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Objectives: To evaluate the efficacy and safety of adjunctive aripiprazole compared with standard antidepressant therapy (ADT) for older patients with major depressive disorder (MDD) who demonstrated an incomplete response to standard antidepressant monotherapy. Methods: Data from three similar 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled for this post hoc analysis. Two age groups were defined: younger patients (aged 18-49 years) and older patients (aged 50-67 years). The older patient group was further divided into three subgroups: 50-55, 56-60, and 61-67 years. The efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of the prospective phase (Week 8) to endpoint (Week 14, last observation carried forward (LOCF)). Remission was defined as MADRS total score ≤10 at endpoint. Results: Four hundred and nine older patients (placebo, n¼198; aripiprazole, n¼211) and 679 younger patients (placebo, n=341; aripiprazole, n=338) were included in this analysis. Older patients receiving aripiprazole demonstrated significantly greater improvement in MADRS total score versus placebo at Week 14 (-10.0 vs. -6.4; p<0.001; LOCF), similar to the improvement seen in younger patients. Remission rates were significantly higher with aripiprazole versus placebo in older (32.5% vs. 17.1%; p<0.001) and younger (26.9% vs. 16.4%; p<0.001) patients. Akathisia was the most common adverse event in both the older (17.1%) and younger (26.0%) patient groups. Conclusions: Adjunctive aripiprazole was effective in improving depressive symptoms in older patients, 50-67 years, with MDD who have had an inadequate response to standard antidepressant medication. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the effectiveness of adjunctive aripiprazole as an antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with baseline anxious/atypical features. The study defined anxious depression using a Hamilton Rating Scale for Depression, while atypical depression was defined using a criteria on the Inventory of Depressive Symptomatology--Self-Report. Study researchers concluded that adjunctive aripiprazole is effective in patients with major depression.

Background: Although electroconvulsive therapy (ECT) in major depression is effective, cognitive effects limit its use. Reducing the width of the electrical pulse and by using the right unilateral electrode placement may decrease adverse cognitive effects, while preserving efficacy. Methods: In a double-masked study, we randomly assigned 90 depressed patients to right unilateral ECT at 6 times seizure threshold or bilateral ECT at 2.5 times seizure threshold, using either a traditional brief pulse (1.5 milliseconds) or an ultrabrief pulse (0.3 millisecond). Depressive symptoms and cognition were assessed before, during, and immediately, 2, and 6 months after therapy. Patients who responded were monitored for a 1-year period. Results: The final remission rate for ultrabrief bilateral ECT was 35%, compared with 73% for ultrabrief unilateral ECT, 65% for standard pulse width bilateral ECT, and 59% for standard pulse width unilateral ECT (all P < .05 after covariate adjustment). The ultrabrief right unilateral group had less severe cognitive side effects than the other three groups in virtually all primary outcome measures assessed in the acute postictal period, and during and immediately after therapy. Both the ultrabrief stimulus and right unilateral electrode placement produced less short- and long-term retrograde amnesia. Patients rated their memory deficits as less severe after ultrabrief right unilateral ECT compared with each of the other three conditions (P < .001). Conclusions: The use of an ultrabrief stimulus markedly reduces adverse cognitive effects, and when coupled with markedly suprathreshold right unilateral ECT, also preserves efficacy. (ClinicalTrials.gov number, NCT00487500.) [Copyright &y& Elsevier]

Electrophysiological studies suggest that α2-adrenoceptors profoundly affect monoaminergic neurotransmission by enhancing noradrenergic tone and serotonergic firing rates. Recent reports suggest that α2-antagonism may hasten and improve the response to antidepressant medications. To test this hypothesis, a randomized double-blind controlled trial was undertaken to determine if the combination of an α2-antagonist (yohimbine) with a selective serotonin reuptake agent (SSRI) (fluoxetine) results in more rapid onset of antidepressant action than an SSRI agent alone. In all, 50 subjects with a DSM-IV diagnosis of major depressive disorder confirmed by SCID interview were randomly assigned to receive either fluoxetine 20 mg plus placebo (F/P) or fluxetine 20 mg plus a titrated dose of yohimbine (F/Y). The yohimbine dose was titrated based on blood pressure changes over the treatment period, in a blind-preserving manner. Hamilton depression scale ratings (HDRS) and clinical global impression (CGI) ratings were obtained weekly over a period of 6 weeks. The rate of achieving categorical positive responses was significantly more rapid in the F/Y group compared to the F/P group using both the HDRS and the CGI scales as outcome measures in a survival analysis using a log-rank test (χ(I) = 5.86, p = 0.016 and χ²(I) = 5.29, p = 0.021, respectively). At the last observed visit, 18 (69%) of the 26 F/Y subjects met the response criteria for CGI compared to 10 (42%) of 24 F/P subjects. Using the HDRS criteria, 17 (65%) of 26 F/Y subject vs 10 (42%) of 24 F/P subjects were responders. The addition of the α2-antagonist yohimbine to fiuoxetine appears to hasten the antidepressant response. There is also a trend suggesting an increased percentage of responders to the combined treatment at the end of the 6-week trial. [ABSTRACT FROM AUTHOR]

Context: We previously used positron emission tomography (PET) measurement of brain metabolism with fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion–induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using α-methylparatyrosine (AMPT). Objective: To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs. Design, Setting, and Participants: Randomized, controlled, double-blind trial in which 18 patients recruited in 1997-2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration. Interventions: After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart. Main Outcome Measures: Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms. Results: AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P = .002) and dorsolateral prefrontal (P = .03) cortex and thalamus (P = .006). Increased resting metabolism in prefrontal and limbic areas... [ABSTRACT FROM AUTHOR]

Background: Although significant evidence suggests that diminished monoamine function is associated with clinical depression, catecholamine or indoleamine depletion alone has not been associated with significant mood changes in unmedicated depressed subjects or never-depressed control subjects. This study assesses the integrated role of these monoamine systems in depressed patients.Methods: Unmedicated depressed subjects underwent a 2-week, double-blind, random-ordered crossover study consisting of the following active and control conditions respectively: indoleamine (via tryptophan depletion) plus catecholamine (via alpha-methyl-paratyrosine administration) depletion and, separately, indoleamine plus sham (via diphenhydramine administration) catecholamine depletion. Ten subjects completed both conditions; two subjects were withdrawn after active testing and one after control testing.Results: Mean Hamilton Depression Rating Scale (HDRS) scores decreased progressively throughout the study days (baseline 26.7 points ± 1.7 SEM and termination 20.0 ± 2.4, active depletion; baseline 26.1 points ± 2.3 SEM and termination 23.2 ± 2.6, control testing) but did not differ between groups. Only three patients demonstrated 20% or greater increases from baseline HDRS at any point during the observation days.Conclusions: Overall, results show that simultaneous disruptions of indoleamine and catecholamine function do not exacerbate symptoms in unmedicated depressed subjects, thus lending further support to the notion that monoamines regulate mood in actively depressed patients via indirect mechanisms. [ABSTRACT FROM AUTHOR]

Scalp recordings of the electroencephalogram (EEG) have been used in association with repetitive transcranial magnetic stimulation (rTMS) investigations as a safety measure in monitoring ongoing EEG activity and as a neurophysiologic tool in examining the specific effects induced by the magnetic stimulus on the EEG or evoked potentials (EPs). Medline review on the use of EEG or EPs with rTMS reveals that this area has been largely unexplored. Limited available studies attest to the potential for studies combining EEG/EPs and rTMS to be useful in further elucidating the normal brain physiology. Herein, we report on our experience with continuous EEG sampling combined with rTMS in patients with major depression (n = 14), schizophrenia (n = 7), and obsessive–compulsive disorder (n = 5). Our data support the practice of using continuous EEG monitoring when the stimulation parameters fall outside established safety guidelines. Depression and Anxiety, 12:166–169, 2000. © 2000 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Several lines of emerging evidence suggest that dysfunction of γ-aminobutyric acid (GABA) systems is associated with major depression. However, investigation of this hypothesis is limited by difficulty obtaining noninvasive in vivo measures of brain GABA levels. In this study we used in vivo proton magnetic resonance spectroscopy to investigate the hypothesis that abnormalities in the GABA neurotransmitter system are associated with the neurobiologic processes of depression. Methods: The GABA levels were measured in the occipital cortex of medication-free depressed patients meeting DSM-IV criteria (n=14) and healthy control subjects with no history of mental illness (n=18) using a localized difference editing proton magnetic resonance spectroscopy protocol. An analysis of covariance was employed to examine the effects of depression, sex, and age. Results: The depressed patients demonstrated a highly significant (52%) reduction in occipital cortex GABA levels compared with the group of healthy subjects. While there were significant age and sex effects, there was no interaction of diagnosis with either age or sex. Conclusion: This study provides the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients. [ABSTRACT FROM AUTHOR]

Background: Although state-related alterations in catecholamine function have been well-described in depressed subjects, enduring abnormalities have been less reliably identified. In our study, medication-free subjects with fully remitted major depression underwent a paradigm of catecholamine depletion, via use of the tyrosine hydroxylase inhibitor α-methylparatyrosine. Method: Subjects underwent 2 sets of testing conditions in a double-blind, random-ordered, crossover design, approximately 1 week apart. They underwent active catecholamine depletion (via oral administration of 5 g α-methylparatyrosine) or sedation-controlled, sham catecholamine depletion (via oral administration of 250 mg diphenhydramine hydrochloride), during a 2-day observation. Serial mood ratings and blood samples were obtained. Results: Fourteen subjects completed the active testing condition; 13 completed sham testing. Subjects experienced marked, transient increases in core depressive and anxiety symptoms, as demonstrated by a mean 21-point increase on Hamilton Depression Rating Scale scores. Furthermore, 10 (71%) of 14 subjects fulfilled relapse criteria during active testing, whereas 1 (8%) of 13 subjects did so during sham testing. The severity of the depressive reaction correlated with baseline plasma cortisol levels (r=0.59; P=.04). Conclusions: Euthymic, medication-free subjects with a history of major depression demonstrate significant depressive symptoms when undergoing testing with α-methylparatyrosine. This depressive reaction may represent a reliable marker for a history of depression. Further work is needed to clarify the significance of this finding. [ABSTRACT FROM AUTHOR]

Focuses on a double-blind, placebo controlled trial in the assessment of the effectiveness of pindolol in hastening response to fluoxetine in the treatment of major depression. Rates of partial remission; Rates of attrition; Side effects of pindolol; Overall response to treatment.

Forty to 50% of depressed patients who are initially prescribed antidepressant medications or administered electroconvulsive therapy do not experience a timely remission. This group typifies treatment-refractory depression (TRD), defined as a failure to demonstrate an "adequate" response to an "adequate" treatment trial (i.e., sufficient intensity of treatment for sufficient duration). The approach to the patient with TRD must be methodical. The clinician should examine potential factors contributing to apparent non-response: trial adequacy, compliance, differential diagnosis, and treatable comorbid conditions. After addressing these variables, a patient who does not demonstrate a remission may be considered treatment resistant (relative or absolute). Although many of these patients will respond to a subsequent treatment regimen, there are no (or only nominally useful) predictors for the initial selection of that "subsequent" antidepressant treatment. Hence, the initial treatment is typically chosen on the basis of safety and convenience, not differential efficacy. The search for the clinical and biological correlates of long-term or acute outcome presents a major nosologic conundrum: Who will respond to treatment? Which treatment? In this manner, TRD challenges the prognostic utility of our current phenomenologic-based diagnostic system. [ABSTRACT FROM AUTHOR]

Objective: Reduced γ-aminobutyric acid (GABA) concentrations have been reported in the plasma, CSF, and cortex of depressed subjects. Of interest is that ECT, one of the most effective treatments for severe refractory depression, produces considerable anticonvulsant effects that may be related to increased GABAergic transmission. The purpose of this study was to determine if cortical GABA concentrations increase following a course of ECT. Method: Occipital cortex GABA concentrations in eight depressed patients were measured by using proton magnetic resonance spectroscopy before and after a course of ECT. Results: A significant increase in occipital cortex GABA concentrations was seen following ECT treatment of depression. Conclusions: Occipital cortex GABA concentrations increase two-fold following ECT. This suggests possible GABAergic involvement in ECT's mechanism of anticonvulsant and antidepressant actions. [ABSTRACT FROM AUTHOR]

An abstract of the article "The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study," by R. M. Berman, R. N. Marcus, R. Swanik, and colleagues is presented.

Electroconvulsive therapy (ECT) is the most effective and most rapidly acting treatment for severe treatment resistant major depression, but its use is limited by its cognitive side effects. Magnetic seizure therapy (MST) is a new form of convulsive therapy using high-dosage repetitive transcranial magnetic stimulation (rTMS) to induce focal cortical seizures under anesthesia. MST is under study as a means of reducing the side effects of ECT through the enhanced control over the sites of seizure initiation and topography of seizure propagation afforded by the relative focality of rTMS. This review traces the stages in the development of MST, from device development, to preclinical testing, to clinical trials. The results of a study on the comparative safety of chronic MST and electroconvulsive shock in non-human primates support the safety of both interventions, and indicate that the seizures induced by MST are more focal and have less impact on deeper brain structures. This non-human primate model and a controlled clinical trial in patients with major depression, suggest that MST may induce fewer side effects and less amnesia than ECT. Ongoing work will yield the first data on the antidepressant efficacy of MST. If ultimately shown to be effective, MST could represent a new, less invasive option for patients with severe treatment resistant depression or other disorders who would otherwise require ECT. [Copyright &y& Elsevier]

Abstract: Background: There is a paucity of evidence for outcome predictors in patients with major depressive disorder (MDD) not responding to initial antidepressant therapy (ADT). This post-hoc analysis evaluated whether MDD severity affects response to adjunctive aripiprazole. Methods: Data from 3 randomized, double-blind, placebo-controlled trials of adjunctive aripiprazole in adults with MDD and inadequate response to 1 to 3 ADT trials were pooled and stratified based on Montgomery–Åsberg Depression Rating Scale (MADRS) total score (mild, ≤24; moderate, 25–30; severe, ≥31). Treatment differences in change in MADRS total score and rates of response (≥50% MADRS improvement) and remission (response with MADRS total score ≤10) were analyzed at endpoint. Adverse events were assessed within each subgroup. Results: Aripiprazole produced greater improvement than placebo in the MADRS total score regardless of MDD severity at baseline (between-treatment difference [95% CI]: mild, −2.5 [−4.0 to −1.1]; moderate, −3.2 [−4.9 to −1.6]; severe, −4.5 [−6.8 to −2.2]). Compared with placebo, adjunctive aripiprazole increased the likelihood of response in all subgroups (risk ratio [95% CI]: mild, 1.50 [1.15, 1.95]; moderate, 1.51 [1.09, 2.11]; severe, 1.95 [1.23, 3.10]). Common treatment-emergent adverse events included akathisia and restlessness. Limitations: The original studies were not designed to assess the efficacy of adjunctive aripiprazole by baseline severity, and this post-hoc analysis was not powered to evaluate differences in severity subgroups. Conclusions: In patients who failed to respond to initial ADT, adjunctive aripiprazole was more effective than placebo in mild, moderate, and severe MDD strata. Clinical trial registration: ClinicalTrial.gov: NCT00095823, NCT00105196, and NCT00095758. [Copyright &y& Elsevier]

Abstract: Background: Although antipsychotic agents have a long history of use in depression, their effectiveness in treating core symptoms of depression such as loss of interest has been questioned. Adjunctive aripiprazole is beneficial for the treatment of patients with major depressive disorder but its effects on specific symptoms have not been reported. The objective of this study was to examine the effects of aripiprazole on core symptoms of depression. Methods: This is a post-hoc, pooled analysis of two trials of aripiprazole augmentation of standard antidepressants (ADT) in patients with major depression. Patients with an inadequate response to ADT received adjunctive aripiprazole (n =373) or placebo (n =368) for 6weeks. Change on four subscales of the 17-item Hamilton Depression Rating Scale (HAM-D17) that capture core depression symptoms was determined and change on individual HAM-D items also was assessed. The magnitude of within-group change for the subscales and individual items was expressed as effect size (ES) and between-group significance tested with ANCOVA. The magnitude of change was also examined comparing the response rates for aripiprazole and placebo on HAM-D17 and the four subscales. Change on three composite subscales — anxiety, insomnia and drive was also examined. Results: Within-group change on the four core subscales was substantial (ES=1.1–1.2) and similar to that for the 17-item HAM-D total score. Between-group comparisons indicated mean change and response rates were significantly greater with adjunctive aripiprazole than placebo for each core subscale (all p <0.01). Individual HAM-D17 items showing the greatest change from baseline with adjunctive aripiprazole: depressed mood (within-group ES=1.03) work and activities (ES=0.86), guilt (ES=0.77) and psychic anxiety (ES=0.67) are the same symptoms identified by each of the core subscales and each of these items differed significantly from change on that item with placebo (p <0.01). On three composite scales, adjunctive aripiprazole was significantly more effective than placebo with respect to mean change for anxiety, insomnia and drive (all p <0.001). Conclusions: Aripiprazole augmentation of standard ADT results in significant, clinically meaningful changes in the core symptoms of depression. It is also associated with significant change in anxiety, insomnia, and drive components of the 17-item HAM-D. [Copyright &y& Elsevier]

Abstract: Introduction: Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is important for maintaining constant cerebral blood flow. A reduced CVR increases the risk of stroke. We recently found that CVR was reduced in patients with depression. This might contribute to the higher risk of stroke that has been found in subjects suffering from depression. The characterization of pathophysiological conditions in the cerebral circulation requires the knowledge of influencing factors on CVR. We therefore investigated the influence that antidepressant administration might have on CVR in humans. Methods: We investigated CVR in 48 healthy men before and after a 10-day application of either mirtazapine or placebo. CVR was determined by calculating the increase in cerebral blood flow velocity after stimulation with acetazolamide. Blood flow velocities were measured by transcranial Doppler ultrasound. Results: There was no significant group-difference of CVR after the treatment trial compared to baseline. Discussion: Mirtazapine does not seem to have an influence on CVR, or any impact on CVR might have been quickly limited by a cerebral autoregulatory response. [Copyright &y& Elsevier]

Background: Major depression is more prevalent in women than men. The present study evaluated if previous findings that demonstrated decreased 5-hydroxytryptamine (5-HT) transporter availability in depressed patients would be confirmed in a larger sample and also evaluated sex differences. Methods: Depressed (n = 32) and healthy subjects (n = 32), including 16 pairs of women and men, participated in an iodine-123-2 beta-carbomethoxy-3beta-(4-iodophenyltropane) ([123I]β-CIT) single photon emission computed tomography (SPECT) and a magnetic resonance imaging (MRI) scan. Participants were administered [123I]β-CIT (225.7 ± 3.7 MBq) and imaged 23.0 ± 1.6 hours later. Statistical analyses included analysis of variance and a regression analysis of the main and interactive effects of age, sex, and depression. Results: Overall, depressed patients demonstrated 12% lower diencephalon and no change in striatal or brainstem [123I]β-CIT uptake. Significant age by sex, sex by depression, and age by sex by depression interactions were noted due to 22% lower diencephalon [123I]β-CIT uptake in depressed women compared with less than a 1% decrease in depressed men. Conclusions: As observed previously, diencephalon 5-HT transporter availability is decreased in depressed patients. However, the decrease appears to be sex-specific and age-dependent. These findings suggest that serotonergic mechanisms mediating depressed mood differ between men and women in an age-dependent manner and may explain why young women respond better to treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants. [Copyright &y& Elsevier]

Abstract: Introduction: It has been proposed that the often found hyperintensities on MRI representing vascular changes might be correlated with a worse outcome of cognitive malfunction in depression. The purpose of this study was to evaluate neuropsychological status in the acute depressed state and following remission and to investigate the potential relationship between MRI hyperintensities and neuropsychological functioning through the treatment course in a group of middle-aged depressed patients. Materials and methods: Twenty-seven depressed patients were assessed by a series of neuropsychological tests at the beginning of the depressive episode and again after an euthymic phase of 6 months following treatment. Thirty healthy controls were tested at comparable intervals. In all patients and controls a MRI was performed to identify hyperintensities representing a possible correlation with test performance during treatment course. Results: At the onset of a depressive episode patients performed significantly worse than the controls in all tests. After sustained remission the patient group still performed significantly worse in verbal memory and verbal fluency compared to controls. There were no significant correlations between number of presence of vascular risk factors, or presence of hyperintensities on MRI, and cognitive abilities at either time point. Discussion: These findings favor the hypothesis that some neuropsychological deficits might persist following treatment for depression, even in middle-aged patients. We found, however, that any residual cognitive deficit is not associated with MRI-hyperintensities in this age-group. [Copyright &y& Elsevier]

Stimulation parameters seem to strongly influence the efficacy of repetitive transcranial magnetic stimulation (rTMS) in the management of treatment-resistant depressed patients. The most effective and safest parameters are yet to be defined. Moreover, systematic follow-up data available to document the duration of the therapeutic effects remain sparse. Twenty-one treatment-resistant depressed patients were randomized to either active rTMS (N=12) or to sham (N=9) treatment in a double-blind design. Patients were kept on their medications. Sub-motor-threshold (MT) stimulation (80% MT) was delivered for 10 consecutive work days (20 Hz, 2-s trains, 20 trains). Subjects meeting pre-set criteria for responding were entered into a follow-up phase for up to 5 months. Utilizing the above stimulation parameters, we found no significant difference between groups. Six patients in the active group and one subject in the sham group met criteria for the follow-up phase. The period of time before subjects met criteria for relapse was highly variable ranging from 2 to 20 weeks. Sub-threshold rTMS stimulation for 2 weeks is not significantly superior to sham treatment for treatment-resistant depressed patients. The duration of the therapeutic effects of rTMS delivered to the left prefrontal cortex using the above-described parameters is highly variable. [Copyright &y& Elsevier]