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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 12, March 2013 — Guest Commentator: Manpreet K. Singh, MD, Stanford University School of Medicine, Stanford, CA

 

Antidepressants Normalize the Default Mode Network in Patients With Dysthymia

Posner J, Hellerstein DJ, Gat I, et al
JAMA Psychiatry. 2013;Feb 6:1-10.

Objective: The default mode network (DMN) is a collection of brain regions that reliably deactivate during goal-directed behaviors and is more active during a baseline, or so-called resting, condition. Coherence of neural activity, or functional connectivity, within the brain's DMN is increased in major depressive disorder relative to healthy control (HC) subjects; however, whether similar abnormalities are present in persons with dysthymic disorder (DD) is unknown. Moreover, the effect of antidepressant medications on DMN connectivity in patients with DD is also unknown. This study aimed to use resting-state functional-connectivity magnetic resonance imaging (MRI) to study (1) the functional connectivity of the DMN in subjects with DD vs HC participants and (2) the effects of antidepressant therapy on DMN connectivity.

Methods:

  • After collecting baseline MRI scans from subjects with DD and HC participants, we enrolled the participants with DD into a 10-week prospective, double-blind, placebo-controlled trial of duloxetine and collected MRI scans again at the conclusion of the study.
  • Enrollment occurred between 2007 and 2011 at a University research institute.
  • Volunteer sample of 41 subjects with DD and 25 HC participants aged 18 to 53 years. Control subjects were group matched to patients with DD by age and sex.
  • We used resting-state functional-connectivity MRI to measure the functional connectivity of the brain's DMN in persons with DD compared with HC subjects, and we examined the effects of treatment with duloxetine vs placebo on DMN connectivity.

Results:

Outcomes

Subjects with Dysthymia (N=41)

Healthy Comparison Participants (N=25)

Baseline imaging

Greater coherence of neural activity within the brain’s default mode network (DMN)

Less coherence of neural activity in the DMN

10-week follow-up after treatment with duloxetine (vs placebo)

Normalized DMN connectivity

Typical DMN connectivity


Conclusions:
The baseline imaging findings are consistent with those found in patients with major depressive disorder and suggest that increased connectivity within the DMN may be important in the pathophysiology of both acute and chronic manifestations of depressive illness. The normalization of DMN connectivity following antidepressant treatment suggests an important causal pathway through which antidepressants may reduce depression.

Clinical Commentary
Over the past several months, several pharmaco-MRI studies have been published. It is exciting to see that neuroimaging methods are now being applied to assess neural mechanisms of treatment response. The most direct and common way to evaluate the effect of a medication is to use a pre-post dose imaging design. This article examines the functional connectivity of the dysthymic brain during rest and aims to determine whether antidepressants can alter the way in which brain regions are connected at rest. This is the first of such a study to examine individuals with dysthymic disorder, as opposed to major depressive disorder, which already restricts generalizability of the findings to a population with more chronic low-grade depression. In addition, the agent used for treatment was duloxetine, a strange candidate given that we know so little about the neural effects of more commonly prescribed selective serotonin reuptake inhibitors. Nevertheless, the study found similarities between the neural networks in individuals with depression and dysthymia suggesting that increased connectivity within the default mode network may represent a biological indicator of both acute and chronic forms of depression. In addition, this connectivity normalized with duloxetine treatment, providing a potential mechanism of action by which this medication reduces symptoms.

 

Relationships Between Changes in Sustained Fronto-Striatal Connectivity and Positive Affect in Major Depression Resulting From Antidepressant Treatment

Heller AS, Johnstone T, Light SN, et al
Am J Psychiatry. 2013;170:197-206. 

Objective: Deficits in positive affect and their neural bases have been associated with major depression. However, whether reductions in positive affect result solely from an overall reduction in nucleus accumbens activity and fronto-striatal connectivity or the additional inability to sustain engagement of this network over time is unknown. The authors sought to determine whether treatment-induced changes in the ability to sustain nucleus accumbens activity and fronto-striatal connectivity during the regulation of positive affect are associated with gains in positive affect.

Methods: 

  • Using fMRI, the authors assessed the ability to sustain activity in reward-related networks when attempting to increase positive emotion during performance of an emotion regulation paradigm in 21 depressed patients before and after 2 months of antidepressant treatment.
  • Over the same interval, 14 healthy comparison subjects underwent scanning as well.


Results:

Outcomes

Subjects with Depression (N=21)

Healthy Comparison Participants (N=14)

Baseline imaging

Greater ability to sustain activity in reward-related networks within the brain’s frontostriatal circuitry

Lesser ability to sustain activity in reward-related networks within the brain’s frontostriatal circuitry

8-week follow-up  after antidepressant treatment

Largest increases in sustained nucleaus accumbens activity have largest increases in positive effect

None of these associations were observed in healthy comparison subjects

 

Largest increases in sustained frontostriatal connectivity have largest increases in positive affect when controlling for negative affect

None of these associations were observed in healthy comparison subjects


Conclusions:
Treatment-induced change in the sustained engagement of fronto-striatal circuitry tracks the experience of positive emotion in daily life. Studies examining reduced positive affect in a variety of psychiatric disorders might benefit from examining the temporal dynamics of brain activity when attempting to understand changes in daily positive affect.

Clinical Commentary
Here is another pre-post medication pharmaco-fMRI study examining the effects of antidepressants on the depressed brain. The design of the study was based on the assumption that there are deficits in positive affect in depression, but it is unknown whether these deficits are a cause or effect of the disorder. To examine this question, authors assessed the ability of depressed individuals to sustain activity in reward-related networks when attempting to increase positive emotion during an emotion regulation task before and after 2 months of antidepressant treatment. The treatment was nonuniform among individuals in the study, but the results were nevertheless interesting. Those individuals who demonstrated the largest increases in sustained nucleus accumbens activity (a region essential for processing rewarding stimuli) and functional connectivity between the prefrontal cortex and striatum over the 2 months of treatment had the largest increases in positive affect. These findings provide another mechanism by which antidepressants exert their action of improving hedonic drive by targeting the brain’s reward centers.

 

Predicting Treatment Response in Social Anxiety Disorder From Functional Magnetic Resonance Imaging

Doehrmann O, Ghosh SS, Polli FE, et al
JAMA Psychiatry. 2013;70(1):87-97.

Objectives: Current behavioral measures poorly predict treatment outcome in social anxiety disorder (SAD). To our knowledge, this is the first study aimed to examine neuroimaging-based treatment prediction in SAD to specifically determine whether brain activation in patients with SAD can serve as a biomarker to predict subsequent response to cognitive behavioral therapy (CBT).

Methods:

  • Functional magnetic resonance imaging (fMRI) data were collected prior to CBT intervention.
  • Changes in clinical status were regressed on brain responses and tested for selectivity for social stimuli.
  • Thirty-nine medication-free patients meeting DSM-IV criteria for the generalized subtype of SAD were treated with protocol-based CBT at anxiety disorder programs at Boston University or Massachusetts General Hospital and underwent neuroimaging data collection at Massachusetts Institute of Technology.
  • Brain responses to angry vs neutral faces or emotional vs neutral scenes were examined with fMRI prior to initiation of CBT.
  • Whole-brain regression analyses with differential fMRI responses for angry vs neutral faces and changes in Liebowitz Social Anxiety Scale score were recorded as the treatment outcome measure.


Results:
 

Outcomes

Subjects with SAD (N=39)

Baseline brain functional responses to angry versus neutral faces or emotional versus neutral scenes.

 

Treatment outcome: Whole-brain regression with differential fMRI responses to angry versus neutral faces correlated with changes in social anxiety scale score

Pretreatment responses significantly predicted subsequent treatment outcome of patients selectively for social stimuli and particularly in regions of higher-order visual cortex.

Variance accounted for by combining neuroimaging with clinical measures versus clinical measures alone

Combining the brain measures with information on clinical severity accounted for more than 40% of the variance in treatment response and substantially exceeded predictions based on clinical measures at baseline.  Prediction success was unaffected by testing for potential confounding factors such as depression severity at baseline.


Conclusions:
 The results suggest that brain imaging can provide biomarkers that substantially improve predictions for the success of cognitive behavioral interventions and more generally suggest that such biomarkers may offer evidence-based, personalized medicine approaches for optimally selecting among treatment options for a patient.

Clinical Commentary
This article examines the differential fMRI responses for angry versus neutral faces in socially anxious individuals before and after cognitive-behavioral therapy. This extends our theme of neural mechanisms of treatment effect to psychotherapeutic intervention. It is no news that psychotherapy has direct neural effects; we have known this for some time now, and as time passes, the field is growing ever more sophisticated in modeling the impact of psychotherapy on the brain. What was unique about this study was that in addition to reporting on positive treatment outcomes, this study illustrated the benefit of adding neural measures to symptom severity in the prediction of treatment response. This has important implications for future clinical trials, particularly if predictions for treatment response can be derived from combining subjective report of symptom improvement with an objective biological measure of brain functioning. This leads us to wonder whether we will ever be better off determining the benefits of an intervention by assessing clinical symptom severity alone.


Neural Correlates of Weight Gain With Olanzapine

Mathews J, Newcomer JW, Mathews JR, et al
Arch Gen Psychiatry. 2012;69(12):1226-1237.

Objectives: Iatrogenic obesity caused by atypical antipsychotics increases the rate of death from all causes. Olanzapine is a commonly prescribed atypical antipsychotic medication that frequently causes weight gain. To our knowledge, the neural correlates of this weight gain have not been adequately studied in humans.  To test the hypothesis that olanzapine treatment disrupts the neural activity associated with the anticipation and receipt (consumption) of food rewards (chocolate milk and tomato juice).

Methods:

  • Twenty-five healthy individuals were recruited in this study.
  • Event-related functional magnetic resonance imaging data was collected at a university neuroimaging center, before and after a 1-week treatment with olanzapine.
  • Changes in blood oxygen level–dependent activations to the anticipation and receipt of food rewards after olanzapine treatment were the outcome measures.


Results:

Outcomes

Healthy Participants (N=25)

1 week follow-up after treatment with olanzapine

Significant increases in weight, food consumption, and disinhibited eating.

Imaging during anticipation of food reward

Enhanced activations in the inferior frontal cortex, striatum, and anterior cingulate cortex to the anticipation of a food reward.

Imaging during receipt of food reward

Activation in the caudate and putamen were enhanced to the receipt of the rewarding food.

Imaging during receipt of food reward

Decreased reward responsivity to receipt of the rewarding food in the lateral orbital frontal cortex, an area of the brain thought to exercise inhibitory control on feeding.


Conclusions:
  Olanzapine treatment enhanced both the anticipatory and consummatory reward responses to food rewards in the brain reward circuitry that is known to respond to food rewards in healthy individuals. We also noted a decrease in responsivity to food consumption in a brain area thought to inhibit feeding behavior.

Clinical Commentary
This study examines the neural effects of an adverse side effect associated with pharmacological treatment. Olanzapine is well known to cause weight gain but the neural mechanisms associated with this common side effect are largely unknown. Previously healthy individuals were administered olanzapine for one week to assess neural responses to processing food rewards. After 1 week of olanzapine treatment, healthy individuals had significant increases in weight, food consumption, and disinhibited eating. Corresponding to this behavior, this study found enhanced anticipatory and consummatory reward responses to food reward in regions well known to be part of the brain’s reward circuitry and decreased responsivity to food consumption in brain regions that exert inhibitory control over feeding behavior. This study provides important insights about risks associated with use of psychotropic medications, and provides a clear neural mechanism to explain the increase in food consumption associated with this atypical antipsychotic. It would be interesting to see if neural outcome measures could be used in comparative effectiveness studies to compare various psychotropic medications on their propensity for weight gain, sedation, and other adverse events.  It would also be informative to see if a number needed to harm could be derived from neural outcome measures.

 

Improvement of Brain Reward Abnormalities by Antipsychotic Monotherapy in Schizophrenia

Nielsen MO, Rostrup E, Wulff S, et al
Arch Gen Psychiatry. 2012;69(12):1195-1204. 

Objectives: Schizophrenic symptoms are linked to a dysfunction of dopamine neurotransmission and the brain reward system. However, it remains unclear whether antipsychotic treatment, which blocks dopamine transmission, improves, alters, or even worsens the reward-related abnormalities. This study aimed to investigate changes in reward-related brain activations in schizophrenia before and after antipsychotic monotherapy with a dopamine D2/D3 antagonist.

Methods:

  • Longitudinal cohort study occurred in psychiatric inpatients and outpatients in the Capital Region of Denmark.
  • Twenty-three antipsychotic-naive patients with first-episode schizophrenia and 24 healthy controls initially matched on age, sex, and parental socioeconomic status were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task.
  • Patients were treated for 6 weeks with the antipsychotic compound amisulpride. Controls were followed up without treatment.
  • Task-related blood oxygen level–dependent activations were measured by functional magnetic resonance imaging before and after antipsychotic treatment.


Results:
 

Outcomes

Subjects with First-episode Schizophrenia (N=23)

Healthy Comparison Participants (N=24)

Baseline imaging

Compared with controls, attenuation of brain activation during reward anticipation in the ventral striatum, bilaterally

Increase in ventral striatum activation during reward anticipation

Longitudinal follow-up

Among the patients, there was a correlation between the improvement of positive symptoms and normalization of reward-related activation

 

6-week follow-up after treatment with amisulpride (vs placebo)

Increases in the anticipation-related functional magnetic resonance imaging signal

 

 

Were no longer statistically distinguishable from healthy controls

 

 

Those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment.

 


Conclusions:
To our knowledge, this is the first controlled, longitudinal study of reward disturbances in schizophrenic patients before and after their first antipsychotic treatment. Our results demonstrate that alterations in reward processing are fundamental to the illness and are seen prior to any treatment. Antipsychotic treatment tends to normalize the response of the reward system; this was especially seen in the patients with the most pronounced treatment effect on the positive symptoms.

Trial Registration  clinicaltrials.gov Identifier: NCT01154829.

Clinical Commentary
This study is the first controlled longitudinal study examining reward disturbances in individuals with schizophrenia before and after their first antipsychotic treatment. Antipsychotic-naïve first-episode schizophrenia patients were scanned at baseline and then treated with the antipsychotic amisulpride for 6 weeks. A healthy comparison group matched on age, sex, and parental socioeconomic status were also examined with functional magnetic resonance imaging while playing a variant of a common reward-processing task called the monetary incentive delay task. At baseline, individuals with schizophrenia showed a blunted response in the ventral striatum, a hub region for reward processing. Remarkably, after 6 weeks of treatment, patients with schizophrenia showed an increase in the anticipation-related functional magnetic resonance imaging signal and were no longer statistically distinguishable from healthy controls. Improvement of positive symptoms in the schizophrenia group correlated with normalization of reward-related activation, and those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment. This study demonstrates the very specific way in which treatment with an antipsychotic can ameliorate illness-related deficits in reward processing. This provides insights about the pathophysiology of schizophrenia as well as a mechanism for treatment response. 

 

MR Imaging of the Effects of Methylphenidate on Brain Structure and Function in Attention-Deficit/Hyperactivity Disorder

Schweren LJ, de Zeeuw P, Durston S
Eur Neuropsychopharmacol. 2012 Nov 17.

Objective: Methylphenidate is the first-choice pharmacological intervention for the treatment of attention-deficit/hyperactivity disorder (ADHD). The pharmacological and behavioral effects of methylphenidate are well described, but less is known about neurochemical brain changes induced by methylphenidate. This level of analysis may be informative on how the behavioral effects of methylphenidate are established.

Methods: This paper reviews structural and functional MRI studies that have investigated effects of methylphenidate in children with ADHD.

Results: Structural MRI studies provide evidence that long-term stimulant treatment may normalize structural brain changes found in the white matter, the anterior cingulate cortex, the thalamus, and the cerebellum in ADHD. Moreover, preliminary evidence suggests that methylphenidate treatment may normalize the trajectory of cortical development in ADHD. Functional MRI has provided evidence that methylphenidate administration has acute effects on brain functioning, and even suggests that methylphenidate may normalize brain activation patterns as well as functional connectivity in children with ADHD during cognitive control, attention, and during rest.

Conclusions: The effects of methylphenidate on the developing brain appear highly specific and dependent on numerous factors, including biological factors such as genetic predispositions, subject-related factors such as age and symptom severity, and task-related factors such as task difficulty. Future studies on structural and functional brain changes in ADHD may benefit from inclusion strategies guided by current medication status and medication history. Further studies on the effects of methylphenidate treatment on structural and functional MRI parameters are needed to address unresolved issues of the long-term effects of treatment, as well as the mechanism through which medication-induced brain changes bring about clinical improvement.

Clinical Commentary
In an era of increasing use of psychostimulants both for the treatment of attention deficit with hyperactivity (ADHD) and cognitive enhancement, it is important to understand the neural effects of stimulant treatment, particularly in the developing brain. This paper reviews the structural and functional MRI studies that have investigated effects of methylphenidate in children with ADHD. Structural MRI studies suggest that long-term stimulant treatment can normalize ADHD-related structural anomalies found in the white matter, the anterior cingulate cortex, the thalamus, and the cerebellum. Moreover, methylphenidate treatment may normalize the trajectory of cortical development in ADHD over time. Functional MRI studies suggest that methylphenidate acutely affects brain function, normalizing brain activation patterns as well as functional connectivity in children with ADHD during cognitive control, attention, and during rest. These appear to be specific effects on the developing brain. However, it is important that treatment effects may be strongly dependent on biological factors such as genetic predispositions, subject-related factors such as age and symptom severity, and task-related factors such as task difficulty. These factors make it nearly impossible to infer a direct or causal neural mechanism of an intervention, especially in the context of a dynamic system such as the developing brain. However, it is reassuring to see several lines of evidence converge on a model for how methylphenidate exerts its beneficial effects on an inattentive brain. Future studies that address the potential confounds in the design of the study may provide more conclusive evidence about the effects of stimulants on the brain.

 

 


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