and health conditions were not directly related to adverse mental health outcomes following Sandy, but having sleep problems, pain, or suicidal thoughts were. Further research is needed to assess the health status of community residents with serious health impairments over time following disasters.

Mental health outcomes at the Jersey Shore after Hurricane Sandy.

On October 29, 2012, Hurricane Sandy made landfall in the most densely populated region in the US. In New Jersey, thousands of families were made homeless and entire communities were destroyed in the worst disaster in the history of the state. The economic impact of Sandy was huge, comparable to Hurricane Katrina. The areas that sustained the most damage were the small- to medium-sized beach communities along New Jersey's Atlantic coastline. Six months following the hurricane, we conducted a random telephone survey of 200 adults residing in 18 beach communities located in Monmouth County. We found that 14.5% (95% CI = 9.9-20.2) of these residents screened positive for PTSD and 6.0% (95% CI = 3.1-10.2) met criteria for major depression. Altogether 13.5% (95% CI = 9.1-19.0) received mental health counseling and 20.5% (95% CI = 15.1-26.8) sought some type of mental health support in person or online, rates similar to those reported in New York after the World Trade Center disaster In multivariate analyses, the best predictors of mental health status and service use were having high hurricane exposure levels, having physical health limitations, and having environmental health concerns. Research is needed to assess the mental health status and service use of Jersey Shore residents over time, to evaluate environmental health concerns, and to better understand the storm's impact among those with physical health limitations.

Improvement in psychopathology among opioid-dependent adolescents during behavioral-pharmacological treatment.

OBJECTIVE: To examine changes in behavioral and emotional problems among opioid-dependent adolescents during a 4-week combined behavioral and pharmacological treatment. METHODS: We examined scales of behavioral and emotional problems in youth using the Youth Self-Report measure at the time of substance abuse treatment intake and changes in scale scores during treatment participants were 36 adolescents (aged 13-18 years, eligible) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for opioid dependence. Participants received a 28-day outpatient, medication-assisted withdrawal with either buprenorphine, or clonidine, as part of a double-blind, double dummy comparison of these medications. All participants received a common behavioral intervention, composed of 3 individual counseling sessions per week, and incentives contingent on opioid-negative urine samples (collected 3 times/week) attendance and completion of weekly assessments. RESULTS: Although a markedly greater number of youth who received buprenorphine remained in treatment relative to those who received clonidine, youth who remained in treatment showed significant reductions during treatment on 2 Youth Self-Report grouping scales (internalizing problems and total problems) and 4 of the empirically based syndrome scales (somatic, social, attention, and thought). On Youth Self-Report competence and adaptive scales, no significant changes were observed. There was no evidence that changes in any scales differed across medication condition. CONCLUSIONS: Youth who were retained demonstrated substantive improvements in a number of clinically meaningful behavioral and emotional problems, irrespective of pharmacotherapy provided to them.

Computer-assisted HIV prevention for youth with substance use disorders.

We developed an interactive, customizable, Web-based program focused on the prevention of HIV, sexually transmitted infections, and hepatitis among youth. Results from a randomized, controlled trial with youth in treatment for substance use demonstrated that this Web-based tool, when provided as an adjunct to an educator-delivered prevention intervention, increased accurate prevention knowledge, increased intentions to carefully choose partners, and was perceived as significantly more useful relative to the educator-delivered intervention when provided alone. Results suggest this Web-based program may be effective and engaging and may increase the adoption of effective HIV and disease prevention science for youth. Limitations are discussed.

Methadone maintenance treatment for youth: experiences of clients, staff, and parents.

In order to better understand the components of effective treatment for the understudied population of opioid-dependent youth, separate focus groups were conducted in 2006 with clients, clinical staff, and clients' parents (total n = 22) at a novel methadone maintenance program for adolescents and young adults in suburban New York. Focus group sessions were audiotaped, transcribed, and analyzed for common themes. Clients, staff, and parents all reported that effective treatment for opioid addiction among young people is a long-term program, combines pharmacological and behavioral approaches, emphasizes a high degree of individual attention from staff, and incorporates clients' family members. The study's limitations were noted.

Differences in Treatment Outcomes between Prescription Opioid-Dependent and Heroin-Dependent Adolescents.

OBJECTIVE: : This study was designed to examine the extent to which heroin-dependent and prescription opioid-dependent adolescents experienced differential outcomes during a clinical trial designed to evaluate combined behavioral-pharmacological treatment. METHODS: : Participants were a volunteer sample of 36 adolescents who met DSM-IV criteria for opioid-dependence (ages 13-18 years eligible), 53% of which were heroin-dependent and 47% of which were dependent on prescription opioids used for nonmedical purposes. Participants received a 28-day, outpatient, medication-assisted withdrawal with the partial opioid agonist, buprenorphine, or the centrally active µ-adrenergic blocker, clonidine, along with behavioral counseling and incentives contingent on opioid abstinence. Heroin-dependent and prescription opioid-dependent participants were compared on baseline characteristics and treatment outcomes, which included retention, opioid abstinence, HIV risk behavior, opioid withdrawal, and medication effects. RESULTS: : Heroin-dependent and prescription opioid-dependent youth had similar characteristics at intake. Heroin-dependent youth had higher baseline rates of drug-related HIV risk behavior and greater opioid withdrawal before receiving medication during treatment; however, this same group showed markedly greater improvements on these domains during treatment relative to prescription opioid-dependent youth. Both participant groups showed comparable outcomes based on clinically meaningful measures of treatment retention and opioid abstinence. Both heroin-dependent and prescription opioid-dependent youth who received buprenorphine experienced markedly better treatment outcomes relative to those who received clonidine. CONCLUSIONS: : These results demonstrate that combined behavioral and buprenorphine treatment seems safe and efficacious in the treatment of both heroin-dependent and prescription opioid-dependent adolescents and provide novel information relating to treatment outcomes for these subgroups of opioid-dependent youth.

Effectiveness of a children's home and community-based services waiver program.

OBJECTIVE: Limited alternatives exist to residential treatment or hospitalization for children with the most serious emotional disturbances. Community-based interventions are intended to offer less restrictive and expensive options than traditional treatment. One such program is New York State's Home and Community-Based Services (HCBS) Waiver Program. METHODS: From 1996 to 2002, 169 children were enrolled in the Manhattan HCBS. All spent at least one month on the wait list prior to admission to the waiver program. We used our wait list as a control group (WLC), allowing for comparison of the HCBS intervention. RESULTS: Sample consisted of 169 children between the ages of five and eighteen. The ethnic composition was 46.8% Hispanic (N = 79), 47.9% African-American (N = 81), and 5.3% Caucasian (N = 9). Average stay was 12 months in the HCBS program and 3.5 months for the WLC. Only 30% of children in the WLC were maintained in the community, while 81% of children in the HCBS were similarly maintained (P < 0.001). Also, the rate of hospitalization for the HCBS group was significantly lower (3 versus 41%; P < 0.001). There was also a trend for the WLC group to have had substantially higher rates of removal by the Administration for Children's Services (New York City's protective service agency) (8.3 versus 1.8%) and to more frequently require residential treatment (13.0 versus 8.9%). CONCLUSIONS: It would seem that the HCBS program appears to be a clinically and cost-effective method of maintaining children in their community.

Preference for spirituality and twelve-step-oriented approaches among adolescents in a residential therapeutic community.

This study sought to determine which adolescents being treated for substance use in a residential Therapeutic Community (TC) would endorse spirituality and Twelve Step oriented approaches as part of their treatment. By identifying individual difference characteristics associated with preference for spirituality and Twelve Step oriented approaches, integrated substance abuse treatments can be targeted to appropriate subgroups of adolescents. A total of 181 adolescents completed a survey assessing their substance use and attitudes toward spirituality and Twelve Step oriented approaches that was similar to a survey completed by 322 adults in the same residential TC program. In the adolescent sample, three spirituality related characteristics: perceived connectedness to others, frequency of prayer, and spiritual orientation to life were associated with preference for both spirituality and twelve step oriented approaches being featured more in TC treatment. Adolescents were less likely than adults to express a preference that both approaches be featured more in TC treatment.

Bupropion SR for the treatment of substance-abusing outpatient adolescents with attention-deficit/hyperactivity disorder and mood disorders.

OBJECTIVE: Few studies exist on pharmacological interventions for adolescents with substance use disorders (SUD). To this end, we evaluated the response of bupropion hydrochloride sustained release (SR) in SUD adolescents with comorbid psychopathology (both attention-deficit/ hyperactivity disorder (ADHD) and a mood disorder). METHODS: Fourteen adolescent outpatients were treated naturalistically and followed openly for 6 months. Adolescents were rated using the Drug Use Screening Inventory--Revised (DUSI-R), ADHD Symptom Checklist, and the Hamilton Rating Scale for Depression (HAM-D). Clinical Global Impression (CGI) Scale scores were obtained for Substance Abuse, ADHD, Anxiety, and Depression. The ratings were completed at baseline, at month 3, and at the 6-month endpoint. Bupropion SR was initiated at 100 mg once-daily and titrated naturalistically to a maximum dose of 400 mg/day. RESULTS: Of the 14 subjects followed, 13 subjects completed 6 months of treatment. At the 6- month endpoint compared to baseline, treatment with bupropion was associated with clinical and significant reductions in DUSI scores (-39%; p < 0.05), ADHD symptom checklist (-43%; p < 0.001), HAM-D (-76%; p < or = 0.001); and reductions in the CGIs for ADHD (p < or = 0.001), depression (p < or = 0.001), and substance abuse (p < 0.05). The mean daily dose of bupropion SR was 315 mg (in divided doses). No significant adverse events were noted during the follow-up period. CONCLUSIONS: These naturalistic data suggest that bupropion is well tolerated and may be an effective medication for the treatment of substance abusing adolescents with comorbid mood disorders and ADHD.

The intoxicated child.

Psychiatric disorders and substance abuse occur frequently together, which leads to difficulty in assessment and treatment. An awareness of the prevalence and manifestations of psychiatric diagnoses is essential for the quality treatment of adolescents who abuse substances. The clinician should keep up-to-date on psychopharmacologic interventions [65, 83]. Frequently, the use of psychiatric medications, such as antidepressants, mood stabilizers, and psychostimulants, is beneficial. Care must be taken, however, to avoid potential interactions between the illicit drugs and the prescribed medications [151]. Use of groups such as Alcoholics Anonymous, Narcotics Anonymous, or "Double-Trouble" groups, which deal with mentally ill and chemical abusing or dual diagnosis issues, often can be a useful adjunct to treatment with a mental health professional [152-154]. Careful observation, history taking, and appropriate consultation result in better detection and treatment of comorbid medical and psychiatric disorders and the initial substance abuse problem.