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Issue 86, Jun 2019
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SSRIs and peripheral inflammatory markers: Relationship of therapeutic effects to their anti-inflammatory properties.

Wang L et al. Brain Behav Immun. 2019 Feb 21. piiS0889-1591(18) 30464-1.doi: 10.1016/j.bbi.2019.02.021. [Epub ahead of print] PMID: 30797959

Background

There has been an increased interest in the study of the role of inflammation in various ailments such as major depressive disorder (MDD) and heart disease. Selective serotonin reuptake inhibitors (SSRIs) affect the peripheral inflammatory markers. This study aimed to address this very issue by investigating the effects of SSRIs on a range of inflammatory markers in MDD patients.

Methods

A systematic search of databases such as PubMed, Web of Science, Embase, and Cochrane was conducted for studies published prior to November 2018. Studies were included if they used SSRI monotherapy and measured peripheral levels of interleukin, tumor necrosis factor, and interferon before and after treatment in MDD patients. Poor quality studies were excluded. Effect sizes were calculated using bias-corrected standardized mean differences between pre-and post -treatment.

Results

827 MDD patients were included in the meta-analysis from 22 eligible studies. There were fifteen studies for IL-6; eleven for TNF-α; eight for IL-10; seven for IL-1β; six for IL-4; five for IL-2; and four for IFN-y. The pooled effect estimate indicates that SSRI treatment decreased levels of pro-inflammatory markers IL-6, TNF-α, IL-1β, and anti-inflammatory marker IL-10.  There were no significant treatment effects on levels of IL-2, IL-4, or IFN-y. There was a high level of heterogeneity between studies.

Conclusions

This study suggests that SSRIs have moderate immunomodulating effects in the course of treatment of MDD. This also indicates that anti-inflammatory properties of SSRIs may be responsible for a portion of their therapeutic effect. These findings are limited by the high level of heterogeneity across studies suggesting the need for prospective focused randomized clinical trials.

Clinical Commentary

There is emerging evidence regarding the interaction between the brain and the immune system. Dysregulations of the immune system have been reported in mood disorders. There is low -grade inflammation and cell mediated immune activation. This led to the proposed ‘cytokine hypothesis of mood disorders.’

  • This is the most extensive review of the effect of SSRIs on the peripheral inflammatory markers in patients with major depression. It provides an excellent update since the previous studies were conducted several years ago.
  • The most consistent and robust effect size was for IL-6 (15 out 22 studies). This response was linked to drug dosage and study design. It was not linked to factors such as age, gender, and study duration.
  • In the case of TNF- α there was a gender link with females having a greater reduction. This was thought to be associated with more females responding to SSRIs.
  • The limitations include the use of meta-analyses and the average study size was N=38. Larger and more focused RCT’s are needed before the measurement of these markers can be ready for prime time.
  • In summary there is strong evidence for a moderate immunomodulating effects of SSRIs in patients with major depression but larger prospective trials need to be conducted to validate these findings.
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Late-onset ADHD ages 10-25: What are the nuances?

Sibley MH et al. Am J Psychiatry. 2018 Feb 1;175(2):140-149. D oi:10.1176/appi. ajp2017.17030298. [Epub ahead of print] PMID:29050505

Background

There has been a surge in the diagnosis and treatment of late-onset ADHD resulting in several fold increase in the use of stimulants in mental health patients. These individuals are without childhood ADHD. They often screen positive by filling out screening questionnaires. These instruments have significant limitations as other causes of these symptoms are not looked into. There is often also a failure to get a complete psychiatric history. In this study the authors assess these limitations by examining psychiatric assessments administered longitudinally to the local normative comparison group of the Multimodal Treatment Study of ADHD.

Methods

Individuals without childhood ADHD (N=239) were administered eight assessments from comparison baseline (mean age=9-89 years) to young adulthood (mean age=24.4 years). The diagnostic procedures utilized parent, teacher, and self-reports of ADHD symptoms, impairment, substance use, and other mental disorders, with consideration of symptom context and timing.

Results

95% of the individuals who screened positive on the symptom checklists were excluded from late onset ADHD diagnosis. Heavy substance use was the most common reason for impairing late-onset ADHD symptoms. Most late onset cases displayed onset in adolescence and an adolescence limited presentation. This study did not find any evidence for adult-onset ADHD independent of a complex psychiatric history.

Conclusions

False late onset ADHD cases are common without careful assessment. More commonly symptoms represent cognitive fluctuations, a comorbid disorder, or cognitive effects of substance use.

Clinical Commentary

 There has been a significant increase in diagnosis of late-onset ADHD. This is partially due to increased awareness, as well as pharmaceutical advertising when branded agents are available. This study has important findings that should keep us clinicians grounded.

  • Patients come to us indicating they can’t focus or have attentional difficulties believing they have ADHD. They most commonly are requesting “Adderall” (dextroamphetamine/amphetamine) and commonly say it helped a family member/friend. Often primary care physicians have patients on “Adderall” and send them to us as regulations with controlled medications are tightening up. These patients often expect the stimulant will be continued. In the real-world patients may be also getting prescription pain killers or benzodiazepines. These become problematic issues for mental health providers as the patient is still not better but does not want to stop the stimulant. This group of patients would screen strongly positive on ADHD checklists.
  • This study highlights, that a high percentage of these individuals have attentional impairment due to substance abuse.
  • Clinicians should also note that other comorbid mental health conditions affect the ability to concentrate. This is especially true with mood disorders (both unipolar and bipolar) where even after mood symptoms may be in remission, concentration is not improved and the patient thinks they have late-onset ADHD.
  • There are truly some individuals with late-onset ADHD, however this number is extremely low.
  • We the clinicians should do a thorough longitudinal assessment in addition to the ADHD questionnaire to look for other psychiatric disorders. These include mood disorder and substance abuse. Hence a urine drug screen (UDS) is important part of the work up. There is important information from a negative urine screen if the patient is being prescribed a stimulant.
  • In summary please look for other psychiatric disorders most commonly partially/untreated mood disorders and substance abuse disorder in those presenting with late-onset ADHD. We should also not deny the appropriate treatment to the late-onset ADHD patient once a through assessment is done and a diagnosis is made or confirmed.
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Opioid dependence: What works for long-term abstinence?

Weiss RD. et al. J Clin Psychiatry. 2019 Mar 26;80 (2) pii18m12292. doi:10.4088/JCP.18m12292. PMID:30920187

Background

Opioid dependence has been declared a national emergency. There has been a dramatic surge in the nonmedical use of opioid analgesics in 2016, more than 12 times the number of those using heroin in the same time period. These individuals have elevated risk of multiple comorbidities including additional substance use disorders and other psychiatric disorders. There is a paucity of outcome data on abstinence after treatment of prescription opioid dependence. Most previous studies have included heroin dependent subjects, and hence there is less information on the outcomes of prescription opioid dependence. This study investigated correlates of opioid abstinence over time after completion of treatment of prescription opioid dependence.

Methods

This multi-site US study was conducted as part of the Prescription Opioid Addiction Treatment Study (POATS). Buprenorphine-naloxone treatment and different intensities of counseling to treat prescription opioid dependence (DSM-IV) were examined as part of this study. This study (N=375) covered the time frame, March 2009-January 2013. Telephone interviews were conducted at 18, 30, and 42 months after treatment entry. Statistical analysis was conducted to examine the association between the treatment modality and opioid abstinence rates at follow-up assessments.

Results

At the three follow-up visits approximately 50% participants reported engaging in current substance abuse treatment. Buprenorphine maintenance (27%-35%) and mutual group attendance (27%-30%) were the most common treatments, followed by outpatient counseling (18%-23%) and methadone maintenance (4%). Opioid agonist treatment showed the strongest association with current opioid abstinence followed by mutual-help group attendance. Outpatient counseling did not show any significant association with abstinence.

Conclusions

Opioid agonist treatment was most strongly associated with opioid abstinence over time, Mutual-help groups were independently associated with opioid abstinence. This study suggests that clinicians should recommend both opioid agonist treatment as well as mutual-help group attendance.

Clinical Commentary

In the Prescription Opioid Addiction Treatment Study participants receiving opioid agonist treatment in the 3.5 years naturalistic follow-up phase of the trial reported significantly higher rates of abstinence from opioids than those not getting treatment. In addition to this finding mutual-help group attendance was also associated with abstinence. These are important findings coming from a study with a large sample size.

  •  These findings underscore the importance of aggressive medication assisted treatment (MAT) for prescription opioid dependence.
  • Clinicians should continue to recommend the mutual-help (self-help) group attendance as there is evidence that it supports abstinence. I would suggest recommending MAT in conjunction with mutual-help groups like narcotics anonymous.
  • As clinicians we should move to the disease model and avoid using the word” addiction” as it may come across as pejorative leading to shame and guilt and dropping out of treatment. A disease model such as diabetes would be worth considering for opiate dependence.  
  • These patients have significant medical and psychiatric comorbidities which results in increased death rate. Psychiatric comorbidities specifically include a 50% prevalence of mood disorders not adequately diagnosed/or treated.  These individuals also have a higher rate of emergency room visits for nonfatal opioid overdoses. The medical field needs to do a better job of care coordination.
  • In summary we need to have greater number of physicians and mid-levels trained for MAT and mutual-help groups should be encouraged. The medical field needs to take a more serious and sensitive approach to address the opioid epidemic as it is not self-limiting. Maintenance of abstinence is the key to treatment.
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Antipsychotic polypharmacy in schizophrenia is frowned upon: New data may suggest differently.

Tiihonen J et al. JAMA Psychiatry. 2019 Feb 20. doi:10.1001/jamapsychiatry.2018.4320. [Epub ahead of print] PMID 30785608

Background

The use of multiple antipsychotic medications to treat schizophrenia has been frowned upon, but clinicians seeing extremely sick patients still continue this practice. The treatment guidelines specifically discourage using antipsychotic polypharmacy. It is done in desperation when patients are not stabilized on one drug. This study has tried to address this very issue in a large cohort of patients looking at specific antipsychotic combinations with regard to psychiatric rehospitalizations.

Methods

This Finnish study followed N=62,250 patients with schizophrenia during the use of 29 different antipsychotic monotherapy and polypharmacy types between January 1, 1996 and December 31, 2015. The risk of rehospitalization was used as a marker for relapse. Data analysis was done for the time frame April 24 to June 15, 2018. The primary outcome for psychiatric hospitalization was use of polypharmacy vs monotherapy within the same individual. 

Results

The group included 50.2% males with a median age of 45.6 years. The clozapine plus aripiprazole combination was associated with the lowest risk of psychiatric rehospitalization in the entire group, being superior to clozapine monotherapy. In patients being treated for their first episode, differences between clozapine plus aripiprazole and clozapine monotherapy were remarkable. Finally, any antipsychotic polypharmacy was associated with a 7% to 13% lower risk of psychiatric rehospitalization compared with any monotherapy. Clozapine was the only monotherapy among the 10 best treatments.

Conclusions

The combination of aripiprazole with clozapine was associated with the lowest risk of rehospitalization. This suggests that certain combinations are effective and feasible in the treatment of schizophrenia. As treatments are added on, when monotherapy is no longer sufficient to control psychosis in patients with schizophrenia, it is likely that the effect sizes of polypharmacy are underestimates. The current guidelines for treatment of schizophrenia should be modified from their current recommendations of discouraging all antipsychotic polypharmacy.

Clinical Commentary

The results of this study were consistent with the observations of clinicians who see extremely ill patients and use combination antipsychotic treatment one of the agents being clozapine.                                  

  • Clozapine use in combination therapy (mean dose 399 mg/day) and monotherapy (426 mg/day) again supports the clinical notion of lowering clozapine dosage with combinations to have better outcomes and lower clozapine related side-effects.  
  • Randomized clinical trials are impossible to do in such a study and hence observational studies are done to gain statistical power. The drawback is selection bias.
  • Clozapine is a highly underutilized drug in the US for various reasons such as need for blood count monitoring, side-effects, lack of resources, and legal climate.   
  • This study included long acting injectable combinations (LAIs) and yet the clozapine-aripiprazole combination was superior. There is one caveat, the clozapine group usually has the selection bias of compliant patients.
  • Any combination therapy had a 10% lower risk of hospitalization and the effect size noted by the authors was greater than statins for preventing cardiovascular events. This is a remarkable finding.
  • In summary this study encourages me to rethink my practice of treating schizophrenia (I was not in favor of combinations). There should be greater utilization of clozapine in the sicker patients, and one should be open to combination therapy. The schizophrenia treatment guidelines need to be updated.
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Binge Eating Disorder and Lisdexamfetamine treatment: Does age and gender impact outcome?

Kornstein SG et al. J Clin Psychiatry. 2019 Feb 26; 80(2). pii:18m12378. doi: 10. 4088/JCP.18m12378. PMID 30817099

Background

Lisdexamfetamine (LDX) is FDA approved for the treatment of adults with moderate to severe Binge Eating Disorder (BED) and for individuals ≥6 years of age with attention deficit disorder. BED is more common in females and younger individuals which has not been investigated. This study looks into this specific issue with a focus on effects of LDX for BED with regard to gender (male vs female) and age (<40 vs ≥40).

Methods

This post hoc study included adults with a DSM-IV TR diagnosis of BED of a moderate to severe nature.  The subjects were randomized to 12 weeks of dose-optimized LDX (50 or 70 mg) or placebo in 2 studies conducted between November 2012 and September 2013. A post hoc analysis was conducted by (men vs women) and age (<40 vs ≥ 40).

Results

The pooled safety analysis and full analysis sets included 745 and 724 participants, respectively (men, n=105 and n=97; women, n=640 and n=627;<40 years n=398 and n=386; ≥ 40 years, n=347 and n=338). The mean baseline number of binge days/week was comparable across gender (4.6-4.7) and age (4.6-4.7). The Yale-Brown Obsessive- Compulsive Scale modified for Binge Eating (Y-BOCS-BE) was used to assess BED symptoms also. Treatment differences nominally favored LDX in all subgroups for changes from baseline in binge eating days/week at weeks 11-12 and Y-BOCS-BE total score at week 12. There were no interactions by age or gender reported. The LDX groups were associated with higher frequencies of treatment related adverse events and increased blood pressure compared with the placebo group.

Conclusions

Across age and gender the participants exhibited comparable clinical characteristics and responses to dose-optimized LDX compared to placebo.

Clinical Commentary

This is the first study to investigate the effects of LDX for the treatment of BED with respect to gender and age. This is a post hoc analysis and there were more females than males in the sample which may be limitations of this study. Information on race and ethnicity was lacking. LDX is a schedule II medication.

  • The clinical characteristics of the participants did not differ as a function of age or gender.
  • The LDX dose range is 50-70 mg/day for BED. The maximum dosage for severe renal disease is 50 mg/day and 30 mg/day for end-stage renal disease. LDX has an FDA boxed warning for abuse and dependence.
  • As a clinician I would suggest a careful evaluation of the patient for substance use disorder (SUD) and avoid use in these individuals. In my practice that would also include cannabis abuse. Periodic surprise urine drug screens are suggested to monitor compliance. Negative screens suggest that the patient is not compliant, but could also be selling the drug, especially to be noted on college campuses. Extra care needs to be taken in those on opiates and benzodiazepines.
  • In summary I suggest that we do a better job of screening for BED as it more common than we think. LDX is a useful FDA approved treatment, however, behavioral interventions must also be used. There were no sex or age differences in clinical response to LDX.
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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]

To contact GME, email us at [email protected]


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