Robert D. Levitan

Antidepressant Monotherapy vs Sequential Pharmacotherapy and Mindfulness-Based Cognitive Therapy, or Placebo, for Relapse Prophylaxis in Recurrent Depression

CONTEXT Mindfulness-based cognitive therapy (MBCT) is a group-based psychosocial intervention designed to enhance self-management of prodromal symptoms associated with depressive relapse. OBJECTIVE To compare rates of relapse in depressed patients in remission receiving MBCT against maintenance antidepressant pharmacotherapy, the current standard of care. DESIGN Patients who met remission criteria after 8 months of algorithm-informed antidepressant treatment were randomized to receive maintenance antidepressant medication, MBCT, or placebo and were followed up for 18 months. SETTING Outpatient clinics at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, and St Josephs Healthcare, Hamilton, Ontario. PARTICIPANTS One hundred sixty patients aged 18 to 65 years meeting DSM-IV criteria for major depressive disorder with a minimum of 2 past episodes. Of these, 84 achieved remission (52.5%) and were assigned to 1 of the 3 study conditions. INTERVENTIONS Patients in remission discontinued their antidepressants and attended 8 weekly group sessions of MBCT, continued taking their therapeutic dose of antidepressant medication, or discontinued active medication and were switched to placebo. MAIN OUTCOME MEASURE Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression on module A of the Structured Clinical Interview for DSM-IV. RESULTS Intention-to-treat analyses showed a significant interaction between the quality of acute-phase remission and subsequent prevention of relapse in randomized patients (P = .03). Among unstable remitters (1 or more Hamilton Rating Scale for Depression score >7 during remission), patients in both MBCT and maintenance treatment showed a 73% decrease in hazard compared with placebo (P = .03), whereas for stable remitters (all Hamilton Rating Scale for Depression scores ≤7 during remission) there were no group differences in survival. CONCLUSIONS For depressed patients achieving stable or unstable clinical remission, MBCT offers protection against relapse/recurrence on a par with that of maintenance antidepressant pharmacotherapy. Our data also highlight the importance of maintaining at least 1 long-term active treatment in unstable remitters.

Dopamine for "wanting" and opioids for "liking": a comparison of obese adults with and without binge eating.

Obesity research suffers from an overinclusion paradigm whereby all participants with a BMI beyond a certain cutoff value (e.g., 30) are typically combined in a single group and compared to those of normal weight. There has been little attempt to identify meaningful subgroups defined by their salient biobehavioral differences. In order to address this limitation, we examined genetic and psychological indicators of hedonic eating in obese adults with (n = 66) and without (n = 70) binge eating disorder (BED). Our analyses focused on dopamine (DA) and opioid genetic markers because of their conjoint association with the functioning of brain reward mechanisms. We targeted three functional polymorphisms related to the D2 receptor (DRD2) gene, as well as the functional A118G polymorphism of the mu‐opioid receptor (OPRM1) gene. We found that significantly more obese controls had the “loss‐of‐function” A1 allele of Taq1A compared to their BED counterparts, whereas the “gain‐of‐function” G allele of A118G occurred with greater frequency in the BED group. A significant gene–gene combination χ2 analysis also indicated that of those participants with the gain‐gain genotype (G+ and A1), 80% were in the BED group whereas only 35% with the loss‐loss genotype (G− and A1+) were in this group. Finally, BED subjects had significantly higher scores on a self‐report measure of hedonic eating. Our findings suggest that BED is a biologically based subtype of obesity and that the proneness to binge eating may be influenced by a hyper‐reactivity to the hedonic properties of food—a predisposition that is easily exploited in our current environment with its highly visible and easily accessible surfeit of sweet and fatty foods.

A naturalistic visual scanning approach to assess selective attention in major depressive disorder

Cognitive biases in information processing play an important role in the etiology and maintenance of emotional disorders. A new methodology to measure attentional biases is presented; this approach encourages subjects to scan and re-scan images with different thematic content, while the pattern of their attentional deployment is continuously monitored by an eye-tracking system. Measures of attentional bias are the total fixation time and the average glance duration on images belonging to a particular theme. Results showed that subjects with depressive disorder (n=8; Beck Depression Inventory Score>/=16) spent significantly more time looking at images with dysphoric themes than subjects in the control group (n=9). Correlation analysis revealed that the differences between the fixation times of the two groups are significantly correlated with the valence ratings, but not with the arousal ratings of the images. The average glance duration on images with social, neutral and threatening themes were similar for both groups, while the average glance duration on images with dysphoric themes was significantly larger for subjects with depressive disorder. The above results suggest that subjects with depressive disorder selectively attend to mood-congruent material and that depression appears to influence the elaborative stages of processing when dysphoric images are viewed.

Reward sensitivity and the D2 dopamine receptor gene: A case-control study of binge eating disorder

OBJECTIVE The sensitivity of dopamine reward pathways has been implicated in the risk for various psychiatric disorders including compulsive overeating. The evidence is divided, however, about the direction of causal association. One argument is that a Reward Deficiency Syndrome is the risk factor, while others contend that hyper-sensitivity to reward enhances the motivation for pleasurable activities like eating. Unfortunately, little human research has bridged the gap between psychological and neurobiological approaches to brain reward functioning and disorder. The present study addressed this issue by implementing psychological and biological markers of reward sensitivity in the assessment protocol. METHODS Adults with binge eating disorder (BED) were compared to samples of normal-weight and obese controls on two personality measures of reward sensitivity and were genotyped for six markers of the DRD2 dopamine receptor gene. RESULTS Genotype x Group ANOVAs revealed significant main effects and an interaction on the personality measures for Taq1A. BED and obese subjects reported greater reward sensitivity than normal-weight controls, but only among those carrying the A1 allele. We also found that normal-weight controls with at least one copy of the T allele of the C957T marker had significantly lower reward sensitivity scores than any of the other groups who did not differ from each other. CONCLUSIONS Given evidence linking the A1 allele with reduced receptor density, an inverse relationship was expected between psychological measures of reward sensitivity and presence of the A1 allele. One explanation for our findings could be that the BED and obese participants possess another genetic variant that interacts with the A1 allele to produce higher dopamine activity. These findings have implications for future studies of the molecular genetics of BED and obesity, and for behavioural and pharmacologic therapies targeting these conditions.

Treatment-specific changes in decentering following mindfulness-based cognitive therapy versus antidepressant medication or placebo for prevention of depressive relapse.

OBJECTIVE To examine whether metacognitive psychological skills, acquired in mindfulness-based cognitive therapy (MBCT), are also present in patients receiving medication treatments for prevention of depressive relapse and whether these skills mediate MBCTs effectiveness. METHOD This study, embedded within a randomized efficacy trial of MBCT, was the first to examine changes in mindfulness and decentering during 6-8 months of antidepressant treatment and then during an 18-month maintenance phase in which patients discontinued medication and received MBCT, continued on antidepressants, or were switched to a placebo. In total, 84 patients (mean age = 44 years, 58% female) were randomized to 1 of these 3 prevention conditions. In addition to symptom variables, changes in mindfulness, rumination, and decentering were assessed during the phases of the study. RESULTS Pharmacological treatment of acute depression was associated with reductions in scores for rumination and increased wider experiences. During the maintenance phase, only patients receiving MBCT showed significant increases in the ability to monitor and observe thoughts and feelings as measured by the Wider Experiences (p < .01) and Decentering (p < .01) subscales of the Experiences Questionnaire and by the Toronto Mindfulness Scale. In addition, changes in Wider Experiences (p < .05) and Curiosity (p < .01) predicted lower Hamilton Rating Scale for Depression scores at 6-month follow-up. CONCLUSIONS An increased capacity for decentering and curiosity may be fostered during MBCT and may underlie its effectiveness. With practice, patients can learn to counter habitual avoidance tendencies and to regulate dysphoric affect in ways that support recovery.

'Food addiction' and its association with a dopaminergic multilocus genetic profile

BACKGROUND Our objective was to employ a novel genetic methodology - whereby functional variants of the dopamine pathway were aggregated to reflect a polygenic liability - in the study of food addiction. We anticipated that the composite index of elevated dopamine signaling (a multilocus genetic profile score [MLGP]) would distinguish those with a designation of food addiction (according to the Yale Food Addiction Scale [YFAS] criteria), and age and weight equivalent controls. Our second aim was to assess whether this index was positively associated with eating-related sub-phenotypes of food addiction (e.g. binge eating and food cravings). METHODS Adults (n=120) recruited from the community were solicited for an overeating/overweight study. Eating-behavior questionnaires were completed and a blood sample was taken for genotyping. RESULTS AND CONCLUSIONS The YFAS identified 21 participants with food addiction. As predicted, the MLGP score was higher in those with YFAS-diagnosed food addiction, and it correlated positively with binge eating, food cravings, and emotional overeating. We then tested a multiple-mediation model proposing that reward-driven overeating facilitates the relationship between the MLGP score and food addiction. The model was statistically significant, supporting the view that the relationship between a composite genetic index of dopamine signaling and food addiction is mediated by certain aspects of reward-responsive overeating.

The dopamine-4 receptor gene associated with binge eating and weight gain in women with seasonal affective disorder: an evolutionary perspective.

BACKGROUND We recently described a preliminary association between the hypofunctional seven-repeat allele of the dopamine-4 receptor gene (DRD4) and increased maximal lifetime body mass index in women with seasonal affective disorder (SAD). In this study, we examined whether binge eating behavior mediated this putative association. METHODS The study sample consisted of 131 women with winter SAD who reported increased intake of high-carbohydrate/high-fat foods during depressive episodes. We compared rates of binge eating behavior in the two genotypic groups defined by the presence or absence of the seven-repeat allele of DRD4. RESULTS Consistent with our working hypothesis, the proportion of binge eaters was significantly greater in probands with the seven-repeat allele (18 of 46, 39.1%) than in probands without this allele (14 of 85, 16.5%) [chi(2)(1)= 8.32, p = .004; odds ratio = 3.25, 95% confidence interval 1.43, 7.41]. CONCLUSIONS Pending replication in other samples, these results point to a genetic factor that could help in the early identification and treatment of women at higher risk for seasonal weight gain associated with binge eating behavior. At a theoretic level, the current results suggest a novel link between evolutionary models of seasonal weight gain on the one hand and the DRD4 gene on the other.

Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder

There is significant evidence that altered dopamine activity plays a role in seasonal affective disorder (SAD). The current study examined three separate genetic hypotheses for SAD related to the 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), a variant associated with decreased affinity for dopamine. We examined the possible contribution of 7R to the overall expression of SAD, attention deficit disorder (ADD) comorbidity, and body weight regulation. As part of an ongoing genetic study of increased eating behavior and mood in female subjects, 108 women with winter SAD and carbohydrate craving/weight gain were administered the Wender-Utah Rating Scale to measure childhood ADD symptomatology, and a questionnaire to assess maximal lifetime body mass index (BMI). To test for an association between 7R and the categorical diagnosis of SAD, the transmission disequilibrium test (TDT) was used in a subsample of probands providing familial DNA. Standard parametric tests were used to compare childhood ADD symptoms and maximal lifetime BMI across the two genotypic groups defined by the presence or absence of 7R. The TDT found no initial evidence for an association between 7R and the categorical diagnosis of SAD. However, 7R carriers reported significantly greater inattention and dysphoria in childhood (p=0.01 and 0.001, respectively) and a higher maximal lifetime BMI (p=0.007) than did probands without this allele. Furthermore, excluding probands with extreme obesity (maximal BMI >40), a strong correlation was found linking childhood inattentive symptoms and maximal lifetime BMI (r=0.35, p=0.001). In overeating women with SAD, the 7R allele of DRD4 may be associated with a unique developmental trajectory characterized by attentional deficits and dysphoria in childhood and mild to moderate obesity in adulthood. This developmental course may reflect different manifestations of the same underlying vulnerability related to central dopamine dysfunction. Given the possibility of population stratification when studying genotype/phenotype relationships, future use of genomic controls and replication of our findings in other overeating and/or ADD populations are needed to confirm these initial results.

Validity of the computerized DIS for diagnosing psychiatric inpatients

The validity of a self-administered, computerized version of the National Institute of Mental Health Diagnostic Interview Schedule (DIS) was evaluated with a group of 41 psychiatric inpatients. Each patient was administered the computerized DIS (C-DIS) and a semi-structured clinical interview using the symptom checklist developed by Helzer et al. The concordance between the C-DIS and symptom checklist was comparable to that found in earlier studies of the original DIS. The overall distribution of kappas was also similar to those of previous studies. Overall, the results suggest that computerized administration may be a feasible alternative to face-to-face administration of the DIS.

Replicating the five factor model of personality in a psychiatric sample

Abstract In this study we examined whether the factor structure and traits of the five-factor model of personality (FFM), derived from non-clinical samples, could be replicated in a sample of psychiatric patients. The revised NEO Personality Inventory (NEO PI-R) was administered to a study group of psychiatric patients ( n =176). The test scores from these patients were intercorrelated, factor analyzed and the obtained factor structure was then compared to the factor structure of the normative data from the NEO PI-R. The factor structure from the psychiatric study group and that from the normative sample were virtually identical, with all five factors showing significant congruence. These results argue favorably for the clinical applicability of the FFM with psychiatric patients.