Older adults with major depression have a poorer prognosis, are less responsive to treatment, and show a significant functional decline compared with younger adults. This highlights the unmet need for effective treatments in this population.

This double-blind study randomized patients with treatment-resistant depression ages ≥ 65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or placebo nasal spray and new oral antidepressant (antidepressant/placebo). The primary endpoint was change in the Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to day 28. The preplanned analysis was done by age (65-74 versus ≥ 75 years). The post-hoc analyses included age at depression onset. These patients had failed 2 or more antidepressants in the current episode. The Mini-Mental Status Examination (MMSE) score was ≥ 25 and ≥ 22 for those with less than the equivalent of a high-school education.  All patients received one of four open-label antidepressants (duloxetine, escitalopram, sertraline, or venlafaxine XR) in addition to the nasal spray (esketamine or placebo). 

Of the 308 patients screened 138 were randomized. The esketamine/antidepressant group did not achieve statistical significance on the primary endpoint (MADRS) p=0.059. Additional endpoints revealed response rates were 27% in the esketamine /antidepressant and 13.3% in the antidepressant/placebo group. The number needed to treat (NNT) was 8 on day 28. The remission rates were 17.5% in the esketamine/antidepressant versus 6.7% in the antidepressant/placebo group. The NNT for remission was 10. There were statistically significant differences by age for the MADRS score decline by day 28 for patients in the 65-74 years age group (p=0.017) compared with those greater ≥ 75 years of age (p=0.930). Age of the patients at depression onset showed greater improvement in patients with an earlier age of depression onset (<55 years of age p=0.006; versus those ≥ 55 years of age p=0.407). Treatment-emergent adverse events occurred in 71% of patients receiving esketamine/antidepressant versus 60 % of individuals receiving antidepressant/placebo. Most TEAE’s were mild or moderate and resolved on the nasal dosing day.

Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (< 55 years).

The ability to use NMDA antagonists to treat depression has brought a significant amount of excitement to the field. Esketamine is the S-enantiomer of ketamine and has a three to four-fold affinity for the NMDA receptor than the R enantiomer. Esketamine has the FDA approval for treating TRD in adults under the Risk Evaluation and Mitigation Strategy (REMS) which includes a two-hour monitoring post-administration. The site administering esketamine as well as the dispensing pharmacy needs to be REMS certified. Esketamine is stored at the location where it is administered and not given to the patient to take home. It is a schedule III drug.

With regard to the primary endpoint, this was a negative study. However, the findings favored esketamine in the 65-74 years age group and those with onset of depression under the age of 55 years. This study suggests that the age of the individual receiving treatment does make a difference as does the age of onset of depression.

This study also suggests that TEAE’s occur in a significant number of the patients but resolve by the two-hour monitoring period. Overall esketamine is well tolerated but the REMS program is necessary for safety monitoring and preventing abuse of the drug.

In summary:

The data for TRDOA is extremely limited and more studies with a larger sample size are needed to assess the role of esketamine/antidepressant in population. The optimal induction, optimization, and maintenance dosing needs to be established along with treatment duration. Assessments unique to this group such as physical function and cognition need further investigation. Many dilemmas exist such as should these individuals be treated by established treatments such as ECT. Now that interventional psychiatry is playing an important role in the treatment of TRDOA an algorithm needs to be established to bring uniformity to the field. Using the Sequenced Treatment Alternatives to Relieve Depression (STAR D) algorithm as a guide, a new algorithm that includes medications, as well as interventional psychiatry, needs to be established. 

Depression in older adults is tough to treat and frequently accompanied by cognitive complaints that increase the risk of dementia. There is an unmet need for new strategies to treat depression and impaired cognition.

This study included a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram +memantine (ESC/MEM) compared to escitalopram +placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints. The patients met the criteria for mild cognitive impairment (MCI). The primary outcome was the change in depression as assessed by the Hamilton Depression Rating Scale (HAM-D) post-treatment at six months. The Montgomery-Asberg Depression Rating Scale (MADRS) was used as a secondary measure of depressive symptoms. Remission was defined as HAM-D ≤ 6; naturalistic follow-up continued until 12 months. The cognition was assessed using the Clinical Dementia Rating Scale as well as an interview with a study psychiatrist. Patients with MMSE ≤ 23 were excluded.

The combination of memantine and escitalopram was well tolerated and was noted to be as effective as the combination of escitalopram and placebo in improving depression using the HAM-D. This combination was significantly more effective than escitalopram and placebo in improving cognitive outcomes at 12 months. In the future biomarkers of aging should be studied with regard to treatment response.

Depression and cognitive impairment are known to be risk factors for dementia and hence the importance of this study. Older adults with MCI and comorbid depression have a 28% higher likelihood of developing dementia. Geriatric depression affects 1%-5% of the general population and 10%-15% of the primary care patients. It is interesting to note that the ESC/MEM combination did not differentiate from MEM/PBO group on the HAMD (primary efficacy measure) but did differentiate on the MADRS which was the secondary efficacy measure for depression. The ESC/MEM combination was statistically significantly ahead of the MEM/PBO group with regard to improving cognitive outcomes.

The HAMD is weighted towards physical symptoms while the MADRS has a focus on psychological symptoms which might be the issue in this study. In addition, this sample might not be severe enough to see changes in HAMD (mean HAMD=17). In most antidepressant trials HAMD > 20 is the criteria for inclusion into the study. The authors do not state the reason for using the HAMD as the primary efficacy measure for depression in this study.

It is also important to note that the MADRS is more commonly used in outpatient studies while the HAMD was used in inpatients studies in the past with a sicker population. Most trials involving the HAMD were done with tricyclic antidepressants.

Summary: In my professional opinion based on these findings ESC/MEM combination does have a clinical role in older adults with MDD and subjective memory complaints. This sample consists of patients with MMSE ≥ 23 and subjective memory complaints but no functional impairment which is suggestive of MCI. The data are not consistent with improvement in depression but were more robust with regard to improvement in delayed recall and executive functioning. Both these cognitive domains are important for day to day activities for an older adult to function and maintain independence. Please keep in mind that these data apply to patients with a minimum MMSE of 23. The reason for using the MMSE criteria of 23 and above (average MMSE score in the trial was 27.9) was unclear. Additionally, I would suggest appropriate exercise, attention to dietary intake (Mediterranean diet), and excellent control of comorbid medical conditions such as cardiovascular and cerebrovascular disease, hypertension, diabetes, and lipid disorders.

Patients with opioid use disorder are commonly prescribed BNZs while also receiving medication-assisted treatment (MAT) with buprenorphine. It is believed that the co-prescription of the BNZ may increase retention in the program by reducing buprenorphine discontinuation and thus preventing relapse to illicit opioid use. This study was designed to assess the relationship between BNZ prescription and fatal opioid overdose, non-fatal opioid overdose, all-cause mortality, and buprenorphine discontinuation (30-day gap without another prescription following the end date of the previous prescription). Hazard ratios (HR) were calculated to test the association between receipt of BNZs and all outcomes restricted to periods during buprenorphine treatment.

This retrospective cohort study used five individually linked data sets from Massachusetts, United States government agencies. The participants included 63,389 Massachusetts residents aged 18 years and older who received buprenorphine treatment between January 2012 and December 2015. Those who filled BNZ prescription during buprenorphine treatment was the independent variable. The primary outcome was time to fatal opioid overdose. The secondary outcomes were time to non-fatal opioid overdose, all-cause mortality and buprenorphine discontinuation.

This study revealed that a quarter of the individuals receiving buprenorphine filled at least one BNZ prescription. 31% of the opioid overdose deaths occurred when individuals received BNZ during buprenorphine treatment. There was an increased risk of fatal opioid overdose when BNZs were prescribed during buprenorphine treatment (HR=2.92), non-fatal opioid overdose (HR=2.05), all mortality adjusted (HR =1.90), and a decreased risk of buprenorphine discontinuation (HR=.87).

BNZ prescription appears to be associated with increased risk of opioid overdose and all-cause mortality and a decreased risk of buprenorphine discontinuation amongst patients receiving buprenorphine.

This is a retrospective study and has many of the limitations of such a study. The sample size was large, being a strength of this study. Opioid use disorder has significant morbidity and mortality and hence caution is suggested in withholding buprenorphine.

There are significant dilemmas for the psychiatrist/person prescribing the BNZ when a patient is on buprenorphine therapy in lieu of the FDA warning. There is a tendency for the patient to abuse the BNZ or divert the prescription for sale. This should be monitored by urine toxicology. If other illegal substances continue to be present in the urine the issue needs to be addressed at a higher level of care. 

When tapering the BNZ, caution should be exercised and the taper of the BNZ done extremely slowly to avoid treatment drop out.

In summary:  We should be using safer medications and smaller prescription amounts. The anxiety symptoms and insomnia should be treated with safer medications and psychotherapy or a combination of both. Psychiatrists can use the help of the physician prescribing the buprenorphine to get the patient to either agree to a dose reduction trial of the BNZ or try alternative anti-anxiety medications other than BNZ. In some instances, it may be best for the physician prescribing the buprenorphine to also prescribe the BNZ.

The long-term benefits of methylphenidate treatment in children and adolescents with ADHD as used in clinical practice are unclear. This study aimed to assess whether methylphenidate remains beneficial after two years of use.  

This was a randomized placebo-controlled discontinuation study conducted in the Netherlands. The sample included N=94 children and adolescents (ages 8-18 years) who had undergone usual care with methylphenidate for more than two years. The subjects were randomized to seven weeks of extended-release methylphenidate (36 or 54 mg/day) or gradual withdrawal over three weeks to four weeks of placebo. The primary outcome measure being the investigator-rated ADHD rating scale (ADHD-RS). The Clinical Global Impression Scale (CGI) and the Connors' Teacher Rating Scale-Revised (CTRS-R:S) were secondary outcome measures. 

There were significant group differences at seven weeks in favor of the group continuing methylphenidate treatment. This was reflected in the primary outcome measure (ADHD-RS) as well as the secondary outcome measures such as the CGI which indicated a 40% worsening of the discontinuation group and a 16 % worsening of the continuation group.

Continued treatment with methylphenidate remains effective with long-term use. It is important to know that some individuals could be withdrawn from methylphenidate without deterioration. This study supports the guideline recommendations that patients be periodically assessed to determine if there is a continued need for methylphenidate therapy.

Stimulant medications have been used to treat ADHD symptoms for eight decades. While short-term efficacy has been established there are no long-term efficacy studies. The Multimodality treatment (MTA) of ADHD study could not address the question of the efficacy of stimulants after one year. This study suggests that there are benefits to long-term continuation of methylphenidate in ADHD patients. The effect size, however, was small (Cohen’s d 0.284). The effect size of the teacher ratings (Cohen’s d=-0.52) was substantially larger than the investigator ratings. I attribute this to the fact that the teachers have a longer observation time frame and also due to the higher cognitive demands in school. This study also suggests that periodically, patients should be reassessed for the need for continuation treatment.

This study was limited by a small sample size and possible selection bias. As the study involved informed consent for participation, a large number of participants declined to participate as there was a discontinuation arm and they indicated “we know methylphenidate works as we have stopped it before”. It appeared that some parents were ahead of the game and had already tried stopping the medication for the kids of their own accord. This suggests that those in the study may have not had a great response and hence were open to trying discontinuation. This study was also limited by two dosages of extended-release methylphenidate 36mg/day and 54 mg/day.

The age of the participants also played a role as the effect of continuing methylphenidate therapy was superior in the younger participants. There is a need for studies with a larger sample size.

In summary:

In my opinion, based on this study ADHD patients at a two-year time frame should be evaluated for the need to continue methylphenidate on an annual basis. This is especially important in older teenagers as there is a chance they may function well off medication. I would also suggest that the medication be restarted at the first signs of recurrence. There is data to suggest that ADHD patients on medication are more likely to drive safely, less likely to get into substance abuse, and criminal offenses. In my professional opinion stimulants should be prescribed long-term as there are benefits to this strategy.  

Violent behavior is uncommon among patients with schizophrenia. This study aimed to assess the correlates of violence in schizophrenia to better guide risk assessment and clinical care.

This study analyzed data from N=1435 individuals enrolled in the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) which had an 18-month follow-up. The dependent variable was self-reported injurious and non-injurious violence during follow -up. The independent variables assessed at study entry were participants' recent injurious and non-injurious violence, demographic and background variables, childhood risk factors, clinical condition, current circumstances, and recent contact with hospitals and prisons. Hazard ratios were calculated for all participants and separately for participants with no injurious violence at study entry.

N=77 participants (5.4%) reported engaging in injurious violence during follow-up, and 119 (8.3%) reported engaging exclusively in noninjurious violence.  The analyzes revealed baseline injurious violence (HR=4.02), recent violent victimization (HR=3.52), the severity of drug use (HR=2.93), baseline noninjurious violence (HR=2.72) childhood sexual abuse (HR=1.85) and medication nonadherence (HR=1.39) were associated with future injurious violence. In the case of participants with no history of baseline injurious violence at study entry, baseline noninjurious violence was the strongest predictor (HR=3.02).

This is the first longitudinal study of the predictors of violence in a large cohort of patients with schizophrenia followed over 18 months. The results revealed the strong effects of baseline injurious violence and recent violent victimization on future injurious violent behavior. Amongst the clinical variables, poor medication adherence but not baseline symptoms of psychosis and depression specifically predicted injurious violence. Treatment strategies to reduce risk should emphasize medication adherence.

The violence in schizophrenia is rare and over publicized. 95% of patients are not violent. Hence the findings of this study are important to know as it predicts the increased chances of violence in an extremely small subset of patients. In previous longitudinal studies, negative symptoms and positive symptoms have been linked to violence which was not the finding in this study. Other symptoms such as delusions have also not been linked specifically to violence. All these symptoms suggest clinical deterioration of the patient.

The limitations of this study are

1. This study relied on self-reported data to identify violent acts. The authors note that self- report used prospectively is a more sensitive measure of violence than official reports and is similar in sensitivity to using multiple sources of information. Information from collateral sources might have added validity to the dependent variable (violence).
2. Clinicians are usually concerned about short-term risk. In this case, the maximum period of follow-up was 18 months. To assess the 6-month risk a larger sample size would be needed.
3.  Although, the violence was measured throughout the study period, the independent variables were measured only at baseline. These variables, for example PTSD symptoms and substance abuse, might reduce over time reducing violence. Similarly, some individuals might find independent accommodations or work. All of these factors’ lower violence. 

We should not be distracted from the overall picture of violence associated with the disease state of schizophrenia being extremely low. 19 out of 20 individuals in this unstable sample do not describe any violence during the follow-up period.

In Summary:  As a clinician, I would still exercise caution and not be under a false sense of complacency. Even though rare, when violence occurs in schizophrenia it can be gruesome. There are examples when a psychiatrist or other mental health providers are brutally beaten or even murdered without a warning. I suggest taking clinical tips from this study such as prior history of injurious violence (past predicts the future), recent violent victimization (often not thought about), and childhood sexual abuse (often not considered clinically for violence assessment in schizophrenia) are important factors. Medication nonadherence is always a common problem that can now be addressed by long-acting injectable antipsychotics.

I also stress that one should not see patients in an office alone without another staff member present so help is available immediately as violence erupts suddenly.