Issue 87, Jul 2019
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Late-life depression treatment: Role of socialization is obvious; now supported by data.

Solomonov N et al. Am J Geriatric Psychiatry. 2019 June; 27(6): 571-578. doi:10.1016/j.jagp. 2018. 12.033.  Epub 2019 Jan 10. PMID: 30797650

Background

Social connectedness has a positive impact over the lifespan. As a result of aging there is a decline in functioning, narrowing of social networks, and limitation of social relationships. This results in social isolation which has been noted to result in negative outcomes such as increased risk of depression, cognitive decline, and even mortality. This study was designed to investigate whether engagement in social and interpersonal activities predicts a reduction in depressive symptoms, and increase in behavioral activation in the treatment of late-life depression.

Methods

This joint US and Swiss study (N=48) included patients 60 years and older (mean age 71 years) diagnosed with major depressive disorder without psychotic features (DSM-IV). These individuals did not have significant cognitive dysfunction (MMSE ≥ 24) and were either off antidepressants or on a stable dose with no intention to change the dose for 9 weeks of the trial. They received 9 weeks of “Engage” psychotherapy. Behavioral activation and depression severity were assessed by trained raters at baseline, week 6, and week 9. The patients’ weekly behavioral plans were categorized into three groups: 1) solitary activities; 2) social-group activities (social gathering or a church or senior center); and 3) interpersonal -individual activities (engaging in an interpersonal interaction with a specific friend/family member).

Results

The principal finding of this study was that interpersonal activities that involved a significant other (family member/friend) predicted an increase in behavioral activation and reduction in depression. Contrary to popular belief or prediction, attending church and other social group activities did not result in reduction in depression.

Conclusions

These findings highlight the importance of understanding the effects of engagement in specific types of rewarding activities in behavioral activation treatments for late-life depression. Exposure to socially rewarding interpersonal interactions could contribute to the efficacy of psychotherapy for late-life depression. The study is limited by a small sample size.

Clinical Commentary

Late-life depression is an extremely debilitating illness resulting in negative outcomes such as enhanced cognitive decline, physical problems, and even mortality. The social isolation these individuals face cannot be expected to just get better by taking more medications. Taking too many medications could also have a negative impact. Hence the field has been using specific treatments such as cognitive behavioral therapy and problem-solving therapy.

  • This study uses “Engage therapy” developed by Drs’ Alexopoulos and Arean to target dysfunction in the reward system. This approach provides structured reward exposure to meaningful rewarding activities specific to the individual.  
  • Biology: Reward processing is often impaired in late-life depression. This is correlated with the severity of anhedonia. Older adults respond with greater activation in the right nucleus accumbens in response to social rewards, while younger adults show greater activation in response to monetary awards. The nucleus accumbens as we know is the reward processing center.
  • In summary: During the evaluation of late life depression look for social isolation and the intensity of specific meaningful interactions the patient may have as a guide to building the treatment plan. Antidepressants are helpful, but the addition of focused socially rewarding and meaningful activities should also be done. Just going to the senior center is not good enough for this population MMSE ≥ 24. We can put this strategy into our practice right away if we are not already doing so.
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Treatment of Major depressive disorder (MDD): Do anti-inflammatory agents enhance response of standard anti-depressants?

Kohler-Forsberg O. et al. Acta Psychiatr Scand. 2019 May; 139 (5):404-419.doi :10.1111/acps.13016. [Epub ahead of print] PMID:30834514

Background

The role of inflammation in depression is gaining ground with the ongoing study of proinflammatory markers. This study was the first to gather evidence from all randomized clinical trials (RCT) with anti-inflammatory drugs measuring antidepressant effects including a detailed assessment of side-effects and bias.

Methods

This study identified RCTs published prior to Jan 1st, 2018 studying antidepressant treatment effects and side-effects of pharmacological anti-inflammatory intervention in adults with MDD or depressive symptoms. The outcomes included assessment of remission, response, and side-effects.

Results

36 RCTs were identified. They consisted of 13 trials investigating NSAIDs (N=4214), 9 cytokine inhibitors (N=3345), 7 statins(N=1576), 3 minocycline (N=151), 2 pioglitazone (N=77), and 2 glucocorticoids (N=59). Anti-inflammatory agents improved depressive symptoms compared to placebo as an add-on in patients with MDD and as monotherapy. The addition of anti-inflammatory agents improved response as well as remission. All studies showed a high risk of bias.

Conclusions

Anti-inflammatory agents improved anti-depressant treatment effects. Future RCTs are needed to identify optimal doses, sub-groups of patients more likely to benefit and gather data on long term-follow-up.

Clinical Commentary

 This is the largest and most comprehensive study covering this area involving 10,000 patients covering 6 different groups of anti-inflammatory agents. The fact that the use of the anti-inflammatory agents as an adjunct to antidepressants enhanced remission and response is impressive. Few studies measured bio-markers and none explored depressive symptoms that predict a positive response.

  • It is remarkable to note the 5 out of 6 drugs improved depressive symptoms without increasing the risk of side-effects.
  • The effect size for the anti-inflammatory agent added to antidepressant compared with antidepressant + placebo was larger than the effects sizes of current antidepressant treatment compared to placebo. Hence this is certainly a strategy worth trying.
  • The most robust effect was observed for celecoxib.
  • In summary these studies have a high bias as well as a lot of heterogeneity. It is not clear which symptoms of MDD predict response to the addition of the anti-inflammatory agents. MDD treatment often involves the use of off-label treatments and this approach is currently under-utilized and can be tried. The antidepressant choice can be based inflammatory parameters. A recent study (Uher R et al. 2014; 171:1278-1286 Am J Psychiatry) predicted that patients with MDD and CRP > 1 mg/l responded better to a tricyclic (TCA) while those with a CRP < 1 mg/l responded better to selective serotonin reuptake inhibitor (SSRIs).  
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Gut microbiome: Implications for generalized anxiety disorder

Jiang HY. et al. J Psychiatr Res. 2018 Sep;104:130-136. doi:10.1016/j.jpsychires.2018.07.007. Epub 2018 Jul18. PMID:30029052

Background

There is growing awareness that human microbiota plays an important role in maintaining mental health and its disruption contributes to manifestations of psychiatric illnesses. The gut microbiota can modulate the gut-brain axis. This Chinese study investigated if there were changes in the gut microbiome of patients with generalized anxiety disorder (GAD) compared with normal controls.

Methods

This was a cross-sectional study (N=76). There were 40 patients with active GAD and 36 normal controls who were compared in terms of composition of GI microbacterial flora. A subgroup that was treatment naïve (N=12) had stool samples collected before initiating medication.The stool was analyzed using the polymerase chain reaction and microbial analysis. The Hamilton Anxiety Rating (HAM-A) Scale was used to follow up the patients. HAM-A score >14 was suggestive of active GAD and <7 was remission.

Results

The stool samples of patients with GAD and normal controls revealed 8 bacterial taxa. Bacteriodetes, Ruminococcus gnavus, and Fusobacterium were increased in GAD patients while Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospora and Butyricicoccus were increased in normal controls. No difference in microbial composition was noted between patients with active symptoms and those in remission.

Conclusions

Patients with GAD have less bacteria that produce short chain fatty acids (Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospora and Butyricicoccus). This could result in disruption of the GI barrier.Fusobacterium can contribute to immunological activation in GAD. This study suggests that targeting the microbiome might be another avenue for treatment of GAD in conjunction with current strategies.

Clinical Commentary

The consumption of processed food has increased significantly in the western nations.The other parts of the world tend to follow as western chains open food outlets in other countries.The response of patients to antidepressants and anti-anxiety agents is limited, and hence other avenues are being explored including alterations in the human microbiome (gut-brain axis).The microbiota-gut-brain axis plays a role in regulating/programming the hypothalamic-pituitary-adrenal (HPA) axis throughout the life span. The HPA axis has a key role to play in psychiatric illness. The study is limited by a small sample size and there is a need for replication in larger studies.

  • Microbiota affect the gut brain signaling via alterations in microbial composition, the immune system, and changes in tryptophan metabolism.
  • Clinicians should consider multiple aspects of the patient’s life when treating psychiatric illness.These patients usually consume a higher amount of processed food and hence the implications. In addition, alcohol and drug use also affects the microbiome as do antibiotics. We should pay greater attention to the food habits with counseling/groups focused not only on life style but also food consumption.
  • The importance of a balanced diet and lifestyle cannot be stressed enough. All these issues were beliefs before, and now are being validated by studies.The Mediterranean diet reduces the incidence of cardiovascular disease and lowers the risk of depression. “What’s good for the heart is good for the brain”
  • In summary: we should begin to counsel our patients on these lines which also includes avoiding unnecessary use of antibiotics and using probiotics which help the microbiome.
  • There is one caveat: There is a cultural issue that applies to this study. These were Chinese patients and food intake including the volume of processed food consumed varies culturally. The concept though, of the microbiome affecting psychiatric illness is the important take home point.
  • References: Cryan JF Rev Neurosci 2012:13 (10):701-712

Pastis I Current Psychiatry 2019 May 18 (5): 40-44

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Major depressive disorder (MDD) with mixed features and irritability: Is lurasidone efficacious?

Swann A et al. CNS Spectr. 2017 Apr;22(2):228-235. doi:10.1017/ S1092852917000232. Epub 2017 Mar 16. PMID 28300012

Background

There is a clear subset of patients with MDD (with mixed features) who meet the criteria for major depression but have two to three manic type symptoms irritability being a prominent one. There has been a dilemma whether to use antidepressants or antipsychotics. This post-hoc analysis was done to evaluate the efficacy of lurasidone in treating MDD with mixed features including irritability.

Methods

This data for this analysis is derived from a study of patients meeting DSM-IV TR criteria for unipolar MDD, with Montgomery-Asberg Rating Scale (MADRS) score >26 presenting with two to three protocol-defined manic symptoms and who were randomized to 6 weeks of double-blind treatment with either lurasidone 20-60 mg/d (N=109) or placebo (n=100). Irritability was defined as a score of > 2 on the Young Mania Rating Scale (YMRS) irritability (item#5) item and the disruptive-aggressive item (item#9). The analysis was done for change in MADRS and item 5 and 9 for patients with and without irritability.   

Results

The irritability criteria were met by one fifth of the patients. MADRS scores were significantly reduced in the lurasidone group at week 6 in both those with and without irritability. Irritable features were significantly reduced with lurasidone.

Conclusions

In this six-week study MDD symptoms and irritability were significantly reduced in the group diagnosed with MDD with mixed features which included 2-3 manic symptoms.

Clinical Commentary

The patients with mixed features are hard to diagnose and treat. In the clinical world they are often treated with antidepressants and the hypomanic/manic symptoms that are subthreshold are often missed. Hence the mixed state is also called “the missed state”. These patients are more prone to substance abuse further complicating the picture. These patients are also more prone to suicide. It should be noted that these are secondary analyses and not a prospective study. Please note that lurasidone is FDA approved for major depressive episode in bipolar disorder as monotherapy and in conjunction with lithium or divalproex.

                                                               

  • This study still makes the point that we should aim to identify this MDD subgroup with mixed features and give a trial of lurasidone. Alternatively, there is data on ziprasidone trial.   
  • Using antidepressants alone may promote rapid cycling or ultimately lead to a manic episode (antidepressant-induced mania)
  • In the clinical world there are no studies but lamotrigine may be an off-label drug to try.
  • In summary this study encourages me to look for manic/hypomanic symptoms in my MDD patients. The presence of these symptoms would require a trial of lurasidone (off-label) or even ziprasidone. Using antipsychotics in those with mood disorders increases the risk of tardive dyskinesia (TD) and metabolic issues. We need to monitor for these side-effects. Patients with mood disorders are more prone to TD and metabolic issues.Overall psychological stability is the cornerstone of management.
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Long-Acting Injectable Antipsychotics (LAIs) in children and adolescents: Limited data speak!

Lytle S et al. J Child Adolesc Psychopharmacol.2017 Feb; 27(1):2-9. doi:10.1089/cap.2016.0055. Epub 2017 Jan 23 PMID 28112539

Background

The data is extremely limited in children and adolescents on LAI.The focus on this population is very limited. This review of the literature evaluated use of LAIs in children and youth under the age of 18.

Methods

This study was conducted with a comprehensive search of PubMed, Psych INFO, CINAHL, and EMBASE databases using keywords related to LAIs, children, and psychiatric conditions, including schizophrenia, bipolar disorder, and schizoaffective disorder. Reports were included if they were in English, conducted between 1971 and 2015, and reported on use of LAIs in individuals less than the age of 18.

Results

The search revealed seven reports including one open-label trial, three case reports, and three case series. No controlled trials were found. The sample sizes ranged from 1-19 with a total of 36 individuals in all cases combined.

Conclusions

This literature review suggests that the LAI use in youth with serious mental illness may improve clinical outcomes and adherence. Side-effects of LAIs among the youth appear similar to oral preparations. The issues of nonadherence are rampant in the youth and they have much to gain from being on LAIs which are under-used as in adults. There are substantial methodological limitations and controlled trials in children and adolescents are much needed.

Clinical Commentary

The use of LAIs in the youth is important as this age group has a high rate of non- adherence to medications and even refusal when offered by parents. Early intervention with LAIs may delay/prevent progression of the disease state and possibly preservation of intellectual capital. This would also help with reintegration in the community.  

  • There is a paucity of studies using LAIs suggesting that the long acting injectable preparations are remarkably understudied and underused in this age group. Non-compliance with medications leads to progression of psychiatric illnesses such as schizophrenia and bipolar disorder.
  • The psychiatric disorders in youth are often associated with self-medication with drugs and alcohol adding fuel to the fire. Hence early intervention with LAIs should be considered important.
  • For youth in college it is easier to get an injection monthly or every two or three months rather than take oral medications twice or even once daily.
  • In summary I suggest that we should rethink our treatment strategy in youth with serious mental illness, and if available and appropriate, include the LAI option in the discussion with the patient and the family.           
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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]