Brian M. Iacoviello

Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies.

Major depressive disorder (MDD) is a disabling medical condition associated with significant morbidity, mortality and public health costs. However, neurocircuitry abnormalities underlying depression remain incompletely understood and consequently current treatment options are unfortunately limited in efficacy. Recent research has begun to focus specifically on cognitive aspects of depression and potential neurobiological correlates. Two fundamental types of cognitive dysfunction observed in MDD are cognitive biases, which include distorted information processing or attentional allocation toward negative stimuli, and cognitive deficits, which include impairments in attention, short-term memory and executive functioning. In this article, we present a selective review of current research findings in these domains and examine neuroimaging research that is beginning to characterize the neurocircuitry underlying these biases and deficits. We propose that deficient cognitive functioning, attention biases and the sustained negative affect characteristic of MDD can be understood as arising in part from dysfunctional prefrontal-subcortical circuitry and related disturbances in the cognitive control of emotion. Finally, we highlight potential new pharmacological and non-pharmacological therapeutic strategies for MDD based on an evolving mechanistic understanding of the disorder.

Behavioral Approach System and Behavioral Inhibition System sensitivities and bipolar spectrum disorders: prospective prediction of bipolar mood episodes

OBJECTIVES Research has found that bipolar spectrum disorders are associated with Behavioral Approach System (BAS) hypersensitivity and both unipolar and bipolar depression are associated with high Behavioral Inhibition System (BIS) sensitivity, but prospective studies of these relationships are lacking. We tested whether BAS and BIS sensitivities prospectively predicted the time to new onsets of major depressive and hypomanic and manic episodes in bipolar spectrum individuals. METHODS We followed 136 bipolar II or cyclothymic and 157 demographically matched normal control individuals prospectively for an average of 33 months. Participants completed the BIS/BAS scales and symptom measures at Time 1 and semi-structured diagnostic interviews every four months of follow-up. RESULTS The bipolar spectrum group exhibited higher Time 1 BAS, but not BIS, scores than the normal controls, controlling for Time 1 symptoms. Among bipolar spectrum participants, high BAS sensitivity prospectively predicted a shorter time to onset of hypomanic and manic episodes, whereas high BIS sensitivity predicted less survival time to major depressive episodes, controlling for initial symptoms. CONCLUSIONS Consistent with the BAS hypersensitivity model of bipolar disorder, a highly responsive BAS provides vulnerability to onsets of (hypo)manic episodes. In addition, a highly sensitive BIS increases risk for major depressive episodes.

Attention Bias Variability and Symptoms of Posttraumatic Stress Disorder

Cognitive theories implicate information-processing biases in the etiology of anxiety disorders. Results of attention-bias studies in posttraumatic stress disorder (PTSD) have been inconsistent, suggesting biases towards and away from threat. Within-subject variability of attention biases in posttraumatic patients may be a useful marker for attentional control impairment and the development of posttrauma symptoms. This study reports 2 experiments investigating threat-related attention biases, mood and anxiety symptoms, and attention-bias variability following trauma. Experiment 1 included 3 groups in a cross-sectional design: (a) PTSD, (b) trauma-exposed without PTSD, and (c) healthy controls with no trauma or Axis I diagnoses. Greater attention-bias variability was found in the PTSD group compared to the other 2 groups (η(p)2=.23); attention-bias variability was significantly and positively correlated (r = .37) with PTSD symptoms. Experiment 2 evaluated combat-exposed and nonexposed soldiers before and during deployment. Attention-bias variability did not differentiate groups before deployment, but did differentiate groups during deployment (ηp2=.16); increased variability was observed in groups with acute posttraumatic stress symptoms and acute depression symptoms only. Attention-bias variability could be a useful marker for attentional impairment related to threat cues associated with mood and anxiety symptoms after trauma exposure.

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial

BACKGROUND Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. METHOD We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale--Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. RESULTS The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. CONCLUSIONS The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

Psychosocial facets of resilience: implications for preventing posttrauma psychopathology, treating trauma survivors, and enhancing community resilience

Background There is a range of potential responses to stress and trauma. Whereas, on one extreme, some respond to stress and trauma by developing psychiatric disorders (e.g., posttraumatic stress disorder, PTSD), on the other extreme are the ones who exhibit resilience. Resilience is broadly defined as adaptive characteristics of an individual to cope with and recover from adversity. Objective Understanding of the factors that promote resilience is warranted and can be obtained by interviewing and learning from particularly resilient individuals as well as empirical research. In this paper, we discuss a constellation of factors comprising cognitive, behavioral, and existential elements that have been identified as contributing to resilience in response to stress or trauma. Results The psychosocial factors associated with resilience include optimism, cognitive flexibility, active coping skills, maintaining a supportive social network, attending to ones physical well-being, and embracing a personal moral compass. Conclusions These factors can be cultivated even before exposure to traumatic events, or they can be targeted in interventions for individuals recovering from trauma exposure. Currently available interventions for PTSD could be expanded to further address these psychosocial factors in an effort to promote resilience. The cognitive, behavioral, and existential components of psychosocial factors that promote individual resilience can also inform efforts to promote resilience to disaster at the community level.

Emotional maltreatment and depression: prospective prediction of depressive episodes

Background: Most research to date on the role of maltreatment experiences in depression has focused on physical and sexual maltreatment. However, several researchers have theorized that emotional maltreatment may be more strongly linked to depression. Furthermore, prospective studies in this area are lacking. This study addressed these issues by examining whether experiences of current emotional maltreatment predicted the development of new prospective episodes of major (MD) or minor depression (MiD), and the subtype of hopelessness depression (HD) in young adults. It also assessed whether current emotional maltreatment from peers and from authority figures separately predicted the occurrence of depressive episodes. Method: One hundred and sixty‐five participants from the Cognitive Vulnerability to Depression Project were followed prospectively for 2.5 years. Current emotional maltreatment and new depressive episodes were assessed with life event and diagnostic interviews administered every 6 weeks. Results: Greater overall emotional maltreatment predicted shorter time to onset of new MD, MiD, and HD episodes. Peer‐ and authority‐perpetrated emotional maltreatment separately predicted shorter time to development of new HD episodes. Conclusions: Greater emotional maltreatment in young adults prospectively predicts onset of depression, particularly HD. These findings highlight the importance of adult emotional maltreatment experiences in determining targets for prevention and treatment. Depression and Anxiety, 2009.

The Early Course of Depression: A Longitudinal Investigation of Prodromal Symptoms and Their Relation to the Symptomatic Course of Depressive Episodes

The present study explored longitudinal evidence for prodromal symptoms of depression episodes. A model based on previous findings of the relations between prodromal and residual symptoms was described and used to generate hypotheses tested in this study. Data were analyzed from 160 participants from the Cognitive Vulnerability to Depression (CVD) project (L. Alloy & L. Abramson, 1999) who experienced an episode of depression during the prospective follow-up period and 60 CVD participants who did not. Congruent with the hypothesis, individuals who subsequently developed an episode of depression experienced significantly greater numbers of depression symptoms in the period of time leading up to the acute episode compared with those who did not develop a depressive episode. Seven depression symptoms were particularly likely to appear before the onset of an acute episode. Furthermore, all 3 predictions from the model were supported: the durations of prodromal and residual phases were correlated, the prodromal and residual symptom profiles were quite similar, and the order of symptom onset was significantly and highly negatively correlated with the order of symptom remission. Additionally, residual symptom profiles were similar to subsequent prodromal symptom profiles in individuals who experienced more than 1 depressive episode. These findings are discussed in terms of the importance of understanding the earliest prodromal symptoms to appear and their relation to the symptomatic course of depression episodes. Implications for early intervention are also discussed.

NEO-FFI factor scores as predictors of clinical response to fluoxetine in depressed outpatients

Research in unipolar depression suggests that neuroticism is associated with poor long-term outcome and greater chronicity. The objective of this study was to determine whether baseline neuroticism scores predict response to treatment with fluoxetine in depressed outpatients. Seventy-six depressed outpatients participating in a clinical trial of fluoxetine (fixed/flexible dosing) completed the NEO-FFI (five factor inventory short form) at baseline. Clinical response was defined as a 50% or greater decrease in the 17-item Hamilton Depression Rating Scale (HAM-D-17) total score (final visit--baseline). Logistic regression evaluated NEO-FFI factor scores as predictors of treatment outcome within an intent-to-treat model. Scores on the neuroticism scale were not found to significantly predict treatment response as measured by the HAM-D-17. Strengths of this study include a standardized treatment protocol and use of structured interview instruments, while limitations include a modest sample size, lack of continuation data, state/trait effects, and lack of generalizability to other antidepressant treatments.

Cognitive-emotional training as an intervention for major depressive disorder.

There is an urgent need for more effective treatments for major depressive disorder (MDD). As understanding of the cognitive and affective neuroscience underlying psychiatric disorders expands, so do opportunities to develop interventions that capitalize on the capacity for brain plasticity. Cognitive training is one such strategy. In this article, we report a proof‐of‐concept study of a novel cognitive‐emotional training exercise designed to enhance cognitive control for emotional information processing and targeting components of the neural networks that have been implicated in MDD.

Risk Factors for the Development of Psychopathology Following Trauma.

Traumatic experiences can lead to a range of mental health problems with posttraumatic stress disorder (PTSD) leading as the most documented disorder following trauma. Epidemiological research has found the rate of exposure to trauma to far outweigh the prevalence of PTSD. Indicating that most people do not develop PTSD following a traumatic event, this phenomenon has led to an interest in evaluating risk factors to determine who develops PTSD. Risk factors for the development of psychopathology following trauma exposure fall into three categories: pre-trauma, peri-trauma and post-trauma factors. Pre-trauma factors can include age, gender, race/ethnicity, education, prior psychopathology, and neurobiological factors. Peri-trauma factors can include the duration/severity of trauma experience and the perception that the trauma has ended. Post-trauma factors can include access to needed resources, social support, specific cognitive patterns, and physical activity. To date, several important risk factors have been found to impact the risk of developing PTSD including gender, age, education, IQ, race and ethnicity, sexual orientation, pre-trauma psychopathology, prior trauma exposure, familial psychiatric history, and neurobiological factors. This article outlines the state of research findings on pretraumatic, peritraumatic, and posttraumatic risk factors for the development of PTSD and associated psychopathology following trauma.