Issue 110, Jun 2021
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Long-Acting Injectable (LAI) Antipsychotics vs Usual care on time to the first hospitalization in early-phase schizophrenia: A randomized clinical trial

Kane JM et al. JAMA Psychiatry 2020 July 15;77(12):1-8. doi:10.101001/jamapsychiatry.2020.

PMID: 32667636

Why is this study important?

Long-acting injectable antipsychotics (LAIs) can potentially reduce hospitalization risk by enhancing medication adherence but are rarely considered for early-phase schizophrenia treatment.

Background

To determine whether encouraging the use of an LAI compared with usual care delays the time to the first hospitalization in patients with early-phase schizophrenia.

Methods

The Prevention of Relapse in Schizophrenia (PRELAPSE) trial was cluster-randomized with a follow-up duration of 2 years. The study began in December 2014, was completed in March 2019, and was conducted in 39 mental health centers in the US. Site randomization assigned 19 clinics to encourage treatment with long-acting aripiprazole monohydrate (aripiprazole once-monthly [AOM] condition) and 20 to provide treatment as usual (clinician's choice [CC] condition). Participant eligibility criteria included (1) schizophrenia diagnosis confirmed by a structured clinical interview, (2) fewer than 5 years of lifetime antipsychotic use, and (3) age 18 to 35 years. The AOM sites identified 576 potentially eligible participants, of whom 234 (40.6%) enrolled; CC sites identified 685 potentially eligible participants, of whom 255 (37.2%) enrolled. There were no restrictions on treatment at CC sites (including using LAIs) or at AOM sites with the exception that aripiprazole monohydrate had to be prescribed within US Food and Drug Administration-approved guidelines. The primary outcome was time to first psychiatric hospitalization based on participant interviews every 2 months, the service use resource form administered every 4 months, and other sources (e.g., health records) as available.

Results

The 489 participants (368 men [75.3%]) had a mean (SD) age of 25.2 (4.2) years and 225 (46.0%) had 1 year or less lifetime antipsychotic use. Fifty-two AOM (22%) and 91 CC participants (36%) had at least 1 hospitalization. The mean survival time until the first hospitalization was 613.7 days for AOM participants and 530.6 days for CC participants. There was a statistically significant difference in time to first hospitalization favoring AOM. The number needed to treat to prevent 1 additional hospitalization was 7 participants treated with AOM compared with CC.

Conclusions

LAI antipsychotic use by patients with early-phase schizophrenia can significantly delay time to hospitalization, a personally and economically important outcome. Clinicians should more broadly consider LAI treatment for patients with early-phase illness.

Clinical Commentary

Long-acting injectable antipsychotics (LAIs) can potentially reduce hospitalization risk by enhancing medication adherence but are rarely considered for early-phase schizophrenia treatment. This is the first large-scale multi-site study of LAI in early-phase schizophrenia. The effects of LAIs might be still underestimated in this study because of high LAI use in the clinician's choice (CC) group. In the case of this trial, CC group was allowed to have patients on LAI and these clinics had good administrative and clinical support so the number of patients on LAIs may be higher than in most clinics. Clinics need a nurse to administer an LAI and support staff to run an injection clinic.

Clinical Insights

  • There was a 44% reduction in hospitalization in the AOM group which is an important finding for clinicians. Additionally, there was a 36% decrease in the total number of hospitalizations. The number needed to treat (NNT=7) to prevent hospitalization was 7.
  • In this study, LAIs were used much earlier in the course of illness compared to other such studies. Notably, 40% of the participants had less than two hospitalizations.
  • This study was conducted in community mental health centers where a lot of patients with schizophrenia are followed. This is a practical clinical trial in my opinion.

Summary

In my professional opinion Long-Acting Injectable (LAI) medications should be used early in the course of the schizophrenia rather than later after multiple relapses, when downward drift has occurred, and significant gray matter has been lost due to recurrent psychotic episodes. This would hopefully promote functional reintegration into the community.

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Psychotic relapse in individuals with schizophrenia spectrum disorders on long-acting injectable (LAI) medications: Meta-analysis

Rubio JM et al. Lancet Psychiatry. 2020. Sept 7 (9):749-761. doi:10.1016/S2215-0366(20)30264-9.

PMID:32828165

Background

Relapses are common in individuals with schizophrenia spectrum disorders, which increase the risk of morbidity and mortality. Because non-adherence to antipsychotic maintenance treatment could affect more than half of patients, psychosis relapse can often be confounded by unnoticed treatment interruption. This study aimed to generate reliable estimates of incidence and predictors of relapse during assured antipsychotic treatment.

Methods

A systematic review and individual participant data (IPD) meta-analysis of clinical trials of LAIs for psychosis relapse-prevention, following IPD-PRISMA guidelines, were done. Datasets were identified by searching relevant repositories from inception to Aug 1, 2019. Each LAI group was reanalyzed as a separate cohort, further identifying sub-cohorts of individuals with and without prospectively determined symptom remission (PSR).

Results

19 treatment cohorts consisting of 5130 individuals (2938 with PSR, 2192 without PSR), with 3959·53 observed participant-years, were meta-analyzed. The pooled incidence of relapse was 22·97 per 100 participant-years (14·76 per 100 participant-years for the PSR sub-cohort, 31·51 per 100 participant-years for the non-PSR sub-cohort). Relapse was associated with functional decline. The strongest predictor of relapse was tardive dyskinesia at treatment onset.

Conclusions

Despite the established efficacy of antipsychotics in preventing relapse, these data indicate that these drugs might not prevent subsequent exacerbations for a proportion of individuals whose illness is stabilized on continuous antipsychotic treatment. Tardive dyskinesia in particular might have pathophysiological implications for relapse.

Clinical Commentary

We do know that lack of medication adherence occurs in over 50% of patients with psychosis. It is difficult to disentangle relapse on medication from relapse due to medication nonadherence. There is a poverty of data on relapse in individuals who have been adherent to medications. Hence this study is important using LAI data as medication adherence was confirmed.

The use of precise participant-level inclusion criteria (e.g., minimum time after injection to assure therapeutic antipsychotic plasma concentration and prospective demonstration of symptom remission) and a harmonized analytic approach across datasets, this meta-analysis generated reliable estimates of relapse risk during antipsychotic exposure.

There is a trade-off between data quality and representativeness between study populations used for comparative effectiveness research.

Clinical insights

  • 20 percent of individuals relapsed over one year. Clinicians should expect that patients with symptoms in remission and confirmed medication adherence will relapse. Hence clinicians should remain vigilant.
  • Red flags for relapse include substance use disorder and tardive dyskinesia. The Bonferroni correction when applied to these two issues resulted in a loss of statistical significance. However, the effect size was large enough that we should pay attention to these two issues.
  • A certain percentage of patients in the US might have relapse due to less availability of family support and counseling.
  • Relapse is associated with a significant worsening in overall functioning.
  • LAIs should be used to rule out treatment-resistant schizophrenia.

Summary

In my professional opinion, this study validates our clinical experience that relapse occurs in a sizable number of patients with schizophrenia spectrum disorders despite the confirmation of medication adherence via LAI administration. As there is no clear known mechanism for relapse in this context, we should be vigilant for early signs of relapse especially when patients are stressed have social, psychological issues, and exacerbation of medical conditions. There is a suggestion that the presence of tardive dyskinesia and substance use disorder may be red flags.

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Time to rehospitalization in patients with bipolar mania discharged on long-acting injectable (LAI) or oral antipsychotics (OAPs)

Lin CH et al.  J Affect Disord. 2021 Jan;15;279: 292-298.doi: 10.1016/j.jad.2020.1023. Epub 2020 Oct 14.

PMID:33096327v

Background

This study aimed to analyze the time to rehospitalization in patients with bipolar mania discharged on LAIs or OAPs. Additionally, temporal trends in LAI prescription were investigated.

Methods

Patients with bipolar mania discharged from the study hospital on antipsychotics between 2006 and 2018 were included. Survival analysis was used to compare time to rehospitalization within one year of discharge between patients discharged on LAIs and OAPs, and between FGA-LAIs (first-generation antipsychotic) and SGA-LAIs (second-generation antipsychotics).

Results

The LAI group (n = 224) had a significantly lower rehospitalization rate and a significantly longer time to rehospitalization than the OAP group (n = 3836). Rehospitalization rate and time to rehospitalization were not significantly different between patients discharged on FGA-LAIs or SGA-LAIs. The LAI prescription rate grew significantly from 2.20% in 2006 to 11.58% in 2018. The prescription rate of SGA-LAIs also increased significantly, but not the prescription rate of FGA-LAIs.

Conclusions

LAIs were significantly superior to OAPs in reducing rehospitalization risk. However, SGA-LAIs were comparable with FGA-LAIs in reducing rehospitalization risk. Use of LAIs increased significantly in discharged patients with bipolar disorder during the study period, especially SGA-LAIs.

Clinical Commentary

The treatment allocation is not randomized in this retrospective study. Furthermore, various clinical characteristics were unavailable for analysis, such as symptom severity and functional impairment. Being a hospital-based study only inpatients were included. This was an observational study and hence provides data on the real-world effectiveness of treatments carried out in natural treatment settings. There is good statistical power (sample size N=4000) which reduces type II error.

LAIs used in this study: haloperidol decanoate, flupenthixol decanoate (not available in USA), risperidone-LAI, and paliperidone LAI.

Clinical Insights

  • LAIs significantly reduced the rehospitalization rates and increased time to rehospitalization compared to the OAPs.
  • There was no difference in the FGA-LAIs versus the SGA-LAIs concerning the efficacy.
  • The SGA-LAIs had a lower discontinuation rate.
  • The prescription rate of SGA-LAIs increased significantly but not that of the FGA-LAIs.
  • Females with a greater number of previous hospitalizations, an earlier age of onset, and extended hospital stay were more likely to receive an LAI at discharge.
  • Aripiprazole once-monthly (AOM) is the only once-monthly SGA FDA approved for the maintenance treatment of bipolar disorder. The risperidone LAI approved for bipolar disorder needs to be administered every two weeks.

Summary

In my opinion, this study points to the need for using LAIs for the treatment of bipolar mania to prevent recurrence and rehospitalization. The LAI could be the core medication used in a three-four medication regimen as is typical for the management of this illness. I would suggest using the SGA-LAIs as they have a better tolerability profile. LAIs are still underutilized in this group of patients.

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Long-Acting Injectable Antipsychotics (LAIs) for the prevention of relapse in bipolar disorder: Review and meta-analysis of Randomized Controlled Trials (RCTs)

Kishi T et al. Int J Neuropsychopharmacol.  2016 Sep 21;19 (9) doi: 10.1093/ijnp/pyw038. Print 2016 Sep.

PMID:27207910

Background

This meta-analysis of RCTs aimed to examine the advantages of long-acting injectable antipsychotics over placebo or oral medications regarding efficacy and safety for patients with bipolar disorder.

Methods

Two categorical meta-analyses of randomized controlled trials were performed to compare study-defined relapse rate (primary), discontinuation rates, and individual adverse events: (1) risperidone-long-acting injectable vs placebo, and (2) long-acting injectable antipsychotics vs oral medications.

Results

The study identified 7 randomized controlled trials (n=1016; long-acting injectable antipsychotics [flupenthixol (1 randomized controlled trial) and risperidone (6 randomized controlled trials) =449]; oral medications [mood stabilizers, antidepressants, antipsychotics, or any combination of these agents=283]; and placebo=284). Risperidone-long-acting injectable antipsychotic was superior to placebo for study-defined relapse rate, relapse of manic symptoms, and all-cause discontinuation. Risperidone-long-acting injectable was associated with a higher incidence of prolactin-related adverse events and weight gain than placebo. The pooled long-acting injectable antipsychotics did not outperform oral medications regarding primary outcome but with significant heterogeneity (I2=74%). Sensitivity analysis, including only studies with rapid cycling or high frequency of relapse patients, revealed that long-acting injectable antipsychotics were superior compared to oral medications. However, the comparators in this sensitivity analysis did not include second-generation antipsychotic monotherapy. In sensitivity analysis, including only studies with second-generation antipsychotic monotherapy as the comparator, long-acting injectable antipsychotics did not outperform second-generation antipsychotic monotherapy. Risperidone-long-acting injectable was also associated with a higher incidence of prolactin-related adverse events than oral medications.

Conclusions

LAIs antipsychotics are beneficial for relapse prevention in patients with rapid cycling. Furthermore, randomized controlled trials comparing long-acting injectable antipsychotics and oral second-generation antipsychotic using larger samples of rapid cycling patients are warranted.

Clinical Commentary

This is the first meta-analyses of RCT’s (seven studies N=1016 patients) examining the efficacy of LAI-antipsychotics in bipolar disorder compared with oral medications and placebo. The limitations of this study include the fact that although there were differences in the sample size of the studies included, the weighing of each was similar. There was significant heterogeneity concerning the primary outcome in the meta-analysis of LAI-APs vs oral medications. In this meta-analysis of seven studies, a funnel plot was used to explore potential publication bias, usually done for 10 or more studies.

This study included flupenthixol decanoate (not available in USA) and risperidone-LAI.

Clinical insights

  • Risperidone LAI had a significant benefit in preventing relapse of any mood symptoms including manic symptoms. It was not effective for depressive symptoms.
  • LAIs were superior to oral antipsychotics when considering studies of rapid cycling or patients with a high frequency of a relapse.
  • Risperidone-LAI was associated with a higher incidence of prolactin-related adverse events and weight gain.

Summary

In my opinion, SGA-LAI antipsychotics should be used for treating bipolar disorder as lack of medication adherence and substance use disorder (comorbid condition) are common in this group of patients. Since the publication of this meta-analysis, the field has advanced with the FDA approval of aripiprazole once-monthly injection (AOM).

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COVID-19 and Posttraumatic Stress Disorder: What is the relationship?

Horn M et al. J Clin Psychiatry. 2020 Dec 8;82(1):20m13641. doi: 10.4088/JCP.20m13641.

PMID: 33296149

Background

This study aimed to assess the prevalence of and risk factors for posttraumatic stress disorder (PTSD) in patients with COVID-19.

Methods

This cohort study was conducted between March and May 2020 in France, which included all patients with laboratory-confirmed COVID-19. Psychological distress symptoms were measured 3 weeks after onset of COVID-19 symptoms using the Impact of Event Scale-6 items (IES-6). The evaluation of PTSD symptoms using the PTSD Checklist for DSM-5 (PCL-5) took place 1 month later. Statistical analyses were conducted to assess the relationship between PCL-5 scores and the demographic and health variables as well as relative contribution to PTSD symptoms

Results

180 patients were included in this study of which 138 completed both evaluations. Among the 180 patients, 70.4% patients required hospitalization, and 30.7% were admitted to the intensive care unit. The prevalence of PTSD was 6.5%, and the predictive factors of PTSD included psychological distress at the onset of the illness and a stay in an intensive care unit.

Conclusions

The prevalence of PTSD in patients with COVID-19 is not as high as that reported among patients during previous epidemics. Initial psychological responses were predictive of a PTSD diagnosis, even though most patients showing acute psychological distress (33.5% of the sample) improved in the following weeks. PTSD symptoms also increased following a stay in an intensive care unit. Future studies should assess the long-term consequences of COVID-19 on patients' mental health.

Clinical Commentary

As the pandemic continues, we learn more about the neuropsychiatric symptoms related to COVID-19. The studies have also been refined as we go from cross-sectional data to studies such as this one, which had two-time points for assessment one month apart. This study included consecutive patients with lab-confirmed COVI-19 while the previous ones had selection bias including only hospitalized patients. The limitations included 23% of the patients who did not respond to the second assessment. The responded group had more hospitalizations and more ICU stays so the actual PTSD prevalence may be lower if this selection bias was avoided. There was a significant amount of health care workers (HCW) in the nonrespondent group which suggests that HCWs are reluctant to address their psychological problems.

Clinical insights

  • This study suggests that the PTSD prevalence based on criteria such as lab confirmation of COVID-19 and not using an exclusively hospital-based sample is lower at 6.5%. It is important to note that this rate is consistent with following natural disasters (5%-10%).
  • The study revealed psychological distress and ICU stays to be important risk factors for PTSD symptoms later.
  • HCW need attention as they often are reluctant to address their psychological issues.

Summary

In my professional opinion patients recovering from COVI-19, especially those with psychological distress and ICU stays, should be monitored for PTSD and treatment recommended. Special attention should be paid to health care workers, to help them address these issues. This will help them be more effective in doing their job.

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Sanjay Gupta, MD
Clinical Professor of Psychiatry, SUNY Buffalo

GME Research Review is a monthly newsletter edited by Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo. Dr. Gupta selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Gupta the citation at [email protected]