Randomized, double-blind comparison of aripiprazole/sertraline combination and placebo/sertraline combination in patients with major depressive disorder.

AIM: This study compared the efficacy and safety of aripiprazole/sertraline combination (ASC) and placebo/sertraline combination (PSC) in patients with major depressive disorder (MDD) who showed an inadequate response to sertraline 100 mg/day. METHODS: The study comprised a screening period, an 8-week prospective treatment (single-blind sertraline 25-100 mg/day) period, and a 6-week double-blind treatment period. Patients with DSM-5-defined MDD were enrolled. Following the prospective treatment, non-responders were randomly assigned to the ASC group (aripiprazole 3-12 mg/day/sertraline 100 mg/day) or the PSC group (sertraline 100 mg/day). The primary efficacy end-point was the mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to 6 weeks. RESULTS: A total of 412 patients were randomly assigned to either the ASC group (n = 209) or the PSC group (n = 203). Mean change in MADRS total score was significantly greater in patients with ASC than PSC (-9.2 vs -7.2; P = 0.0070). Treatment-emergent adverse events (TEAE) that occurred in ≥10% of patients with ASC versus PSC were nasopharyngitis (13.4% vs 11.3%) and akathisia (12.9% vs 3.4%). All TEAE reported in the ASC group were mild or moderate in severity. Rates of discontinuations due to TEAE were low in both the ASC (1.9%) and PSC (1.5%) groups. There were no notable issues in safety assessments in the ASC group compared with the PSC group. CONCLUSION: In patients with MDD who showed an inadequate response to treatment with sertraline 100 mg/day, ASC was efficacious and well tolerated.

Hypofunction of left dorsolateral prefrontal cortex in depression during verbal fluency task: A multi-channel near-infrared spectroscopy study.

BACKGROUND: Previous functional neuroimaging studies of depression have demonstrated frontotemporal dysfunction, including the dorsolateral prefrontal cortex, while patients perform working memory and language comprehension tasks. Recent near-infrared spectroscopy (NIRS) studies have shown frontotemporal hypofunction in depression by verbal fluency task, but the regions of impairment affecting respective depressive symptoms still remain unclear. We investigated frontotemporal function during word production task in depression with multi-channel NIRS. Further, we aimed to clarify whether any depressive symptoms affect frontotemporal dysfunction. METHODS: One hundred seventy-seven major depressive patients and 50 healthy control volunteers participated in this study. Their cerebral activations were compared during verbal fluency task. RESULTS: Although performance was not significantly different, hypoactivation in the bilateral frontotemporal regions was significantly observed in depressed patients, compared with controls. Left lateral frontotemporal activation was significantly reduced in the group with mandatory symptom, which is depressed mood, or loss of interest or pleasure, compared with the group that still has residual depressive symptoms in spite MDD having been remitted. LIMITATION: the MDD group had significantly higher age and education level than the controls. Conclusions Our findings indicate hypofunction of the bilateral frontotemporal regions in depression during verbal fluency task. Further, hypofunction of these regions in the left hemisphere by this task could reflect whether the subjects recovered from depressed mood, or loss of interest or pleasure.

Acute Poststroke Depression Is Associated with Thalamic Lesions and Clinical Outcomes: A Case-Control Study.

BACKGROUND: We investigated the role of acute-phase stroke lesions and patient characteristics in poststroke depression (PSD) and its effect on the clinical outcome. PATIENTS AND METHODS: Five and 30 days after admission, 175 patients self-reported their depressive symptoms on the Patient Health Questionnaire-9. We compared the clinical characteristics and outcomes in patients with (n = 41) and without PSD (n = 134). Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS); the modified Rankin Scale (mRS) was used to determine the functional outcome. RESULTS: There was no significant difference between patients with and without PSD in the age, gender ratio, lesion side, and the history of hypertension, diabetes mellitus, alcohol and tobacco use, and previous stroke. Thalamic lesions were significantly associated with PSD (P = .03), although there was no significant difference in both the NIHSS score and the final mRS score of patients with thalamic lesions. Backward stepwise logistic regression analysis showed that a higher NIHSS score and thalamic lesions were independent predictors of PSD. Total hospitalization was significantly longer in patients with PSD. At the time of admission, the NIHSS score was significantly higher in patients who developed moderate to severe PSD than in those with mild PSD or without PSD. CONCLUSIONS: PSD in the acute phase was associated with thalamic lesions and severe stroke. Hospitalization was significantly longer in patients with PSD and their functional disability was more severe, suggesting that PSD played a role in the unsatisfactory results of poststroke rehabilitation.

Comparison of regional gray matter volume abnormalities in Alzheimer׳s disease and late life depression with hippocampal atrophy using VSRAD analysis: a voxel-based morphometry study.

Previous voxel-based morphometry (VBM) studies revealed that hippocampal volume loss in patients with late life depression (LLD) is associated with cognitive impairment and a higher risk for dementia. However, LLD patients can experience hippocampal atrophy without cognitive impairment. Thus, while LLD and AD can show comparable hippocampal atrophy, they may encompass different neuropathological changes. Using VBM, we therefore investigated differences in regional gray matter changes in 17 late-onset LLD patients and 21 AD patients (without a history of LLD) who exhibited comparably severe atrophy of the entorhinal cortex and the parahippocampal gyrus on MRI scans for voxel-based specific regional analysis system for AD (VSRAD). Relative to the VSRAD database for healthy individuals, significant atrophy was observed in mesial temporal lobe structures and the anterior cingulate cortex in both groups. Atrophy of the posterior cingulate cortex and precuneus was observed only in the AD group. Comparisons of gray matter volume by multivariate analysis of variance revealed significantly reduced volume of the right middle and inferior temporal gyrus, uncus, posterior cingulate cortex, and precuneus in the AD group only, suggesting impairment of different networks in AD and LLD. Indeed, structural changes in the posterior part of the default-mode network are believed to be associated with cognitive impairments specific to AD.

Two cases of emotional disorder after middle cerebral artery infarction showing distinct responses to antidepressant treatment.

Many emotional disturbances such as post-stroke depression (PSD) and emotional incontinence (EI) commonly occur following cerebrovascular events. The efficacy of antidepressants for these conditions has been established but their comorbid treatment has not been well characterized. In the current study, the authors describe two cases of post-stroke emotional dysregulation; one case with EI; and the other with EI complicated by PSD. The authors describe their differential responses to treatment. Case 1 developed EI after an infarct due to occlusion of the penetrating branches of the left middle cerebral artery (MCA). Case 2 developed both PSD and EI after right MCA stem occlusion. Both patients were initially treated with the selective serotonin reuptake inhibitor (SSRI) paroxetine. Case 1 reacted promptly to SSRI treatment. However, Case 2 had only a partial response to paroxetine, even after many months of treatment. Adjunctive therapy with low-dose aripiprazole was eventually added, resulting in complete improvement of both EI and PSD after 2 additional months of treatment. Thus, Case 2 required a different treatment strategy than Case 1. These findings suggest that aripiprazole adjunctive therapy could be effective for some complex post-stroke emotional disorders.

[A psychotropic drug treatment of psychiatric symptoms after stroke].

Psychiatric syndromes are common in the patients with cerebrovascular disease. Poststroke depression (PSD) is a most frequent complication of after cerebrovascular disease. Depression affects 20-50% of patients within a year after stroke. PSD has a negative impact on functional recovery. Poststroke anxiety disorder, apathy and pathological laughing and crying are also frequent and under-detected symptoms. In this chapter, we described an outline mainly on treatment of PSD among these symptoms, in paticular, about antidepressant medications. There is an association between depression and atherosclerosis. Several trials have shown evidence that antidepressants may prevent depressive symptoms after stroke. The concept of "vascular depression" will suggest that the establishment of a new treatment strategy is demanded in future.

Oral cenesthopathy examined by Rorschach test.

Experience of abnormal pains and unusual sensations in the mouth without a somatic base, for example abnormal mucus secretion, pulling sensation on the jaw or teeth, or a vibrating sensation, is termed 'oral cenesthopathy'. Psychological factors were investigated in terms of cognitive functions and personality tendencies, using Rorschach test in 28 patients with this condition (three men and 25 women). In oral cenesthopathy patients (i) the processing of new information is inefficient; (ii) the necessary resources for social adaptation are lacking, emotional control is inadequate, and uncomfortable emotions are expressed less; and (iii) with regard to interpersonal interaction, less interest is shown in others, trust in others is diminished, and they tend to have a higher Coping Deficit Index.

Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: a Multicenter Study.

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary-adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.

Landiolol attenuates acute hemodynamic responses but does not reduce seizure duration during maintenance electroconvulsive therapy.

Maintenance electroconvulsive therapy (mECT) is an outpatient procedure that requires further consideration in terms of management of ambulatory anesthesia. Although many adjunctive drugs for stabilizing hemodynamic changes during ECT have been reported, side-effects of these drugs may delay recovery and discharge from hospital. The effects of landiolol, a novel ultra-short-acting beta-adrenergic blocker, have been measured on seizure duration, hemodynamic changes, recovery from anesthesia, and cognitive function during mECT under propofol anesthesia. A total of 10 patients with depression in the remission phase, were studied in a randomized, double-blind, placebo-controlled, crossover manner. Administration of 0.1 mg/kg of landiolol immediately before anesthesia significantly blunted the increase in heart rate and blood pressure during convulsions compared with placebo; landiolol was not associated with excessive hypotension or bradycardia. Landiolol did not affect seizure duration, recovery from anesthesia, or cognitive function before or after ECT. These results suggest that landiolol can be used effectively and safely during mECT.

Regional cerebral blood flow in vascular depression assessed by 123I-IMP SPECT.

OBJECTIVE: As the prevalence of white matter hyperintensities detected on T2 weighted MRI scans in patients with late-onset depression is higher than that in nondepressed patients, the concept of"vascular depression" (VDep) was introduced in 1997. However, the pathology of vascular depression has not been clarified. This study examined the differences in functional imaging between vascular and non-vascular depression (non-VDep). METHODS: We utilized (123)I-IMP single photon emission computed tomography (SPECT) to compare regional cerebral blood flows (rCBF) between 9 patients with VDep (Krishnan criteria) and 11 age- and sex-matched patients with non-VDep in both depressed and remitted states. RESULTS: In both VDep and non-VDep patients, mean rCBF increased significantly as depression improved, partially aided by changes in left anterior temporal blood flow. In addition, compared to non-VDep patients, the left anterior frontal rCBF for VDep patients was significantly lower in both depressed and remitted states. CONCLUSIONS: Left anterior temporal rCBF therefore appears to represent a state marker that increases as symptoms associated with late-onset depression improve, regardless of vascular changes. Furthermore, in VDep patients, left anterior frontal rCBF was low in both states compared to non-VDep patients, and might not only represent a trait marker, but also correlated with the duration of disease and likelihood of recurrence and relapse.

Therapeutic effects of milnacipran (serotonin noradrenalin reuptake inhibitor) on depression following mild and moderate traumatic brain injury.

BACKGROUND: The present study investigated the efficacy and safety of milnacipran, a serotonin noradrenalin reuptake inhibitor (SNRI), for the treatment of depression following mild and moderate traumatic brain injury (MMTBI). While other reports have been published on the use of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and tricyclics for the treatment of depression following MMTBI, no previous study has examined the use of a SNRI for this condition. METHODS: A six-week open study was conducted using 10 patients (4 males and 6 females) of ages ranging from 28 to 74 years. DSM-IV (diagnostic statistical manual of mental disorders, 4th Ed. American psychiatric association, 1994) was used to diagnose mood disorders. The severity of depression was measured with the 21-item Hamilton rating scale for depression (HAM-D). The cognitive state of the patients was assessed using the mini-mental state examination (MMSE). RESULTS: The maximum daily milnacipran dosage for the patients ranged from 30 to 150 mg. One patient experienced side effects, but none of the side effects were serious. On the basis of having a decrease in a final HAM-D score of more than 50%, the response rate for the nine patients was 66.7%, while in a final score of 7 or less, the remission rate for the nine patients was 44.4%. Furthermore, significantly greater improvement in cognitive function was seen in patients treated with milnacipran. CONCLUSION: The results demonstrated that milnacipran is a safe and effective drug for depression following mild and moderate TBI and could be the first choice drug for the treatment of this condition.

Treatment of poststroke generalized anxiety disorder comorbid with poststroke depression: merged analysis of nortriptyline trials.

OBJECTIVE: The existence of anxiety disorders plays an important role in the prognosis and associated impairment among patients with poststroke depression. The authors examined the efficacy of nortriptyline treatment for patients with comorbid generalized anxiety disorder (GAD) and depression after stroke. METHODS: Data from three studies were merged to provide 27 patients with comorbid GAD and depression, who participated in double-blind treatment studies comparing nortriptyline (N=13) and placebo (N=14). Severity of anxiety was measured with the Hamilton Rating Scale for Anxiety (Ham-A), and severity of depression was measured with the Hamilton Rating Scale for Depression (Ham-D). Activities of daily living were assessed by use of the Johns Hopkins Functioning Inventory (JHFI). RESULTS: There were no significant differences between the nortriptyline and placebo groups in demographic characteristics, stroke type, and neurological findings. Patients receiving nortriptyline treatment showed significantly greater improvement on the Ham-A, Ham-D, and JHFI than patients receiving placebo. The anxiety symptoms showed earlier improvement than depressive symptoms in patients treated with nortriptyline. CONCLUSIONS: These findings suggest that poststroke GAD comorbid with poststroke depression may be effectively treated with nortriptyline, and data indicate the need for a trial specifically designed to examine treatment of anxiety disorder.

Phenomenological characteristics of poststroke depression: early- versus late-onset.

OBJECTIVE: Authors compared poststroke major (n=17) or minor (n=28) depression diagnosed 3 to 6 months poststroke with major (n=16) or minor (n=22) depression diagnosed at 12 to 24 months to identify changes in the phenomenological characteristics of poststroke depression over time. METHODS: Depressive symptoms were divided into vegetative, psychological symptoms, and melancholic features elicited by the Present State Exam (PSE). Patients were also examined for severity of depression, social impairment, and neurological findings. RESULTS: Early-onset poststroke major depression was associated with a higher frequency of vegetative symptoms and larger lesion volume than late-onset major depression. Similarly, early-onset minor depression was associated with poorer social functioning and a higher frequency of melancholic, vegetative, and psychological symptoms than late-onset minor depression. CONCLUSION: These findings suggest that the phenomenological characteristics of both major and minor poststroke depression change over time and that both early-onset major and minor poststroke depression may result from similar etiological mechanisms provoked by brain injury.