Effects of lithium on serum Brain-Derived Neurotrophic Factor in Alzheimer's patients with agitation.

BACKGROUND: There is ample evidence in animal models that lithium increases Brain-Derived Neurotrophic Factor (BDNF) with supporting evidence in human studies. Little is known, however, about the effects of lithium on BDNF in Alzheimer's Dementia (AD). In one study of patients with Mild Cognitive Impairment, serum BDNF increased after treatment with lithium. These patients also showed mild improvement in cognitive function. OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD). METHOD: We measured levels of BDNF in patients treated with lithium prior to and after a 12-week randomized placebo-controlled trial. RESULTS: BDNF levels did not change significantly and were not associated with improvement in overall neuropsychiatric symptoms or in cognitive function. CONCLUSIONS: More research is needed to understand the potential effects of lithium on BDNF in AD including whether its use might be dependent on the stage of cognitive decline and dementia.

Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial.

BACKGROUND: A case series suggested efficacy for lithium to treat agitation in dementia, but no placebo-controlled trials have been conducted. OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD). METHOD: In a four-site trial, patients with AD and agitation/aggression score ≥4 on the Neuropsychiatric Inventory (NPI) were randomized, double-blind, to lithium carbonate 150-600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response (30% reduction in NPI score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved). Safety profile of lithium was assessed. RESULTS: Fifty-eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium was not significantly superior to placebo for agitation/aggression. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p = 0.26). Moderate or marked improvement (CGI) was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher's exact test p <0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p's<0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (ß=5.06; 95%CI,1.18 to 8.94, p = 0.01). Oral dose and serum levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on safety outcomes. CONCLUSIONS: Low-dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted of likely lithium-responsive behavioral symptoms that overlap with mania.

How treatable is refractory depression?

INTRODUCTION: Patients who do not remit following one or more attempts at treatment present a clinical challenge, as well as prolonged suffering and disability. Discouragement is common, so knowledge of likelihood of eventual remission as well as which treatments might ultimately be effective would help patient and clinician alike. METHOD: Thirty-one patients with major depression were recruited, 28 beginning study treatment. All had remained significantly depressed following adequate (4 weeks taking ≥ PDR maximum dose) trials on ≥ two antidepressants having different presumed mechanisms. Patients were begun on tranylcypromine to 60 mg/d, were then treated with up to 120 mg/d and then had dextroamphetamine added. Following two week wash-out, patients were then treated with nortriptyline+lithium, and then phenelzine was added. Each successive phase was entered only if remission had not been achieved, and phases could be skipped. RESULTS: Eighteen of the 28 patients (65%) remitted in one of the five phases of the study, plus 5 additional patients with open post-study treatment (total remitting, 82%). By study phase, Eight of 27 (30%) patients remitted with initial dosing of tranylcypromine up to 60 mg/d, 6/18 (33%) remitted with above PDR dosing of tranylcypromine up to 120 mg/d, and 1/6 (17%) to adding dextroamphetamine. With nortriptyline, 1/10 (10%) remitted with nortriptyline+lithium, and 1/5 (20%) when phenelzine was added. Eighteen of the 28 patients (64%), or 78% of those who remitted, maintained their good benefit for at least six months. DISCUSSION: The majority of depressed patients refractory to two or more adequately utilized differently acting antidepressant medications can still remit and about half may maintain remission for extended periods. "Refractory depression" appears to be a relative description for many unresponsive depressed patients.

Combination antidepressant therapy for major depressive disorder: speed and probability of remission.

INTRODUCTION: Only about a third of patients with an episode of major depressive disorder remit with a given treatment and few remissions occur within the first weeks of treatment. This study tested whether combining escitalopram and bupropion as initial treatment would result in quicker remission and a higher remission rate than monotherapy with either drug. METHOD: Two hundred forty-five outpatients aged 18-65 having non-psychotic, non-bipolar major depression were randomly assigned to double-blind treatment with bupropion or escitalopram or the combination dosed to a maximum of bupropion 450 mg/d and/or escitalopram 40 mg/d for 12 weeks. A Montgomery-Asberg Depression Rating Scale score of 22 was required for randomization, while a Hamilton Rating Scale for Depression score ≤ 7 defined remission. We hypothesized that bupropion plus escitalopram would outperform both monotherapies in both earlier onset of remission and higher rate of remission. RESULTS: Primary analyses did not demonstrate that dual therapy outperformed both monotherapies in either timing of remission or remission rate. All three treatments were well tolerated. DISCUSSION: These results do not support initial use of bupropion plus escitalopram to speed or enhance antidepressant response. CLINICAL TRIALS REGISTRATION: NCT00519428.

A randomized controlled trial of duloxetine versus placebo in the treatment of nonmajor chronic depression.

OBJECTIVE: Numerous double-blind studies have assessed the efficacy of antidepressants in treating chronic depressive disorder, including dysthymic disorder, low-grade chronic depression. However, there are no double-blind, placebo-controlled studies of serotonin-norepinephrine reuptake inhibitors in chronic depressive disorder. METHOD: Outpatients with chronic depressive disorder, but without concurrent major depressive disorder (MDD), were randomly assigned to prospective double-blind duloxetine (beginning at 30 mg/d, increased to a maximum dose of 120 mg/d) versus placebo for 10 weeks. Inclusion criteria were current DSM-IV-TR diagnosis of dysthymic disorder or depression not otherwise specified, age 18-75 years, and a Hamilton Depression Rating Scale (HDRS) score ≥ 12. Exclusion criteria included current major depression. The study was conducted between August 2006 and December 2011. HDRS, Cornell Dysthymia Rating Scale (CDRS), Clinical Global Impressions (CGI), Beck Depression Inventory (BDI), Global Assessment of Functioning (GAF), Social Adjustment Scale (SAS), and other assessments were administered at each visit. We hypothesized that duloxetine would be superior to placebo in (1) 24-item HDRS total score, (2) the percentage of subjects classified as responders and remitters, and (3) secondary measures (CDRS, BDI, CGI). Response was defined as > 50% decrease in 24-item HDRS and CGI-Improvement scale score of 1 or 2 ("very much improved" or "much improved"). Remission was defined as HDRS-17 item score ≤ 4 and 0 on item 1 of the HDRS (depressed mood). RESULTS: 65 subjects were enrolled, of whom 57 began medication. They ranged in age from 19 to 70 years (mean ± SD = 41.63 ± 11.22) and included 24 women and 33 men. Baseline 24-item HDRS score (mean ± SD) for both groups was 20.75 ± 4.92. After 10 weeks, duloxetine-treated subjects had significantly lower 24-item HDRS scores than placebo-treated subjects (time-by-drug group effect on analysis of variance: F1,55 = 9.43, P = .003). Responder and remitter analyses significantly favored duloxetine treatment. The response rate was 65.5% for duloxetine versus 25.0% for placebo (χ(2)(1) = 9.43, P = .003); and the remitter rate was 55.2% for duloxetine versus 14.3% for placebo (χ(2)(1) = 10.46, P = .002). After 10 weeks, duloxetine-treated subjects did not differ significantly better from placebo-treated subjects on the SAS (time-by-drug group effect on analysis of variance: F(1,46) = 0.35, P = .555) or on the GAF (time-by-drug group effect on analysis of variance: F(1,51) = .01, P = .922). CONCLUSIONS: Results on the 24-item HDRS, CGI, and CDRS suggest that duloxetine is efficacious in acute treatment of chronic nonmajor depressive disorder. Response and remission rates also differed significantly, favoring duloxetine treatment, but BDI, GAF, and social functioning (Social Adjustment Scale) did not. Duloxetine appears to be effective in acute treatment of nonmajor chronic depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00360724.

Can people with nonsevere major depression benefit from antidepressant medication?

BACKGROUND: Several meta- or mega-analyses suggest antidepressant medications should be given only to severely depressed patients. In our experience, mild depression benefits from medication. We reanalyzed 1 clinic's randomized placebo-controlled antidepressant studies, limiting analyses to patients with major depressive disorder (MDD) without severe illness, to determine whether nonsevere depression responds to antidepressant medication. DATA SOURCES: Archives of the Depression Evaluation Service outpatient clinic of the New York State Psychiatric Institute were searched for randomized, placebo-controlled antidepressant studies that were conducted between 1977 and 2009 and included patients having MDD and pretreatment Hamilton Depression Rating Scale (HDRS) scores < 23. STUDY SELECTION: Six placebo-controlled studies were found, including 8 active treatment arms and 1,440 patients. 825 patients were randomized and had MDD and an HDRS score < 23. DSM-III, DSM-III-R, or DSM-IV diagnostic criteria contemporary to each study were employed. DATA EXTRACTION: Treatments were compared within study and via a patient-level meta-analysis using analysis of covariance (ANCOVA) of HDRS end point scores adjusted for pretreatment score. The number needed to treat (NNT) was calculated from remission rates (HDRS end point score ≤ 7), which were compared by χ². Effect sizes were calculated from change in HDRS scores. Secondary analyses investigated the effect of chronicity and atypical features on treatment response. DATA SYNTHESIS: Three of 6 studies showed significant (P < .001) treatment effects by ANCOVA, and 4 of 6 studies showed significant (P < .04) differences in remission. The NNT ranged from 3 to 8. Effect sizes ranged from -0.04 to 0.8, with 4 of 8 greater than 0.4. The patient-level meta-analysis confirmed these results; neither chronicity nor atypical features significantly affected outcome. Secondary analyses utilizing global ratings and self-report mimicked the main findings. CONCLUSIONS: Several studies demonstrated significant antidepressant efficacy for patients having nonsevere MDD. Efficacy was not trivial, as NNT ranged from 3 to 8, a range accepted by researchers as sufficiently robust to recommend treatment. These findings suggest mild-moderate MDD can benefit from antidepressants, contrary to findings by several other meta- or mega-analyses.

Is duloxetine effective treatment for depression with atypical features?

Depression with atypical features responds preferentially to monoamine oxidase inhibitors relative to tricyclic antidepressants. The efficacies of newer agents have been little studied in this group, although fluoxetine was more effective than placebo. Studies with newer agents seem indicated. Twenty outpatients having major depression with atypical features were treated for 8 weeks with up to 120 mg/day of duloxetine. Fifty percent responded (>50% decrease in 24-item Hamilton Rating Scale for Depression) and 35% remitted (final 24-item Hamilton Rating Scale for Depression < or =7). The small sample size results in wide confidence intervals and lack of a placebo control group limits inferences of efficacy. Response and remission rates for depressed patients with atypical depression were similar to those reported for depressed patients in general. Placebo-controlled studies are required to definitively demonstrate whether these pilot results represent the efficacy of duloxetine in treating atypical depression.