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.

Postoperative but not preoperative depression is associated with cognitive impairment after cardiac surgery: exploratory analysis of data from a randomized trial.

BACKGROUND: In this study we hypothesize that depression is associated with perioperative neurocognitive dysfunction and altered quality of life one month after surgery. METHODS: Data were obtained as part of a study evaluating cerebral autoregulation monitoring for targeting arterial pressure during cardiopulmonary bypass. Neuropsychological testing was performed before surgery and one month postoperatively. Testing included the Beck Depression Inventory, a depression symptoms questionnaire (0-63 scale), as well as anxiety and quality of life assessments. Depression was defined as a Beck Depression Inventory score > 13. RESULTS: Beck Depression data were available from 320 patients of whom cognitive domain endpoints were available from 88-98% at baseline and 69-79% after surgery. This range in end-points data was due to variability in the availability of each neuropsychological test results between patients. Depression was present in 50 (15.6%) patients before surgery and in 43 (13.4%) after surgery. Baseline depression was not associated with postoperative domain-specific neurocognitive function compared with non-depressed patients. Those with depression one month after surgery, though, had poorer performance on tests of attention (p = 0.017), memory (p = 0.049), verbal fluency (p = 0.010), processing speed (p = 0.017), and fine motor speed (p = 0.014). Postoperative neurocognitive dysfunction as a composite outcome occurred in 33.3% versus 14.5% of patients with and without postoperative depression (p = 0.040). Baseline depression was associated with higher anxiety and lower self-ratings on several quality of life domains, these measures were generally more adversely affected by depression one month after surgery. CONCLUSIONS: The results of this exploratory analysis suggests that preoperative depression is not associated with perioperative neurocognitive dysfunction, but depression after cardiac surgery may be associated with impairment in in several cognitive domains, a higher frequency of the composite neurocognitive outcome, and altered quality of life. TRIAL REGISTRATION: www. CLINICALTRIALS: gov, NCT00981474 (parent study).

Interplay between spirituality and religiosity on the physical and mental well-being of cancer survivors.

PURPOSE: This study explored the relationship of spirituality and religiosity as it affects the physical and mental quality of life (pQOL, mQOL) of cancer survivors. METHODS: This is a prospective observational study that included adults ≥ 19 years who received treatment for various types of cancer. Patients' QOL was obtained at baseline, 6, and 12 months. Cohorts were categorized according to spirituality/religiosity levels: low spirituality-low religiosity (LSLR), low spirituality-high religiosity (LSHR), high spirituality-low religiosity (HSLR), and high spirituality-high religiosity (HSHR). RESULTS: Of the 551 eligible, 248 (45%) had HSHR, 196 (36%) had LSHR, 75 (14%) had LSLR, and 32 (6%) had HSLR. The pQOL of LSLR were significantly lower than those with HSHR (p = 0.02). The differences in pQOL between LS and HS were observed among those who have HR (p < 0.0001). Among patients with LR, pQOL did not differ. The mQOL of patients with LSLR was significantly lower than those with HSHR (p < 0.0001). The mQOL of those with HS was significantly higher than those with LS in both cohorts having LR (p < 0.0001) or HR (p < 0.0001). pQOL decreased while mQOL increased over time regardless of spirituality or religiosity levels. CONCLUSION: Spirituality is important in the improvement of both pQOL and mQOL of cancer survivors, while religiosity may have some impact on pQOL. Clinicians' incorporation of spirituality into cancer treatment facilitates well-rounded care, which offers measurable improvements for patients with an illness, of which the treatment is often arduous, and uncertain.

Personality disorders and physical comorbidities: a complex relationship.

PURPOSE OF REVIEW: It is not uncommon for clinicians to label patients' complaints as 'psychogenic' when they present with symptoms that are difficult to understand. This article reviews recent reports about the comorbidity of personality disorders and nonpsychiatric medical problems, which call into question the adequacy of the mind-body dichotomy in medicine. RECENT FINDINGS: The strong association of any personality disorders with poor health in cross-sectional and community-based studies is now confirmed by personality disorder predicting future deterioration in longitudinal studies. Borderline personality disorder has been studied most frequently, but recent data suggest that severity of any personality disorder is associated with poor and worsening health. SUMMARY: Personality disorder is associated with the full range of physical, mental, and social disorders. Greater attention to the common features of personality disorders, which are crucial for the self-regulation of behavior, would facilitate more effective health promotion and disease prevention across all medical specialties, thereby helping to relieve the burdens of chronic common diseases.

Transcranial magnetic stimulation for the treatment of major depression.

Major depression is often difficult to diagnose accurately. Even when the diagnosis is properly made, standard treatment approaches (eg, psychotherapy, medications, or their combination) are often inadequate to control acute symptoms or maintain initial benefit. Additional obstacles involve safety and tolerability problems, which frequently preclude an adequate course of treatment. This leaves an important gap in our ability to properly manage major depression in a substantial proportion of patients, leaving them vulnerable to ensuing complications (eg, employment-related disability, increased risk of suicide, comorbid medical disorders, and substance abuse). Thus, there is a need for more effective and better tolerated approaches. Transcranial magnetic stimulation is a neuromodulation technique increasingly used to partly fill this therapeutic void. In the context of treating depression, we critically review the development of transcranial magnetic stimulation, focusing on the results of controlled and pragmatic trials for depression, which consider its efficacy, safety, and tolerability.

Neuromodulation Treatments for Schizophrenia.

Schizophrenia is a psychiatric disorder that causes great suffering and debilitation worldwide. We have a multitude of medications that are effective for psychosis. However, these have not been successful in treating the negative and cognitive symptom domains of schizophrenia. These symptoms are responsible for the larger part of functional impairments that result from schizophrenia. In addition, there are many patients for whom no significant improvement is achieved even in the positive symptom domain. Hence, other treatment modalities have been explored to help these patients. Electroconvulsive therapy and transcranial magnetic stimulation are two of the most promising adjunct treatment methods for medication resistant schizophrenia. Electroconvulsive therapy is the gold standard treatment for catatonias whether associated with schizophrenia, mood disorders or other non-psychiatric disorders. Although not effective for negative symptoms, electroconvulsive therapy provides substantial augmentation to antipsychotic medications in improving positive symptoms and overall severity. Electroconvulsive therapy should be considered more often in patients with inadequate response to antipsychotic medications even when they do not have prominent affective symptoms. Transcranial magnetic stimulation has emerged as a promising useful therapeutic tool in targeting medication resistant auditory hallucinations and negative symptoms. Transcranial magnetic stimulation has proven to be very safe and well-tolerated by the patients in spite of its labor intensiveness. The incorporation of transcranial magnetic stimulation to routine clinical use awaits further studies to substantiate its efficacy and to optimize and customize treatment parameters to individual patients and their symptom patterns. Moreover, combining transcranial magnetic stimulation with electroconvulsive therapy to synergize their likely different mechanisms of action is another exciting possibility.

Targeted enhancement of cortical-hippocampal brain networks and associative memory.

The influential notion that the hippocampus supports associative memory by interacting with functionally distinct and distributed brain regions has not been directly tested in humans. We therefore used targeted noninvasive electromagnetic stimulation to modulate human cortical-hippocampal networks and tested effects of this manipulation on memory. Multiple-session stimulation increased functional connectivity among distributed cortical-hippocampal network regions and concomitantly improved associative memory performance. These alterations involved localized long-term plasticity because increases were highly selective to the targeted brain regions, and enhancements of connectivity and associative memory persisted for ~24 hours after stimulation. Targeted cortical-hippocampal networks can thus be enhanced noninvasively, demonstrating their role in associative memory.

Interrater reliability and coding guide for nonpsychotic formal thought disorder.

Reliable and valid assessment of abnormal speech patterns may enable earlier recognition of nonpsychotic disorders through characteristic speech patterns. This study sought to establish interrater reliability using a standardized guide for scoring. A scoring guide defining 27 elements (e.g., inappropriate self-reference, simple loss of goal, circumstantiality) of disordered thought was developed. The seminal work of Andreasen's and Holzman's groups provided 12 elements, and 15 new elements were suggested by clinical literature. Audiotaped interviews with 12 psychiatric inpatients, adults of both sexes and various ages hospitalized for acute management of nonpsychotic psychiatric disorders, provided speech samples for observation of disordered thought by two independent raters. Using the guide's definitions and accompanying examples of elements of disordered thought, reliability in scoring was high (kappa of .85 for agreement on the presence of any abnormal speech element and kappa values from .66 to 1.00 for agreement on the presence of individual elements).

Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila.

Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3beta gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3beta gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3beta as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3beta heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.

Omega-3 fatty acids decreased irritability of patients with bipolar disorder in an add-on, open label study.

This is a report on a 37-patient continuation study of the open ended, Omega-3 Fatty Acid (O-3FA) add-on study. Subjects consisted of the original 19 patients, along with 18 new patients recruited and followed in the same fashion as the first nineteen. Subjects carried a DSM-IV-TR diagnosis of Bipolar Disorder and were visiting a Mood Disorder Clinic regularly through the length of the study. At each visit, patients' clinical status was monitored using the Clinical Monitoring Form. Subjects reported on the frequency and severity of irritability experienced during the preceding ten days; frequency was measured by way of percentage of days in which subjects experienced irritability, while severity of that irritability was rated on a Likert scale of 1-4 (if present). The irritability component of Young Mania Rating Scale (YMRS) was also recorded quarterly on 13 of the 39 patients consistently. Patients had persistent irritability despite their ongoing pharmacologic and psychotherapy. Omega-3 Fatty Acid intake helped with the irritability component of patients suffering from bipolar disorder with a significant presenting sign of irritability. Low dose (1 to 2 grams per day), add-on O-3FA may also help with the irritability component of different clinical conditions, such as schizophrenia, borderline personality disorder and other psychiatric conditions with a common presenting sign of irritability.

The presentation of irritable bowel syndrome in the context of somatization disorder.

BACKGROUND AND AIMS: Somatization disorder, a female predominant disorder, has been found with higher than expected prevalence in previous studies of irritable bowel syndrome (IBS) and might be responsible for some of the comorbidity and excessive health care resource use associated with IBS. The study's aim was to determine within a female IBS population the degree of segregation of psychiatric illness, functional disorders, and health care utilization with somatization disorder. METHODS: In a prospective, 6-month follow-up study, psychiatric disorders were assessed with the Diagnostic Interview Schedule, gastrointestinal and other symptoms with self-report questionnaires, and medically unexplained complaints by thorough chart review. The setting was a university gastroenterology clinic. The participants were a convenience sample of female clinic attendees with IBS (N = 56). RESULTS: Somatization disorder was diagnosed in 25% of patients and highly probable in another 5%. Somatization disorder was associated with significantly greater numbers of gastrointestinal and other symptoms, psychiatric disorders, physicians consulted, telephone calls to physicians, urgent care visits, medication changes, and missed work days and with benzodiazepine use. On follow-up, somatization disorder was associated with psychiatric and IBS symptoms, medication changes, and treatment dissatisfaction. Both somatization disorder and other psychiatric illnesses were associated with other functional gastrointestinal disorders; only somatization disorder remained predictive in a regression model that controlled for the presence of other psychiatric illness. CONCLUSIONS: Among female IBS patients attending a university gastroenterology clinic, many aspects of comorbidity and health care behaviors previously associated with IBS segregated with the diagnosis of somatization disorder. Recognition and appreciation of somatization disorder in IBS have important ramifications for the conduct of research and clinical practice.