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Background: As many patients with unipolar depression do not respond sufficiently to initial antidepressant monotherapy, a dose increase of the current administered antidepressant (dose escalation, high-dose treatment) is frequently carried out as next treatment measure. Methods: We conducted a meta-analysis which included all double-blind randomized controlled trials (RCTs) comparing a dose increase of antidepressants directly to continuation of standard-dose treatment in unipolar depressive patients who were non- responders to standard-dose pharmacotherapy. A mean change in the Hamilton Rating Scale for Depression (HAM-D) total score was the primary outcome. Secondary outcomes were response rates and discontinuation rates due to any reason, inefficacy, and adverse effects. Hedges g and risk ratios were calculated as effect sizes. Results: Seven double-blind RCTs (8 study arms) representing 1,208 participants were included. Fluoxetine (N [number of studies] = 2, n [number of patients] = 448), sertraline (N = 2, n = 272), paroxetine (N = 2, n = 146), duloxetine (N = 1, n = 255), and maprotiline (N = 1, n = 87) were investigated. Dose escalation was not more efficacious in HAM-D total score reduction than maintaining standard-dose treatment, neither for the pooled antidepressant group (N = 7, n = 999; Hedges g = -0.04, 95% CI: -0.20 to 0.12; p = 0.63) nor the individual antidepressants. No differences could be determined for response rates, all-cause discontinuation, and drop-outs due to inefficacy. Significantly more patients in the dose escalation group dropped out due to adverse effects than in the standard-dose continuation group. The metaregressions indicate no influence of baseline symptom severity or amounts of dose increments on effect sizes. Conclusions: According to our meta-analytic findings, dose escalation after initial non-response to standard-dose pharmacotherapy cannot be regarded as general evidence-based treatment option in unipolar depression.

Introduction: Inflammatory processes play an important and complex role in the pathophysiology of major depressive disorder (MDD), but, so far, no specific investigation of chemokines exists. Methods: In this study, we investigated the changes of plasma chemokine levels (eotaxin-1, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, and TARC) in 47 MDD patients before (PRE) and after 1 and 6 weeks of pharmacological treatment (POST1 and POST6) in relation to the response to antidepressive therapy. We hypothesized that the direction of alterations in levels of chemokines would significantly differ between the 2 groups, responders and nonresponders. Results: Among the investigated chemokines, only the level of macrophage-derived chemokine (MDC) changed significantly in relation to therapy response. MDC levels were significantly elevated in the responder group at POST6. Discussion: MDC is a constitutively expressed chemokine involved in the pathophysiology of infectious and neoplastic diseases. This is the first study providing valuable hints that MDC might serve as a marker of pharmacological therapy response in MDD.

Background: Repetitive transcranial magnetic stimulation (rTMS) has been studied as a treatment option for chronic tinnitus for almost ten years now. Although most of these studies have demonstrated beneficial effects, treatment results show high interindividual variability and yet, little is known about predictors for treatment response. Methods: Data from 538 patients with chronic tinnitus were analysed. Patients received either low-frequency rTMS over the left temporal cortex (n= 345, 1 Hz, 110% motor threshold, 2000 stimuli/day) or combined temporal and frontal stimulation (n = 193, 110% motor threshold, 2000 stimuli at 20 Hz, left dorsolateral prefrontal cortex plus 2000 stimuli at 1 Hz, temporal cortex). Numerous demographic, clinical and audiological variables as well as different tinnitus characteristics were analysed as potential predictors for treatment outcome, which was defined as change in the tinnitus questionnaire (TQ) score. Results: Both stimulation protocols resulted in a significant improvement in TQ scores. In the group receiving combined treatment, patients with comorbid temporomandibular complaints benefited more from rTMS than patients without those complaints. In addition, for both stimulation protocols the TQ score at baseline as well as the change in TQ score from screening to baseline correlated significantly with treatment response. Patients with higher TQ scores at baseline had more pronounced TQ reductions than patients with low TQ baseline scores. Also, patients who had already improved from screening to baseline benefited less than patients without initial improvement. Conclusions: The results from this large sample confirm the effectiveness of rTMS for the treatment of chronic tinnitus. Nonetheless, the high interindividual variability in treatment response can only be partly explained by the investigated clinical variables.

Haloperidol, a dopamine receptor antagonist and sigma-receptor-active neuroleptic drug, is cytotoxic to primary hippocampal neurones, C6 glioma cells and NCB20 cells. A 24 h challenge of these cells with haloperidol resulted in reduced cell viability and ultimately cell lysis. The most dramatic changes in cellular morphology were the retraction of cellular extensions, development of membrane blebs, and finally cell detachment from the culture dish. DNA isolated from haloperidol-treated cells was randomly degraded, indicating a necrotic rather than an apoptotic pathway of cell death. Vitamin E (alpha-tocopherol), a lipophilic free radical scavenger, prevented haloperidol-induced DNA fragmentation and ultimately cell death. These findings suggest that haloperidol induces necrotic cell death in which free radicals play a major role.