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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.


ISSUE 10, January 2013 — Guest Commentator: Rakesh Jain, MD, MPH, University of Texas Medical School, Houston, TX


State-Dependent Changes in Hippocampal Grey Matter in Depression

Arnone D, McKie S, Elliott R, et al
Mol Psychiatry. 2012; November 6. doi: 10.1038/mp.2012.150. [Epub ahead of print]

Objective: Reduced hippocampal volume has been reported in depression and may be involved in the etiology of depressive symptoms and vulnerability to depressive relapse. Neuroplasticity following antidepressant drug treatment in the hippocampus has been demonstrated in animal models but adaptive changes after such treatment have not been shown in humans. In this study, we determined whether grey matter loss in the hippocampus in depression (1) is present in medication-free depressed; (2) changes in response to antidepressant treatment; and (3) is present as a stable trait in medication-free remitted patients.

Methods: Sixty-four medication-free unipolar depressed patients (39 currently depressed and 25 in remission) and 66 healthy controls (HC) underwent structural magnetic resonance imaging in a cross-sectional and longitudinal design. Thirty-two currently depressed participants were then treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring plasma citalopram concentration. We measured regional variation in grey matter concentration by using voxel-based morphometry-Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra.

Results: Patients with current depression had bilaterally reduced grey matter in the hippocampus compared with HC and untreated patients in stable remission, with the latter groups not differing. An increase in grey matter was observed in the hippocampus following treatment with citalopram in currently depressed patients.

Conclusion: Grey matter reduction in the hippocampus appears specific to the depressed state and is a potential biomarker for a depressive episode.

Clinical Commentary
This article should make the list of “Top Ten” most interesting articles of 2012. Arnone and colleagues elegantly demonstrate the impact depression has on hippocampal volume. What makes this study so impressive is the prospective follow-up of three groups: medication-free, currently depressed individuals; non-depressed controls; and medication-free remitted patients. In addition, the depressed individuals were treated with citalopram (compliance to which was confirmed by measuring it in the serum) and their hippocampal volumetric changes were re-examined in just eight weeks. The findings are as follows: at baseline, currently depressed individuals had significantly decreased hippocampal volumes compared to both of the other groups. Treatment with citalopram, even for eight weeks, was associated with volumetric increases in hippocampal volume. This demonstrates that hippocampal volume changes are state dependent and that this change is responsive, even in a short amount of time, to treatment. This study therefore lends further support to the “neurotoxic” impact depressive symptoms have on the brain, and the positive impact of treatment. This study perhaps foretells the future potential use of volumetric brain studies by everyday treating clinicians as a means to assess treatment response. While its too early to tell if this will be the case, this study adds valuable information to our emerging understanding of the neurobiology of depression and its treatment.


Might Different Cytokine Trends in Depressed Patients Receiving Duloxetine Indicate Differential Biological Backgrounds

Fornaro M, Rocchi G, Escelsior A, et al
J Affect Disord. 2012; Sep 13.

Background: Correlational studies investigating neurohormonal-cytokine modulation by antidepressants suggest, among others, variations in cytokines balances as state markers of different biological subtypes of major depressive disorder (MDD) and response predictors to specific treatments. Objective of the study was to investigate cytokines modulation by duloxetine, a relatively newer SNRI with "clean" dual serotonin/norepinephrine mechanism.

Methods: 30 MDD patients and 32 healthy controls were assessed using Hamilton Depression Scale (HAM-D) and monitored for levels of IL-1β, IL-2, IL-4, IL-10, IL-12, IFN-γ and TNF-α, at baseline, week 6 and week 12 of duloxetine treatment (60mg/day) and at baseline, respectively.

Results: Early responders (ER: defined at week 6 by reduction >50% of baseline HAM-D score) and early non-responders (ENR) showed opposite trends in cytokine levels during duloxetine treatment: ENR were characterized by baseline Th2 shift compared to controls (lower IL-1β, IFN-γ and TNF-α) with increase in Th1 cytokines levels during treatment (increase of IL-1β, IL-12, IFN-γ, IL-1β/IL-10 and TNF-α/IL-10, decrease of IL-10), achieving clinical response at week 12; ER were characterized by baseline Th2-to-Th1 relative switch compared to ENR (higher IL-1β, IL-1β/IL-10 and TNF-α/IL-10) with reduction in Th1 cytokines levels during treatment (decrease of TNF-α and TNF-α/IL-10), achieving clinical response at week 6. Limitations: Small sample size.

Conclusions: In accordance to early clinical response, duloxetine treatment could divide depressed patients into at least 2 subgroups characterized by clinical and laboratory differentiated behavior, suggesting different neurobiological background within depressive syndrome differentially sensitive to different drug components: pro-serotonergic effect and increase in Th1 cytokines in ENR vs. pro-noradrenergic effect and decrease in Th1 cytokines in ER.

Clinical Commentary
The year 2012 marked the beginning of dramatically increased interest in the area of psychoneuroimmunology. It is now fairly well established that the immune system plays a significant role in the pathogenesis of major depression. However, much less is known about how treatment impacts the immune system, and whether or not cytokine changes (the foot soldiers in the immune system) are different in early responders to antidepressants versus late or nonresponders. This important study adds to our understanding of this issue by examining cytokine changes that occur during treatment with the SNRI duloxetine in two groups of patients: those who achieve early response (50% reduction of symptoms in 6 weeks) and those who did not. The study results reveal that no single cytokine clearly helped differentiate these two groups. However, when ratios of Th1 cytokines (cell-based immunity markers such as TNF-alpha, IL-12, etc) and Th2 cytokines (humoral-based immunity markers such as IL-4, IL-6, IL-10) were examined, these two groups showed opposite trends. This is an important finding as it sheds light on why some depressed individuals do not respond early to antidepressants. This study raises the possibility that we may soon be able to use a patient’s immune response patterns to individualize treatment and improve outcomes.


What Predicts Outcome, Response, and Drop-out in CBT of Depressive Adults? A Naturalistic Study

Schindler A, Hiller W, Witthoft M.
Behav Cogn Psychother. 2012; Dec 5:1-6.

Background: The efficacy of CBT for unipolar depressive disorders is well established, yet not all patients improve or tolerate treatment. The aim was to identify factors associated with symptomatic outcome, response, and drop-out in depressive patients under naturalistic CBT.

Method: 193 patients with major depression or dysthymia were tested. Sociodemographic and clinical variables were entered as predictors in hierarchical regression analyses. Results: A higher degree of pretreatment depression, early improvement, and completion of therapy were identified as predictors for symptomatic change and response. Drop-out was predicted by concurrent personality disorder, less positive outcome expectancies, and by failure to improve early in treatment.

Conclusions: Our results highlight the importance of early response to predict improvement in routine CBT. Attempts to refine the quality of treatment programs should focus on avoiding premature termination (drop-out) and consider motivational factors in more depth. Routinely administered standardized assessments would enhance symptom monitoring and help to identify persons at risk of not improving under therapy.

Clinical Commentary
The scientific approach of rigorous observation and analysis of data is beneficial to both biologically based studies and nonpharmacological treatment studies. This German CBT intervention study is a shining example of how data, when well analyzed, offer pearls of wisdom for clinicians. The study naturalistically followed 193 patients to identify who responds to CBT, who does not, and who is at risk for premature dropouts—all of which are incredibly important questions that deserve close scrutiny. Interestingly, three factors predicted a good response: higher degree of depression at treatment initiation; early response; and completion of prescribed CBT therapy sessions. As expected, dropouts were predicted by presence of a concurrent personality disorder, lower positive outcome expectations, and a failure to improve early. These findings, when examined in their totality, may help clinicians assign CBT to appropriate patient profiles. Those at risk for early dropouts may benefit from proactive measures such as open and frank early discussions regarding expectations, more frequent visits, and use of rating instruments to track symptom progress.

Treatment Resistant Adolescent Depression with Upper Airway Resistance Syndrome Treated with Rapid Palatal Expansion: A Case Report

Miller P, Iver M, Gold AR
J Med Case Rep. 2012 Dec 4;6(1):415.

Background: To the best of our knowledge this is the first report of a case of treatment-resistant depression in which the patient was evaluated for sleep disordered breathing as the cause and in which rapid palatal expansion to permanently treat the sleep disordered breathing produced a prolonged symptom-free period off medication.

Case Presentation: An 18-year-old Caucasian man presented to our sleep disorders center with chronic severe depression that was no longer responsive to medication but that had recently responded to electroconvulsive therapy. Ancillary, persistent symptoms included mild insomnia, moderate to severe fatigue, mild sleepiness, and severe anxiety treated with medication. Our patient had no history of snoring or witnessed apnea, but polysomnography was consistent with upper airway resistance syndrome. Although our patient did not have an orthodontic indication for rapid palatal expansion, rapid palatal expansion was performed as a treatment of his upper airway resistance syndrome. Following rapid palatal expansion, our patient experienced a marked improvement of his sleep quality, anxiety, fatigue and sleepiness. His improvement has been maintained off all psychotropic medication and his depression has remained in remission for approximately two years following his electroconvulsive therapy.

Conclusions: This case report introduces the possibility that unrecognized sleep disordered breathing may play a role in adolescent treatment-resistant depression. The symptoms of upper airway resistance syndrome are non-specific enough that every adolescent with depression, even those responding to medication, may have underlying sleep disordered breathing. In such patients, rapid palatal expansion, by widening the upper airway and improving airflow during sleep, may produce a prolonged improvement of symptoms and a tapering of medication. Psychiatrists treating adolescents may benefit from having another treatment option for treatment-resistant depression.

Clinical Commentary
Can depression be caused by breathing problems? Case reports inherently possess strengths and weaknesses. Despite the fact that a sample size of 1 is inadequate to fully examine any issue, our own experience in treating individual patients often forms the basis our treatment habits. This particularly dramatic case report deserves our attention. Here, a young man’s case of treatment-refractory depression is presented. After correction of obstructive airway disease, the patient remarkably went into sustained remission of depression, anxiety, fatigue, and sleepiness, even though he was off all psychotropic medications. This case report adds to the burgeoning literature on the importance of airway obstruction and how this can create symptoms that resemble major depression. The lessons learned from this case report and other literature on this topic are clear: when we encounter patients with symptoms of depression, we should take a full medical history, including a history of snoring or other symptoms that could indicate airway disease obstruction. If potential concerns are found, a referral to a sleep specialist is highly warranted.


The Nature of the Association Between Childhood ADHD and the Development of Bipolar Disorder: a Review of Prospective High-Risk Studies

Duffy A.
Am J Psychiatry. 2012 Dec 1;169(12):1247-55.

Objective: The author reviewed prospective longitudinal studies of the offspring of parents with bipolar disorder to inform our understanding of the nature of the association between childhood ADHD and the risk of developing bipolar disorder in adolescence and young adulthood.

Methods: A literature review of published prospective cohort studies of the offspring of bipolar parents since 1985 was undertaken using a comprehensive search strategy in several electronic databases. The author provides a qualitative synthesis of results focusing on ADHD and the association with bipolar disorder in prospectively assessed high-risk offspring. These results are discussed in light of findings from other prospective epidemiological and clinical cohort studies.

Results: From the reviewed high-risk studies, evidence suggests that the clinical diagnosis of childhood ADHD is not a reliable predictor of the development of bipolar disorder. However, the author found evidence that symptoms of inattention may be part of a mixed clinical presentation during the early stages of evolving bipolar disorder in high-risk offspring, appearing alongside anxiety and depressive symptoms. The author also found preliminary evidence that childhood ADHD may form part of a neurodevelopmental phenotype in offspring at risk for developing a subtype of bipolar disorder unresponsive to lithium stabilization.

Conclusions: While childhood ADHD does not appear to be part of the typical developmental illness trajectory of bipolar disorder, subjective problems with attention can form part of the early course, while neurodevelopmental abnormalities may be antecedents in a subgroup of high-risk children.

Clinical Commentary
It is doubtful one will find a more controversial topic in mental health than that of pediatric bipolar disorder and ADHD. Questions abound here: Which comes first? Are they reliably differentiable? Is inattentiveness solely a symptom of ADHD, or is it shared with pediatric bipolar disorder? Do parents with bipolar disorder only produce children with this disorder, or is risk for ADHD also elevated? This comprehensive literature review by Dr. Duffy bravely attempts to answer many of these questions by conducting a literature search of prospective cohort studies of the offspring of bipolar parents. The results are both surprising and clinically useful. Some of the findings include: the presence of pediatric ADHD does not reliably predict, even in children of bipolar parents, that these children will go on to develop bipolar disorder; early-onset ADHD followed by bipolar disorder may predict lack of responsiveness to lithium; and inattention in a high-risk child (ie, one with a parent with bipolar disorder) may predict development of mixed bipolar states. All of these findings are worrisome. Children of bipolar individuals should be closely monitored for both emergence of ADHD and bipolar symptoms. One should not assume bipolar disorder when only ADHD symptoms are present. If bipolar disorder does emerge in such children with ADHD, lithium has a lower likelihood of being beneficial. Finally, it appears that mixed states are common in these children. Judicious interventions can be based on these emerging findings.


A Randomized Controlled Trial of the Tumor Necrosis Factor Antagonist Infliximab for Treatment-Resistant Depression: The Role of Baseline Inflammatory Biomarkers

Raison CL, Rutherford RE, Woolwine BJ, et al
Arch Gen Psychiatry. 2012 Sep 3:1-11.

Background: Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants.

Objectives: To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response.

Methods: A double-blind, placebo-controlled, randomized clinical trial was conducted at the Outpatient infusion center at Emory University in Atlanta, Georgia. Participants included a total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n=37) or medication-free (n=23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. Three infusions of the TNF antagonist infliximab (5 mg/kg) (n=30) or placebo (n=30) at baseline and weeks 2 and 6 of a 12-week trial. The 17-item Hamilton Scale for Depression (HAM-D) scores. Were the primary efficacy measure.

Results: No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P=.01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P=.19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P<.05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P<01). Dropouts and adverse events were limited and did not differ between groups.

Conclusions: This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers.

Clinical Commentary
Some proof-of-concept studies are so remarkable that you do a double take at first glance. This is one of those rare studies. We have known for a few years that elevated levels of inflammatory cytokines predict poor response to antidepressants. This study treated resistant depression patients with a TNF-alpha antagonist (infliximab), knowing fully well that this anti-inflammatory agent does not cross the blood brain barrier. Hence, it would only attack peripheral inflammation without any direct effects on the brain. Results showed that the use of the peripheral TNF-alpha produced a significant antidepressant effect, but only in those who had elevated peripheral inflammatory markers. Remarkably, even “attacking” the periphery with medications that do not cross the blood-brain barrier can have positive effects. This groundbreaking study furthers our understanding of personalized treatment of treatment-resistant patients and the mind-body treatment approach to major depression.

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