Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Corrigendum: Functional MRI study of feedback-based reinforcement learning in depression.

[This corrects the article DOI: 10.3389/fninf.2022.1028121.].

Functional MRI study of feedback-based reinforcement learning in depression.

Reinforcement learning depends upon the integrity of emotional circuitry to establish associations between environmental cues, decisions, and positive or negative outcomes in order to guide behavior through experience. The emotional dysregulation characteristic of major depressive disorder (MDD) may alter activity in frontal and limbic structures that are key to learning. Although reward and decision-making have been examined in MDD, the effects of depression on associative learning is less well studied. We investigated whether depressive symptoms would be related to abnormalities in learning-related brain activity as measured by functional magnetic resonance imaging (fMRI). Also, we explored whether melancholic and atypical features were associated with altered brain activity. We conducted MRI scans on a 4T Varian MRI system in 10 individuals with MDD and 10 healthy subjects. We examined event-related brain activation during feedback-based learning task using Analysis of Functional NeuroImages (AFNI) for image processing and statistical analysis. We observed that MDD patients exhibited reduced activation in visual cortex but increased activation in cingulate and insular regions compared to healthy participants. Also, in relation to features of depressive subtypes, we observed that levels of activation in striatal, thalamic, and precuneus regions were negatively correlated with atypical characteristics. These results suggest that the effects of MDD change the neural circuitry underlying associative learning, and these effects may depend upon subtype features of MDD.

Neural response to stress and perceived stress differ in patients with left temporal lobe epilepsy.

Patients with epilepsy are often able to predict seizure occurrence subsequent to an acute stress experience. However, neuroimaging investigations into the neural basis of this relationship or the potential influence of perceived life stress are limited. The current study assessed the relationship between perceived stress and the neurobehavioral response to stress in patients with left temporal lobe epilepsy (LTLE) and healthy controls (HCs) using heart rate, salivary cortisol level, and functional magnetic resonance imaging and compared these effects between HCs and LTLE. Matched on perceived stress levels, groups of 36 patients with LTLE and 36 HCs completed the Montreal Imaging Stress Task, with control and stress math task conditions. Among LTLEs, 27 reported that prior (acute) stress affected their seizures (LTLES+), while nine did not (LTLES-). The results revealed that increased perceived stress was associated with seizure frequency in LTLE. Further, cortisol secretion was greater in LTLE, but did not vary with perceived stress as observed in HCs. A linear mixed-effects analysis revealed that as perceived stress increased, activation in the hippocampal complex (parahippocampal gyrus and hippocampus) decreased during stressful math in the LTLES+, increased in HCs, but did not vary in the LTLES-. Task-based functional connectivity analyses revealed LTLE differences in hippocampal functional connectivity with sensory cortex specific to stressor modalities. We argue that the current study demonstrates an inhibitory hippocampal mechanism underlying differences in resilience to stress between HCs and LTLE, as well as LTLE patients who report stress as a precipitant of seizures.

Bipolar I disorder and major depressive disorder show similar brain activation during depression.

OBJECTIVES: Despite different treatments and courses of illness, depressive symptoms appear similar in major depressive disorder (MDD) and bipolar I disorder (BP-I). This similarity of depressive symptoms suggests significant overlap in brain pathways underlying neurovegetative, mood, and cognitive symptoms of depression. These shared brain regions might be expected to exhibit similar activation in individuals with MDD and BP-I during functional magnetic resonance imaging (fMRI). METHODS: fMRI was used to compare regional brain activation in participants with BP-I (n = 25) and MDD (n = 25) during a depressive episode as well as 25 healthy comparison (HC) participants. During the scans, participants performed an attentional task that incorporated emotional pictures. RESULTS: During the viewing of emotional images, subjects with BP-I showed decreased activation in the middle occipital gyrus, lingual gyrus, and middle temporal gyrus compared to both subjects with MDD and HC participants. During attentional processing, participants with MDD had increased activation in the parahippocampus, parietal lobe, and postcentral gyrus. However, among these regions, only the postcentral gyrus also showed differences between MDD and HC participants. CONCLUSIONS: No differences in cortico-limbic regions were found between participants with BP-I and MDD during depression. Instead, the major differences occurred in primary and secondary visual processing regions, with decreased activation in these regions in BP-I compared to major depression. These differences were driven by abnormal decreases in activation seen in the participants with BP-I. Posterior activation changes are a common finding in studies across mood states in participants with BP-I.

Physiologic and cortical response to acute psychosocial stress in left temporal lobe epilepsy - a pilot cross-sectional fMRI study.

Stress is commonly reported as a seizure precipitant in individuals with poorly controlled seizures including temporal lobe epilepsy. The aim of the study was to assess the neural and physiologic correlates of psychosocial stress response during functional magnetic resonance imaging (fMRI) and their relationship with seizure occurrence in patients with left temporal lobe epilepsy (LTLE). We enrolled 23 patients with LTLE and 23 age- and sex-matched healthy controls (HCs); all underwent fMRI with control math task (CMT) and stress math task (SMT) and pre-/post-fMRI salivary cortisol analysis (acute stress reactivity calculated as % reduction from post-stress to recovery baseline; dCORT). The Beck Depression Inventory-II (BDI-II) and Perceived Stress Scale (PSS-10) were administered. T-tests of performance and cortisol variables were performed. Processing and single-subject modeling of fMRI response to CMT positive feedback and SMT negative feedback, group comparisons, and whole-brain correlation of seizure occurrence and fMRI response in patients with poorly controlled LTLE were performed. Patients with LTLE and healthy controls were similar in demographics, math performance, heart rate, and PSS-10 scores (all p>0.05). Patients with LTLE exhibited greater dCORT (p=0.048) and lower BDI-II scores (p=0.016) compared with HCs. Patients with poorly controlled LTLE showed a positive association between seizure frequency and dCORT (r=0.73, p=0.016). Functional MRI activation to feedback was similar between groups, including midfrontal, temporal, parietal, and occipital regions. Regression analyses revealed no group differences to positive feedback, but, compared with HCs, patients with LTLE showed decreased activation to negative feedback in the left cerebellum/middle occipital/fusiform gyri, left hippocampus/parahippocampus, bilateral medial frontal/cingulate/superior frontal gyri, right postcentral gyrus/inferior parietal lobule, and right insula/postcentral gyrus (p<0.05, corrected). Patients with poorly controlled LTLE showed negative association between seizure frequency and activation in the bilateral subgenual anterior cingulate (p<0.05, corrected). This study is the first to characterize the cortical and physiologic responses to acute psychosocial stress and to show a significant relationship between seizure control in LTLE and both the hypothalamic-pituitary-adrenal axis and fMRI signal reactivity to acute psychosocial stress. These findings extend our understanding of the complex interplay between stress, physiologic stress markers, and seizures/epilepsy.

Psychotic depression--beyond the antidepressant/antipsychotic combination.

Psychotic depression is an identified subtype of major depression that has many features of a distinct psychiatric disorder. Recent studies support previous findings that psychotic depression is associated with a less favorable course of illness. Moreover, the presence of a single psychotic symptom appears to predict decreased responsiveness to antidepressant monotherapy. Recent studies also support biological differences between psychotic and non-psychotic depression. Previous findings of greater HPA axis dysregulation are supported by evidence of diminished cortisol suppression with the mineralocorticoid antagonist fludrocortisone in psychotic depression. Moreover, a functional neuroimaging study demonstrated greater activation in parahippocampal and tempoparietal regions in psychotic depression during a memory task. In support of several previous treatment studies, a recent meta-analysis of studies that compared an antidepressant-antipsychotic combination to antidepressants or antipsychotics alone found a therapeutic advantage with the combined treatment over monotherapy. A recent clinical trial suggests that mifepristone, a glucocorticoid antagonist, may be an effective adjunctive treatment for psychotic depression.

Olanzapine in the treatment of pathological gambling: a negative randomized placebo-controlled trial.

OBJECTIVE: Pathological gambling is associated with bipolar disorder and dopamine dysfunction. Olanzapine is a second-generation antipsychotic with mood-stabilizing properties and antagonistic activity at several dopamine receptors. The purpose of this study was to evaluate olanzapine in the treatment of pathological gambling. METHOD: In this 12-week, single-center, randomized, double-blind, placebo-controlled, flexible-dose (2.5-15 mg/day) trial, 42 outpatients with pathological gambling by DSM-IV-TR criteria received olanzapine (N = 21) or placebo (N = 21). The primary outcome measure was the Pathological Gambling Adaptation of the Yale-Brown Obsessive Compulsive Scale (PG-YBOCS). The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Subjects were enrolled from June 2, 2000, through November 28, 2005. RESULTS: Compared with placebo, olanzapine was associated with a similar rate of reduction in total scores on the PG-YBOCS scale, as well as in gambling episodes/week, hours gambled/week, and Clinical Global Impressions-Severity of Illness scale scores. The mean (SD) olanzapine daily dose at endpoint evaluation was 8.9 (5.2) mg/day. Eleven subjects (52%) receiving olanzapine and 6 (29%) receiving placebo discontinued prematurely; 3 subjects receiving olanzapine and 2 receiving placebo discontinued because of adverse events. Events causing olanzapine discontinuation were pneumonia, sedation, and hypomania. CONCLUSION: Olanzapine was not superior to placebo in the short-term treatment of pathological gambling. It was also associated with a high discontinuation rate. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00438776 (http://www.clinicaltrials.gov).

Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial.

OBJECTIVE: Binge-eating disorder (BED) is associated with obesity. Atomoxetine is a highly selective norepinephrine reuptake inhibitor associated with weight loss. The purpose of this study was to evaluate atomoxetine in the treatment of BED. METHOD: In this 10-week, single-center, randomized, double-blind, placebo-controlled, flexible dose (40-120 mg/day) trial, outpatients with DSM-IV-TR BED received atomoxetine or placebo. The primary outcome measure was binge-eating episode frequency. The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Patients were enrolled from September 2004 through October 2005. RESULTS: Compared with placebo (N = 20), atomoxetine (N = 20) was associated with a significantly greater rate of reduction in binge-eating episode frequency, as well as in binge day frequency, weight, body mass index, and scores on the Clinical Global Impressions-Severity of Illness scale, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating obsession sub-scale, and Three Factor Eating Questionnaire hunger subscale. The mean (SD) atomoxetine daily dose at endpoint evaluation was 106 (21) mg/day. Four patients (N = 3 receiving atomoxe-tine, N = 1 receiving placebo) discontinued because of adverse events. The reasons for atomoxetine discontinuation were increased depressive symptoms (N = 1), constipation (N = 1), and nervousness (N = 1). CONCLUSION: Atomoxetine was efficacious and fairly well tolerated in the short-term treatment of BED. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00327834.

Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial.

OBJECTIVE: Binge eating disorder (BED) is associated with obesity. Zonisamide is a novel antiepileptic drug associated with weight loss. The purpose of this study was to evaluate zonisa-mide in the treatment of BED associated with obesity. METHOD: In this 16-week, single-center, randomized, double-blind, placebo-controlled, flexible-dose (100-600 mg/day) trial, 60 outpatients with DSM-IV-TR BED received zonisamide (N = 30) or placebo (N = 30). The primary outcome measure was weekly frequency of binge eating episodes. The primary analysis of efficacy was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the effect measure. Patients were enrolled from September 5, 2003, through October 1, 2004. RESULTS: Compared with placebo, zonisamide was associated with a significantly greater rate of reduction in binge eating episode frequency (p = .021), body weight (p < .001), BMI (p = .001), and scores on the Clinical Global Impressions-Severity scale (p < .001), Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (p < .001), and Three Factor Eating Questionnaire disinhibition scales (p < .001). Plasma ghrelin concentrations increased with zonisamide but decreased with placebo (p = .001). The mean (SD) zonisamide daily dose at endpoint evaluation was 436 (159) mg/day. Twelve patients (N = 8 receiving zonisamide, N = 4 receiving placebo) discontinued because of adverse events. The most common reasons for discontinuing zonisamide were accidental injury with bone fracture (N = 2), psychological complaints (N = 2), and cognitive complaints (N = 2). CONCLUSION: Zonisamide was efficacious, but not well tolerated, in the short-term treatment of BED associated with obesity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00221442.

Are mood disorders and obesity related? A review for the mental health professional.

OBJECTIVE: We reviewed evidence regarding a possible relationship between mood disorders and obesity to better inform mental health professionals about their overlap. METHOD: We performed a MEDLINE search of the English-language literature for the years 1966-2003 using the following terms: obesity, overweight, abdominal, central, metabolic syndrome, depression, mania, bipolar disorder, binge eating, morbidity, mortality, cardiovascular, diabetes, cortisol, hypertriglyceridemia, sympathetic, family history, stimulant, sibutramine, antiobesity, antidepressant, topiramate, and zonisamide. We evaluated studies of obesity (and related conditions) in persons with mood disorders and of mood disorders in persons with obesity. We also compared studies of obesity and mood disorders regarding phenomenology, comorbidity, family history, biology, and pharmacologic treatment response. RESULTS: The most rigorous clinical studies suggest that (1). children and adolescents with major depressive disorder may be at increased risk for developing overweight; (2). patients with bipolar disorder may have elevated rates of overweight, obesity, and abdominal obesity; and (3). obese persons seeking weight-loss treatment may have elevated rates of depressive and bipolar disorders. The most rigorous community studies suggest that (1). depression with atypical symptoms in females is significantly more likely to be associated with overweight than depression with typical symptoms; (2). obesity is associated with major depressive disorder in females; and (3). abdominal obesity may be associated with depressive symptoms in females and males; but (4). most overweight and obese persons in the community do not have mood disorders. Studies of phenomenology, comorbidity, family history, biology, and pharmacologic treatment response of mood disorders and obesity show that both conditions share many similarities along all of these indices. CONCLUSION: Although the overlap between mood disorders and obesity may be coincidental, it suggests the two conditions may be related. Clinical and theoretical implications of this overlap are discussed, and further research is called for.

Psychiatric and legal features of 113 men convicted of sexual offenses.

BACKGROUND: To increase understanding of the relationships among sexual violence, paraphilias, and mental illness, the authors assessed the legal and psychiatric features of 113 men convicted of sexual offenses. METHOD: 113 consecutive male sex offenders referred from prison, jail, or probation to a residential treatment facility received structured clinical interviews for DSM-IV Axis I and II disorders, including sexual disorders. Participants' legal, sexual and physical abuse, and family psychiatric histories were also evaluated. We compared offenders with and without paraphilias. RESULTS: Participants displayed high rates of lifetime Axis I and Axis II disorders: 96 (85%) had a substance use disorder; 84 (74%), a paraphilia; 66 (58%), a mood disorder (40 [35%], a bipolar disorder and 27 [24%], a depressive disorder); 43 (38%), an impulse control disorder; 26 (23%), an anxiety disorder; 10 (9%), an eating disorder; and 63 (56%), antisocial personality disorder. Presence of a paraphilia correlated positively with the presence of any mood disorder (p <.001), major depression (p =.007), bipolar I disorder (p =.034), any anxiety disorder (p=.034), any impulse control disorder (p =.006), and avoidant personality disorder (p =.013). Although offenders without paraphilias spent more time in prison than those with paraphilias (p =.019), paraphilic offenders reported more victims (p =.014), started offending at a younger age (p =.015), and were more likely to perpetrate incest (p =.005). Paraphilic offenders were also more likely to be convicted of (p =.001) or admit to (p <.001) gross sexual imposition of a minor. Nonparaphilic offenders were more likely to have adult victims exclusively (p =.002), a prior conviction for theft (p <.001), and a history of juvenile offenses (p =.058). CONCLUSIONS: Sex offenders in the study population displayed high rates of mental illness, substance abuse, paraphilias, personality disorders, and comorbidity among these conditions. Sex offenders with paraphilias had significantly higher rates of certain types of mental illness and avoidant personality disorder. Moreover, paraphilic offenders spent less time in prison but started offending at a younger age and reported more victims and more non-rape sexual offenses against minors than offenders without paraphilias. On the basis of our findings, we assert that sex offenders should be carefully evaluated for the presence of mental illness and that sex offender management programs should have a capacity for psychiatric treatment.

Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial.

BACKGROUND: Binge-eating disorder is characterized by recurrent episodes of uncontrollable overeating without compensatory weight-loss behaviors. It commonly co-occurs with obesity. Zonisamide is a novel antiepileptic drug associated with weight loss. The purpose of this study was to preliminarily assess zonisamide in the treatment of binge-eating disorder. METHOD: Fifteen outpatients with DSM-IV-TR binge-eating disorder were enrolled from Jan. 25, 2002, through Sept. 10, 2002, in an open-label, prospective, 12-week, flexible dose (100-600 mg/day) study of zonisamide. The primary outcome measure was binge-eating episode frequency. Secondary measures included binge day frequency, body mass index (BMI), weight, Clinical Global Impressions-Severity of Illness scale (CGI-S) scores, Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating (YBOCS-BE) scores, Three Factor Eating Questionnaire (TFEQ) scores, and Hamilton Rating Scale for Depression scores. Safety measures included adverse events, routine blood chemical and hematology laboratory values, urinalyses, plasma zonisamide levels, physical examination findings, and electrocardiograms. Outcome measures were analyzed by a repeated-measures random regression analysis using all data and an endpoint analysis using last observation carried forward. RESULTS: Eight subjects completed the 12 weeks of treatment. The mean (SD) zonisamide daily dose at endpoint evaluation was 513 (103) mg/day. Both the random regression and endpoint analyses found a highly significant decrease in binge-eating episode frequency, binge day frequency, BMI, weight, CGI-S scores, YBOCS-BE total scores, and TFEQ hunger and disinhibition scores (p <.0001 for all measures in both analyses except p =.001 for endpoint analysis of binge eating frequency, p =.0001 for endpoint analysis of TFEQ disinhibition, and p =.0008 for endpoint analysis of TFEQ hunger). The 7 subjects who discontinued zonisamide prematurely did so due to lack of response (N = 1), protocol non-adherence (N = 2), and adverse events (N = 4). CONCLUSION: Zonisamide was effective in reducing binge-eating frequency, severity of illness, and weight and was generally well tolerated in an open trial of binge-eating disorder. Controlled trials appear warranted.

Citalopram in the treatment of binge-eating disorder: a placebo-controlled trial.

BACKGROUND: Binge-eating disorder is a newly recognized eating disorder characterized by recurrent episodes of binge eating without compensatory weight loss behaviors. It commonly co-occurs with depressive disorders and obesity. Citalopram is a highly selective serotonin reuptake inhibitor antidepressant. The purpose of this study was to assess the efficacy and safety of citalopram in the treatment of binge-eating disorder. METHOD: Thirty-eight outpatients with a DSM-IV diagnosis of binge-eating disorder were enrolled in the study between August 2000 and July 2001 and were randomly assigned to receive either citalopram (N = 19) or placebo (N = 19) in a 6-week, double-blind, flexible-dose (20-60 mg/day) study. The primary measure of efficacy was frequency of binge-eating episodes. Secondary measures included frequency of binge days, body mass index (BMI), weight, Clinical Global Impressions-Severity of Illness scale scores, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (YBOCS-BE) scores, Hamilton Rating Scale for Depression (HAM-D) scores, and response categories. The outcome measures were analyzed using 2 random regression methods, with a time trend analysis (primary analysis) and an endpoint analysis. In addition, response categories were analyzed using an exact trend test. RESULTS: Compared with placebo-treated subjects, subjects receiving citalopram (mean dose of 57.9 mg/day) had a significantly greater rate of reduction in frequency of binge eating (p =.003), frequency of binge days (p <.001), BMI (p <.001), weight (p <.001), severity of illness (p =.028), and YBOCS-BE score (p =.007) and a marginally significant rate of reduction in HAM-D score (p =.053). Differences between groups in response categories were marginally significant (p =.068 for intent-to-treat analysis). CONCLUSION: In a 6-week, placebo-controlled, flexible-dose trial, citalopram was efficacious in reducing binge-eating frequency, weight, and severity of illness and was generally well tolerated in subjects with binge-eating disorder.

Advances in the pharmacologic treatment of bipolar depression.

The pharmacologic treatment of bipolar depression has not been well studied in randomized, controlled trials. Thus important clinical questions regarding the efficacy in bipolar depression of mood stabilizers, antidepressants, and new antiepileptic and atypical antipsychotic agents have been relatively unaddressed. Until recently there were few data regarding the degree to which mood stabilizers reduce the risk of switching associated with antidepressant treatment. Likewise, although treatment guidelines have often recommended limiting antidepressant exposure in the maintenance treatment of bipolar depression, the potential risks of depressive relapse after antidepressant discontinuation were largely unknown. We review here data from new randomized, controlled trials published or presented during the past 5 years regarding the efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in the acute and maintenance treatment of bipolar depression. We also review new studies clarifying the protective effect of coadministration of mood stabilizers from antidepressant-associated switching and the risk of depressive relapse when antidepressants are discontinued during maintenance treatment.