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Unipolar major depressive disorder is a debilitating condition with a lifetime prevalence of 17%. Recent epidemiological evidence indicates that MDD is the fourth leading cause of disease burden and the leading cause of disability-adjusted life years.
Unipolar major depressive disorder (MDD) is a debilitating condition with a lifetime prevalence of 17%.1 Recent epidemiological evidence indicates that MDD is the fourth leading cause of disease burden and the leading cause of disability-adjusted life years.2 Fortunately, a wide range of MDD treatments are available, including psychotherapy and psychopharmacology. Available data suggest that psychotherapy for MDD is effective, protects against relapse, and does not carry the same risks of adverse effects as comparably effective psychopharmacology. Despite the evidence that psychotherapy is an effective intervention for MDD, relatively little is known about its potential neurobiological mechanisms of action. That is, how does psychotherapy affect brain function? This stands in stark contrast to the wealth of research documenting brain changes that accompany psychopharmacological treatments for MDD.
The potential reasons for this disparity are unclear, although probable contributors include:
Despite these challenges, several studies of brain imaging have examined the effects of psychotherapy on brain function and compared these changes to those of various psychopharmacological interventions. The overall conclusions of these initial reports are that effective psychotherapy can robustly change brain functioning in specific brain areas related to cognitive control, self-referential processing, reward based decision making, and assigning emotional salience to external events. However, the short-term effects of psychotherapy on brain function appear to be in different brain areas than psychopharmacological treatment, despite comparable symptom outcomes. The reasons for these disparities are a current focus of study and speak to how little is presently understood about the pathophysiology of MDD, as well as the multiple ways that brain functioning can normalize with the remission of depression symptoms.
Psychotherapy for unipolar MDD
Treatment guidelines formulated by the American Psychiatric Association recommend
psychotherapy, pharmacotherapy, or a combination of the 2 as first-line treatment for mild to moderate MDD. Most notably, the protective effects of psychotherapy against MDD relapse after termination of treatment is impressive.3 A study of more than 100 patients who responded to treatment found that relapse occurred in 76.2% of those who had received medication. The relapse rate was only 30.8% among those who had received psychotherapy.4
The most common empirically validated modalities of psychotherapy for MDD include cognitive therapy (CT), behavioral activation therapy (BAT), CBT, problem-solving therapy, and IPT. In outpatients with mild MDD, there do not appear to be outcome differences between psychotherapy, psychopharmacological intervention, and placebo, although in outpatients with moderate to severe MDD, both treatment approaches outperform placebo.5 In addition, there is growing evidence that certain psychotherapies are as effective as psychopharmacology for acute, severe major depression.5
For example, in a randomized, triple-blind study that compared BAT, CT, medication, and placebo for depression, Dimidjian and colleagues6 reported that symptom remission rates were not significantly different between BAT and paroxetine treatment for participants with severe MDD. In addition, psychotherapy appears to have more enduring effects than antidepressants. Hollon and colleagues4 reported that CT was as effective as psychopharmacology during the acute phase of treatment, yet more effective than psychopharmacology at preventing relapse during continuation phases of treatment. The investigators argued that although psychotherapy may be more expensive than psychopharmacology in the short term, psychotherapy becomes less expensive after the eighth month of treatment.
A host of brain imaging techniques are available, including computed tomography, single photon emission computed tomography, and positron emission tomography (PET), and MRI. MRI has become the tool of choice in psychiatric treatment-outcome research because of its excellent contrast properties and its noninvasive nature (a particularly important feature given that longitudinal treatment-outcome research requires repeated scanning).
Research MRI uses a clinical scanner with specific pulse sequences. MRI detects signal changes when hydrogen nuclei fall back into alignment after a strong radio pulse. These signal changes may be converted to an image based on different types of body tissue. Structural MRI assesses precise volumetric measurements of brain structures, whereas functional MRI (fMRI) measures regional brain activity during particular task conditions. These 2 modalities may be coregistered to allow for structural localization of changes in brain function brought about by effective interventions (for an in-depth review of the technical aspects of fMRI, see Huettel et al7).
The effects of psychotherapy
As noted, the majority of brain-imaging research into the neuroanatomical correlates of antidepressant treatment has focused on the effects of psychopharmacology. A well-established
model of the pathophysiology of MDD has emerged that implicates impaired corticolimbic functioning at the onset and maintenance of depressive symptoms.8-11 That is, MDD affects cortical regions that mediate directed attention, reward-based decision making, and monitoring of emotional salience; subcortical regions that modulate emotional memory formation and memory retrieval; and perhaps most critically, the coordinated interactions of distributed networks of limbocortical pathways. As eloquently summarized by Helen Mayberg, MD, a pioneer in the field of biomedical MDD research: "Depression is unlikely a disease of a single gene, brain region, or neurotransmitter system. Rather, the syndrome is conceptualized as a systems disorder with a depressive episode viewed as the net effect of failed network regulation under circumstances of cognitive, emotional, or somatic stress.12"
This conceptualization of MDD as a “systems disorder” may account, at least partly, for the varied and seemingly contradictory findings in the neuroimaging literature that address brain regions implicated in the disorder. That is, functioning of particular brain regions may be up or down-regulated depending on functioning of other, interconnected regions.
Studies of the effects of psychotherapy for MDD are broadly consistent with this corticolimbic model of MDD. Frontocortical and limbic regions are implicated in MDD, and functioning of these regions changes with symptom remission. However, direct comparisons of the effects of psychopharmacology and psychotherapy for MDD demonstrate that while clinical effects are positive and typically comparable, their effects on the brain are often quite different. At least 4 published brain imaging studies have directly compared psychotherapy and psychopharmacology outcomes (Table), and all indicate distinct and overlapping brain areas that are responsive to each form of treatment.13-16 Two other published studies of the effects of psychotherapy alone, (ie, without a psychopharmacology comparator), implicate unique regions of action as well.17,18
For example, Kennedy and colleagues15 compared clinically successful CBT treatment with venlafaxine treatment using PET imaging. Both study groups showed decreased bilateral orbitofrontal cortex and left medial prefrontal cortex metabolism and increased right occipitotemporal cortex metabolism. However, metabolism changes in a number of regions were markedly different between treatment modalities. For example, metabolism of the posterior cingulate and the left inferior temporal cortex decreased with venlafaxine response, yet metabolism in these same regions increased in CBT responders. There were also regions responsive to one modality but not the other: thalamus metabolism decreased in CBT responders but did not change in response to venlafaxine, whereas metabolism of the right nucleus accumbens and subgenual cingulate decreased in venlafaxine responders but did not change in response to CBT.
A PET comparison of CBT with paroxetine documented comparable rates of treatment response between the 2 interventions.16,19 Common brain areas that were responsive to treatment included metabolic increases in hippocampus and dorsal cingulate metabolic decreases in dorsal, ventral, and medial frontal cortex. However, metabolic changes in the subgenual cingulate, insula, brain stem, and cerebellum were unique to paroxetine treatment response, and differences in dorsal mid-cingulate, ventromedial frontal cortex, and pos terior cingulate were unique to CBT treatment effects.
To help explain these seemingly inconsistent or even contradictory results, Goldapple and colleagues16 proposed a model whereby treatment-specific effects “target different primary sites with differential top-down and bottom-up effects, both resulting in a net change in critical prefrontal-hippocampal pathways.” In other words, psychotherapy may initially affect so-called higher-order cortical functions (eg, processes mediated by the prefrontal cortex, such as working memory, decision making, and executive functions) because the initial effects of psychotherapy are cognitively mediated. Over time, the downstream effects of changes in cognitive functioning may have an affect on limbic/affective structures (perhaps via reciprocal interconnections and/or because of the effects of initial symptom remission and accompanying novel behavioral patterns and learned associations). Conversely, the initial impact of psychopharmacology may be on subcortical regions that mediate circadian and vegetative functions, yet downstream effects may include a normalization of functioning of the same cortical structures that are initially responsive to psychotherapy. A full test of this model would require multiple brain imaging assessments over time to track the chronometry of brain responses to different treatment modalities to evaluate whether the effects of various treatment modalities affect the brain in this fashion. Figure 1 summarizes this proposed model.
Models of the psychobiology of response to psychotherapy in MDD that emanate from brain
imaging studies have successfully integrated a wealth of data into a coherent structure. However, most data that have contributed to these models are derived from either so-called resting state paradigms or tasks that present negative emotional stimuli as probes. Notably absent are data that examine response to psychotherapy in brain regions mediating the symptom domain of anhedonia in MDD. By definition, such studies would need to include measurements of responses to positive hedonic stimuli to assess whether and how psychotherapy may increase functioning of brain structures mediating responses to putatively pleasurable events.
Our own research group is currently taking such an approach by investigating Behavioral Activation Therapy for Depression outcomes in MDD with an fMRI paradigm that assesses response to monetary incentives. In other words, in the fMRI environment, brain functioning is assessed in response to cues that signal monetary rewards to probe functioning of the striatum and associated reward centers both pretreatment and posttreatment (Figure 2). Though analyses of these data are ongoing, initial unpublished results suggest that MDD is characterized by hypoactivation in the striatum and related structures during reward anticipation, and effective psychotherapy for MDD is associated with improved functioning of these same brain regions (Smoski, unpublished data, 2008; Dichter, unpublished data, 2008). Pending replication of these findings, the implications of this research
are that psychotherapy may be effective not only for normalization of functioning of brain systems that mediate responses to sad events but also functioning of those circuits that mediate approach motivation towards cues of pleasure and reward.
Brain imaging may one day help psychiatrists predict which patients will respond to specific treatment modalities based on individual patterns of baseline brain functioning. Initial results suggest that this may be possible. A study of the effects of CBT in MDD demonstrated that better treatment response was predicted by lower pretreatment fMRI activity in the subgenual cingulate cortex and higher pretreatment activity in the right amygdala.18 In other words, a particular pattern of brain functioning during the depressed state predicted who responded to a specific modality of psychotherapy. Although the replicability of such a finding has yet to be established, such individualized matching of patients to specific treatments based on a single brain scan is clearly the holy grail of psychiatric brain imaging treatment-outcome research.
The authors report no conflicts of interest concerning the subject matter of this article.
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