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.
Amsterdam JD, Luo L, Shults J.
Br J Psychiatry. 2013;202:301-316.
Objectives: Multiple studies suggest an association between rapid cycling and antidepressant use in bipolar disorder. To test the hypothesis that antidepressant monotherapy is associated with poor outcomes, this study reports an exploratory analysis of the safety and efficacy of fluoxetine versus lithium monotherapy in individuals with rapid- and non-rapid-cycling bipolar II disorder.
Odds of depressive relapse
No significant difference; OR=0.6, 95%, CI 0.2-1.8
No significant difference
No significant difference
Conclusions: In this study of rapid- and non-rapid-cycling subjects with bipolar disorder type II, the rates of depressive relapse and syndromal and subsyndromal hypomania were similar during long-term lithium and fluoxetine monotherapy and placebo.
Most current treatment guidelines advise against the use of antidepressant monotherapy (without concomitant therapy with a mood stabilizer) in bipolar disorder, especially for patients with rapid-cycling bipolar disorder. The current report appears to challenge this expert consensus: the authors report that patients with a history of rapid-cycling bipolar II disorder show no increased risk of affective switches during 50 weeks of fluoxetine monotherapy (compared to lithium monotherapy). Before deciding to discard the current treatment guidelines in bipolar disorder, it is useful to note several details. First, the classification of “rapid cycling” in this study involved an average of 4 or more syndromal or subsyndromal episodes per year during the course of their illness (not in the past year, as per DSM-IV-TR criteria). Some of the subjects designated as rapid cycling in this study may have had fewer episodes in the last year compared to the non-rapid cycling subjects. In the rapid-cycling group the most recent depressive episode was 13.3 months, which is not consistent with current rapid cycling. Second, all subjects randomized to lithium or fluoxetine had previously tolerated a 12-week course of high dose (80 mg) fluoxetine monotherapy. Since only subjects stable at the end of the initial treatment entered the randomized phase of the study, we can conclude these subjects represent a subgroup of patients pre-selected for their ability to not experience affective shifts during fluoxetine monotherapy. On balance, the current study importantly highlights the existence of a subgroup of subjects with bipolar disorder type II which may tolerate and experience good outcomes on long-term fluoxetine monotherapy. This usefully challenges the dogma of always avoiding antidepressants in bipolar subjects. However, the specific design of the study prevents us from generalizing these results to the entire population of subjects with bipolar II disorder (and especially those bipolar subjects with recent rapid-cycling).
Brunoni AR, Valiengo L, Baccaro A, et al
JAMA Psychiatry. 2013;70(4):383-391.
Objectives: The aim of this study was to assess the efficacy and safety of transcranial direct current stimulation (tDCS) compared to a standard SSRI antidepressant (sertraline) in subjects with major depressive disorder (MDD).
Mean Difference in MADRS Scores Compared to Sertraline + tDCS1
CI; P Value
95% CI, 2.96 to 14.03; P=.002
95% CI, 0.36 to 11.43; P=.03
95% CI, 6.03 to 17.10; P>.001
1At 6 weeks, the combination of tDCS and sertraline had superior efficacy compared to either treatment alone.
2 tDCS and sertraline used alone were associated with comparable efficacy (mean difference=2.6 points; 95% CI, -2.90 to 8.13; P=.35.
3 Active tDCS alone (but not sertraline alone) was superior to placebo+sham tDCS.
Adverse effects include skin redness on the scalp in active tDCS (P = .03). There were 7 episodes of treatment-emergent mania or hypomania, 5 occurring in the combined treatment group. The integrity of the blinding was problematic: participants correctly guessed both sertraline and tDCS use (although the authors stress that most participants were “only moderately confident in their choices”).
Conclusions: In this group of MDD subjects with low levels of treatment resistance, treatment with tDCS or low-dose sertraline was associated with similar rates of improvement and adverse events. The combination of tDCS and sertraline had superior efficacy compared to either treatment alone or compared to sham.
Over the last decade a series of novel devices using different forms of energy for brain stimulation have been proposed as treatment strategies for mood disorders. Transcranial direct current stimulation is an old technology; its efficacy as an antidepressant appears questionable based on poorly designed older studies. This is the first well-designed study testing this treatment, but in a population with very low levels of treatment resistance and in comparison to a low dose of a standard antidepressant. The blinding appears imperfect, which raises additional questions on the full validity of the results. The tDCS treatment is easy to deliver and may be associated with standard antidepressants for additional efficacy. On balance, tDCS appears a valid treatment for milder, non treatment-resistant forms of depression.
Fortney JC, Pyne JM, Mouden SB, et al
Am J Psychiatry. 2013;170(4):414-425.
Objective: Practice-based collaborative care is a complex, evidence-based practice; it is however difficult to implement in smaller primary care practices that lack on-site mental health staff. Telemedicine-based collaborative care may represent a solution, as it allows integration of mental health providers into remote primary care settings. The objective of this multisite randomized comparative effectiveness trial was to evaluate the outcomes of patients assigned to practice-based and telemedicine-based collaborative care.
Better outcomes for both response and remission
Greater reductions in depression severity over time (Per Hopkins Symptom Checklist)
Higher patient satisfaction with treatment
Note: Improvements in outcomes appears to be attributable to higher fidelity to the collaborative care evidence base
in the telemedicine-based group compared to the practice-based group.
Conclusions: In the context of small remote primary care practices with no mental health staff, better trained/supervised nurse care managers obtain superior outcomes via telemedicine compared to minimally trained local part-time care managers with no additional supervision from mental health professionals and pharmacists.
The effectiveness of collaborative care programs in the treatment of depression in primary care has been supported by several previous studies. However, in most previous studies collaborative care involved local care managers and mental health specialists. The current study has important implication for the organization of collaborative care in remote settings lacking local mental health providers. For such settings, the current study suggests that centralized care management using full-time managers supervised by specialists yields superior outcomes, even if such care is delivered via teleconference. The benefit of local relationships between patients and providers appears to be surpassed by the higher quality of the care and monitoring delivered as part of the centralized program.
Tansey KE, Guipponi M, Hu X, et al
Biol Psychiatry. 2013;73(7):679-682.
Objectives: The field of pharmacogenetics assumes that drug responses are heritable traits. However, whether an individual’s response to a given drug is heritable has not, in general, been established. The aim of this study was to estimate the heritability of response to antidepressants, by combining genetic data and clinical outcome data after treatment with SSRI or SNRI antidepressants from two large studies in MDD.
Conclusions: These results suggest that response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect.
Multiple previous pharmacogenetics studies have tried to detect genetic markers of antidepressant response, with very limited results so far. The current report suggests that a significant (42%) proportion of the variance in antidepressant response may be related to genetic factors. However, the data implicate a high number of common genetic variants scattered across the genome, none of which have very large effects, but cumulatively contribute to a substantial proportion of variation. This makes more unlikely the possibility of a simple genetic test to predict antidepressant response in clinical populations. Moreover, these data do not imply that one could explain 42% of the variability in antidepressant response, or have 42% accuracy, in a very complex genetic test taking into account all the SNPs highlighted by on these data; the accuracy of such genetic tests may be significantly lower. This report is definitely not the final word on this subject and future studies, with even larger samples, may focus our understanding of genetic predisposition for antidepressant response on a narrower group of genes. However this is a sobering result, which highlights the difficulty of finding a genetic test to accurately predict antidepressant response in clinical populations.
Lithium, Gray Matter, and Magnetic Resonance Imaging Signal
Cousins DA, Aribisala B, Nicol Ferrier I, et al
Biol Psychiatry. 2013;73(7):652-657.
Objectives: Multiple previous magnetic resonance imaging (MRI) studies have reported that lithium can increase the volume of gray matter or the thickness of cortical layers in the human brain. This finding has been interpreted as the result of neurotrophic or neuroprotective effects of the drug (which have also been detected in animal models). The current study has tested an alternate hypothesis, that lithium may influence directly the intensity of the MRI signal and that reported changes in gray matter volumes may be artifacts resulting from the altered image contrasts. This hypothesis was tested by measuring gray matter volume change after a short course of lithium with two neuroimaging methods: voxel-based morphometry and Structural Image Evaluation using Normalization of Atrophy (SIENA).
Lithium (11 days)
Placebo (11 days)
Grey Matter Volume:
Grey Matter Volume:
Conclusion: Magnetic resonance images of the brain differ before and after a short course of lithium, but this difference might derive from a change in the characteristics of the MRI signal rather than an actual increase in gray matter volume.
Lithium remains the gold standard in the treatment of bipolar disorder. However, its clinical effects occur over longer periods of treatment. Multiple studies have highlighted neurotrophic or neuroprotective effects of lithium in animals, while high-definition MRI studies have reported significant increases in gray matter volume even after relatively brief periods of lithium treatment (several weeks). The current report raises the likelihood that such significant increases in gray matter volume after short periods of lithium treatment probably represent an artifact. This should not change our enthusiasm for using lithium for bipolar subjects, but it puts in perspective simplistic biological “explanations” of lithium efficacy.
Milaneschi Y, Hoogendijk W, Lips P, et al.
Molecular Psychiatry advance online publication 9 April 2013; doi: 10.1038/mp.2013.36
Objective: It has been hypothesized that hypovitaminosis D is associated with depression but epidemiological evidence supporting this assertion is limited and contradictory. This study investigated the association between depressive disorders and related clinical characteristics with blood concentrations of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in a large cohort of depressed patients, subjects with remitted depression and healthy controls. Associations between serum 25(OH)D and specific clinical features and the course of illness in currently depressed subjects were also tested.
P value, Statistics
Lower 25 (OH)D levels compared with controls
P=0.001, Cohen’s d=0.21
Lowest 25 (OH)D levels in those with most severe depression
P=0.001, Cohen’s d=0.44
Inverse relationship between vitamin D status and:
- Risk of depressive disorder at 2-year follow-up
P=0.003, β=−0.19, s.e.=0.07,
P=0.03, Relative risk=0.90, 95% CI=0.82–0.99
Conclusions: This large cohort study indicates that low levels of 25(OH)D were associated to the presence and severity of depressive disorder, suggesting that hypovitaminosis D may represent an underlying biological vulnerability for depression.
Low levels of vitamin D are relatively common in the general population, especially at northern latitudes and during winter months. This large study has the merit of carefully assessing the association between vitamin D levels and depression while taking into account a host of possible confounders, including sociodemographic factors, sunlight, urbanization, lifestyle and health. As such, the association reported appears credible: low serum vitamin D levels were found in subjects with both current and remitted depression, and among currently depressed patients lower vitamin D levels were associated with a less favorable course. This study lends credibility to previously reported results on the efficacy of vitamin D supplementation in the treatment of depression. Of note, this cross sectional study does not inform on the directionality of this association. It is possible that low vitamin D levels may trigger depression, but it is also possible that changes in lifestyle associated with depression (obesity, staying indoors and avoiding sunlight, etc.) may result in lower vitamin D levels. However, given the inexpensive and generally benign nature of vitamin D supplementation, these data justify future efforts to study the role of vitamin D supplementation as part of preventive or treatment interventions in major depression.
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