Quetiapine monotherapy for bipolar depression

Bipolar depression is more common, disabling, and difficult-to-treat than the manic and hypomanic phases that define bipolar disorder. Unlike the treatment of so-called “unipolar” depressions, antidepressants generally are not indicated as monotherapies for bipolar depressions and recent studies suggest that -even when used in combination with traditional mood stabilizers – antidepressants may have questionable value for bipolar depression. The current practice is that mood stabilizers are initiated first as monotherapies; however, the antidepressant efficacy of lithium and valproate is modest at best. Within this context the role of atypical antipsychotics is being evaluated. The combination of olanzapine and the antidepressant fluoxetine was the first treatment to receive regulatory approval in the US specifically for bipolar I depression. Quetiapine was the second medication to be approved for this indication, largely as the result of two pivotal trials known by the acronyms of BOLDER (BipOLar DEpRession) I and II. Both studies demonstrated that two doses of quetiapine (300 mg and 600 mg given once daily at bedtime) were significantly more effective than placebo, with no increased risk of patients switching into mania. Pooling the two studies, quetiapine was effective for both bipolar I and bipolar II depressions and for patients with (and without) a history of rapid cycling. The two doses were comparably effective in both studies. Although the efficacy of quetiapine monotherapy has been established, much additional research is necessary. Further studies are needed to more fully investigate dose-response relationships and comparing quetiapine monotherapy to other mood stabilizers (lithium, valproate, and lamotrigine) in bipolar depression, both singly and in combination. Head-to-head studies are needed comparing quetiapine to the olanzapine-fluoxetine combination. Longer-term studies are needed to confirm the persistence of response and to better gauge effects on metabolic profiles across months of therapy. A prospective study of patients specifically seeking treatment for rapid cycling and those with a history of treatment-emergent affective shifts also is needed. Despite the caveats, as treatment guidelines are revised to incorporate new data, the efficacy and tolerability of quetiapine monotherapy must be given serious consideration

Analysis of potentially predictive factors of efficacy of adjunct extended-release quetiapine fumarate in patients with major depressive disorder

Identification of predictors of treatment response in patients with major depressive disorder (MDD) may facilitate improved disease management. Data were pooled from two 6-week, double-blind, placebo-controlled studies of extended-release quetiapine (quetiapine XR; 150 or 300 mg/day) as adjunct to ongoing antidepressant therapy. Effects of psychiatric history and baseline demographic and disease characteristics on efficacy outcomes (Week 6 Montgomery Åsberg Depression Rating Scale [MADRS] total score reduction) were evaluated in population subgroups (quetiapine XR both doses pooled, n = 616; placebo, n = 303). Baseline Clinical Global Impressions-Severity (CGI-S) score and previous depressive episodes on Week 6 MADRS total score change, and baseline MADRS individual item scores on Week 6 change in CGI-Improvement score, were also evaluated. No major differences between responders and non-responders to quetiapine XR were observed for patient characteristics or demographic and disease characteristics. No suggestion of a predictive association was found between baseline CGI-S score, number of depressive episodes, and baseline MADRS item scores and efficacy outcomes. These analyses showed no major differences between responders and non-responders, and no predictive association between the parameters assessed and efficacy outcomes for adjunct quetiapine XR in patients with MDD and an inadequate response to prior antidepressant therapy

ORIGINAL ARTICLES Can’t Shake that Feeling: Event-Related fMRI Assessment of Sustained Amygdala Activity in Response to Emotional Information in Depressed Individuals

individuals engage in prolonged elaborative processing of emotional information. A computational neural network model of emotional information processing suggests this process involves sustained amygdala activity in response to processing negative features of information. This study examined whether brain activity in response to emotional stimuli was sustained in depressed individuals, even following subsequent distracting stimuli. Methods: Seven depressed and 10 never-depressed individuals were studied using event-related functional magnetic resonance imaging during alternating 15-sec emotional processing (valence identification) and nonemotional processing (Sternberg memory) trials. Amygdala regions were traced on high-resolution structural scans and coregistered to the functional data. The time course of activity in these areas during emotional and nonemotional processing trials was examined. Results: During emotional processing trials, never-depressed individuals displayed amygdalar responses to all stimuli, which decayed within 10 sec. In contrast, depressed individuals displayed sustained amygdala responses to negative words that lasted throughout the following nonemotional processing trials (25 sec later). The difference in sustained amygdala activity to negative and positive words was moderately related to self-reported rumination. Conclusions: Results suggest that depression is associated with sustained activity in brain areas responsible for coding emotional features. Biol Psychiatry 2002;51

Parsing Heterogeneity in the Brain Connectivity of Depressed and Healthy Adults During Positive Mood

There is well-known heterogeneity in affective mechanisms in depression that may extend to positive affect. We used data-driven parsing of neural connectivity to reveal subgroups present across depressed and healthy individuals during positive processing, informing targets for mechanistic intervention

Altered synaptic marker abundance in the hippocampal stratum oriens of Ts65Dn mice is associated with exuberant expression of versican

DS (Down syndrome), resulting from trisomy of chromosome 21, is the most common cause of genetic mental retardation; however, the molecular mechanisms underlying the cognitive deficits are poorly understood. Growing data indicate that changes in abundance or type of CSPGs (chondroitin sulfate proteoglycans) in the ECM (extracellular matrix) can influence synaptic structure and plasticity. The purpose of this study was to identify changes in synaptic structure in the hippocampus in a model of DS, the Ts65Dn mouse, and to determine the relationship to proteoglycan abundance and/or cleavage and cognitive disability. We measured synaptic proteins by ELISA and changes in lectican expression and processing in the hippocampus of young and old Ts65Dn mice and LMCs (littermate controls). In young (5 months old) Ts65Dn hippocampal extracts, we found a significant increase in the postsynaptic protein PSD-95 (postsynaptic density 95) compared with LMCs. In aged (20 months old) Ts65Dn hippocampus, this increase was localized to hippocampal stratum oriens extracts compared with LMCs. Aged Ts65Dn mice exhibited impaired hippocampal-dependent spatial learning and memory in the RAWM (radial-arm water maze) and a marked increase in levels of the lectican versican V2 in stratum oriens that correlated with the number of errors made in the final RAWM block. Ts65Dn stratum oriens PNNs (perineuronal nets), an extension of the ECM enveloping mostly inhibitory interneurons, were dispersed over a larger area compared with LMC mice. Taken together, these data suggest a possible association with alterations in the ECM and inhibitory neurotransmission in the Ts65Dn hippocampus which could contribute to cognitive deficits

Impact of Reproductive Status and Age on Response of Depressed Women to Cognitive Therapy

Previous research suggests that reproductive hormones are potential affective modulators in mood disorders and may influence response to antidepressant medications. To our knowledge, there are no data on relationships between hormonal status and response to psychotherapy for recurrent major depressive disorder (MDD)

Divergent Relationship of Depression Severity to Social Reward Responses Among Patients With Bipolar Versus Unipolar Depression

Neuroimaging studies of mood disorders demonstrate abnormalities in brain regions implicated in reward processing. However, there is a paucity of research investigating how social rewards affect reward circuit activity in these disorders. Here, we evaluated the relationship of both diagnostic category and dimensional depression severity to reward system function in bipolar and unipolar depression. In total, 86 adults were included, including 24 patients with bipolar depression, 24 patients with unipolar depression, and 38 healthy comparison subjects. Participants completed a social reward task during 3T BOLD fMRI. On average, diagnostic groups did not differ in activation to social reward. However, greater depression severity significantly correlated with reduced bilateral ventral striatum activation to social reward in the bipolar depressed group, but not the unipolar depressed group. In addition, decreased left orbitofrontal cortical activation correlated with more severe symptoms in bipolar depression, but not unipolar depression. These differential dimensional effects resulted in a significant voxelwise group by depression severity interaction. Taken together, these results provide initial evidence that deficits in social reward processing are differentially related to depression severity in the two disorders

Predicting outcome of internet-based treatment for depressive symptoms.

In this study we explored predictors and moderators of response to Internet-based cognitive behavioral therapy (CBT) and Internet-based problem-solving therapy (PST) for depressive symptoms. The sample consisted of 263 participants with moderate to severe depressive symptoms. Of those, 88 were randomized to CBT, 88 to PST and 87 to a waiting list control condition. Outcomes were improvement and clinically significant change in depressive symptoms after 8 weeks. Higher baseline depression and higher education predicted improvement, while higher education, less avoidance behavior and decreased rational problem-solving skills predicted clinically significant change across all groups. No variables were found that differentially predicted outcome between Internet-based CBT and Internet-based PST. More research is needed with sufficient power to investigate predictors and moderators of response to reveal for whom Internet-based therapy is best suited. © 2013 Copyright Society for Psychotherapy Research