Ropinirole Augmentation for Depression: A Randomized Controlled Trial Pilot Study.

OBJECTIVE: Evidence both from animal and human studies suggests a role for dopaminergic pathways in the treatment of depression. Ropinirole, a selective agonist of dopamine D2/D3, is in use for the treatment of parkinsonism. Preliminary evidence suggests that such agonists might be useful as antidepressants. We tested whether an add-on ropinirole is an effective in depressed patients. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of add-on ropinirole in depressed patients unresponsive to at least one antidepressant. We recruited 32 unipolar and bipolar patients who remained depressed (modified 21-item Hamilton Depression Rating Scale) despite at least 4 weeks of treatment with an adequate dose of antidepressant medication. Patients received either 2 mg of oral ropinirole or placebo twice daily added on to their current medication and were evaluated weekly for 7 weeks using the Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale. RESULTS: No difference in primary or secondary outcome measures was detected between the treatment and control groups. DISCUSSION: These results differ from previous studies and are unexpected in light of theoretical considerations. This may indicate that there are differences in pharmacological activity between ropinirole and other dopaminergic agents such as pramipexole.

Applying Transcranial Magnetic Stimulation (TMS) Over the Dorsal Visual Pathway Induces Schizophrenia-like Disruption of Perceptual Closure.

Perceptual closure ability is postulated to depend upon rapid transmission of magnocellular information to prefrontal cortex via the dorsal stream. In contrast, illusory contour processing requires only local interactions within primary and ventral stream visual regions, such as lateral occipital complex. Schizophrenia is associated with deficits in perceptual closure versus illusory contours processing that is hypothesized to reflect impaired magnocellular/dorsal stream. Perceptual closure and illusory contours performance was evaluated in separate groups of 12 healthy volunteers during no TMS, and during repetitive 10 Hz rTMS stimulation over dorsal stream or vertex (TMS-vertex). Perceptual closure and illusory contours were performed in 11 schizophrenia patients, no TMS was applied in these patients. TMS effects were evaluated with repeated measures ANOVA across treatments. rTMS significantly increased perceptual closure identification thresholds, with significant difference between TMS-dorsal stream and no TMS. TMS-dorsal stream also significantly reduced perceptual closure but not illusory contours accuracy. Schizophrenia patients showed increased perceptual closure identification thresholds relative to controls in the no TMS condition, but similar to controls in the TMS-dorsal stream condition. Conclusions of this study are that magnocellular/dorsal stream input is critical for perceptual closure but not illusory contours performance, supporting both trickledown theories of normal perceptual closure function, and magnocellular/dorsal stream theories of visual dysfunction in schizophrenia.

Allopurinol for mania: a randomized trial of allopurinol versus placebo as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder.

OBJECTIVE: An emerging body of evidence supports a role for dysfunctional purinergic neurotransmission in mood disorders. Adenosine agonists have been shown to have properties similar to those of dopamine antagonists; there is a well-characterized interaction between adenosine and dopamine receptors in the ventral striatum, and increasing adenosinergic transmission has been demonstrated to reduce the affinity of dopamine agonists for dopamine receptors. Allopurinol increases adenosine levels in the brain, and hence is hypothesized to reduce the symptoms of mania. Two randomized, placebo-controlled trials administering add-on allopurinol to manic patients showed significantly greater improvements in Young Mania Rating Scale (YMRS) scores for drug compared to placebo, while a more recent, relatively small, add-on study showed negative results. Based on these data, our objective was to examine the efficacy of allopurinol as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. METHODS: We performed a large, well-powered, multicenter, six-week, randomized, placebo-controlled trial of allopurinol added to mood stabilizers and/or antipsychotic agents in 180 patients with bipolar disorder in an acute manic episode. RESULTS: Both groups showed improvement on the YMRS (effect size of 1.5 for placebo and 1.6 for allopurinol), with no difference observed between groups on YMRS scores (t = 0.28, p = 0.78). There was no difference in the proportion of patients who responded to treatment (defined as showing at least 50% improvement in YMRS score) between the two groups (p = 0.92), or in dropout rates (p = 0.84). LIMITATIONS: None of our patients received lithium. However, the side effects of lithium and its narrow therapeutic index made the use of lithium less common and, therefore, our study results reflect common current clinical practice. In the present study, we used a variety of antipsychotic and/or mood stabilizing treatments, to which we added allopurinol; one might hypothesize that add-on allopurinol has a different effect in combination with different antipsychotic agents or mood stabilizers. CONCLUSIONS: The findings of this large, well-powered study do not support add-on allopurinol as a treatment for acute mania. This study did not test the efficacy of allopurinol as monotherapy.

A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia.

BACKGROUND: Observations that antagonists of the N-methyl-d-aspartate (NMDA) receptor of glutamatergic neurons can mimic symptoms of schizophrenia have raised the hope that NMDA agonists can improve symptoms. On the basis of encouraging results of trials in which NMDA agonists were added to antipsychotics, we conducted an adequately powered randomized controlled trial adding d-serine, an NMDA modulator, to antipsychotics. METHOD: This study was a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 g/d as an add-on treatment to antipsychotics. Subjects had DSM-IV schizophrenia or schizoaffective disorder and were inpatients or outpatients stabilized on antipsychotics, with persistent negative symptoms. The primary outcome measures were changes in negative symptoms and cognition as measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery, respectively. The study was performed between 2003 and 2007. RESULTS: Mean total Positive and Negative Syndrome Scale scores at baseline were 75.5. Subjects receiving d-serine and placebo improved in scores on the SANS and MATRICS, but no significant differences were observed between groups: improvement on SANS was 11.4% for d-serine vs 14.8% for placebo, F1,147=1.18, P=.32; and improvement on MATRICS was 6.8% for d-serine vs 6.1% for placebo, F1,125=0.96, P=.39, respectively. d-Serine was well tolerated. DISCUSSION: This study did not find a significant difference between drug and placebo. However, the results are limited by a relatively large placebo response and somewhat lower-achieved doses than in prior studies. Future studies will administer higher doses and will attempt to affect the NMDA receptor using other mechanisms, such as agonists of the presynaptic metabotropic glutamate 2/3 receptor or glycine reuptake inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00138775.

A randomized controlled trial of allopurinol vs. placebo added on to antipsychotics in patients with schizophrenia or schizoaffective disorder.

Adenosine agonists produce behavioral effects similar to dopamine antagonists, hence increasing adenosine levels might improve symptoms of schizophrenia. This hypothesis is supported by three single-site studies indicating that allopurinol, which increases adenosine levels, improved symptoms in patients with schizophrenia. We performed a multi-center, 8-week RCT of allopurinol vs. placebo added to anti-psychotic medications in 248 patients with schizophrenia or schizoaffective disorder. Both groups showed improvement in the PANSS (effect size 1.13) and in clinical and cognitive measures. No difference was observed between groups in primary (t=0.01, p=0.992) or secondary outcome measures. These findings do not support allopurinol as a treatment for schizophrenia.

An open-label pilot study to evaluate the efficacy of sildenafil citrate in middle-aged men with late-onset dysthymia.

Late onset dysthymic disorder (DD) in middle-aged and elderly men responds poorly to established antidepressants. Previous studies noted an improvement in mood accompanying sildenafil citrate treatment for erectile dysfunction. We sought to evaluate whether sildenafil's mood effects were independent of the effect on erectile function. A 6-week open label study was conducted with 20 male participants, aged 41-60 who were diagnosed with DD and who had normal erectile function. Participants were treated with sildenafil citrate 25 mg per day for 6 weeks. The primary outcome measure was the 21-item Hamilton Depression Rating Scale. Depressive and sexual symptoms were also evaluated using self-report questionnaires. Treatment with sildenafil resulted in a significant reduction in Hamilton Depression Rating Scale mean scores: from 14.61 +/- 3.5 at baseline to 6.39 +/- 5.13 at end of study (F(3,51) = 32.52, p

Dopamine D2-like receptors and the antidepressant response.

Converging lines of evidence suggest a role for the mesolimbic dopamine system in the response to somatic antidepressant therapies. Here, we review evidence suggesting that antidepressant treatments of different types share the effect of increasing the sensitivity of dopamine D2-like receptors in the nucleus accumbens, clinical studies suggesting that activation of these receptors has antidepressant efficacy, as well as relevant imaging and genetic data on the role of this system in the antidepressant response. We then attempt to reconcile this data with evidence of a common target of antidepressant drugs in the cyclic adenosine monophosphate (cAMP) response element binding protein-brain-derived neurotrophic factor (CREB-BDNF) pathway in a model that suggests potential directions for future inquiry.

Transcranial magnetic stimulation in the treatment of depression.

OBJECTIVE: Transcranial magnetic stimulation (TMS) is a noninvasive and easily tolerated method of altering cortical physiology. The authors evaluate evidence from the last decade supporting a possible role for TMS in the treatment of depression and explore clinical and technical considerations that might bear on treatment success. METHOD: The authors review English-language controlled studies of nonconvulsive TMS therapy for depression that appeared in the MEDLINE database through early 2002, as well as one study that was in press in 2002 and was published in 2003. In addition, the authors discuss studies that have examined technical, methodological, and clinical treatment parameters of TMS. RESULTS: Most data support an antidepressant effect of high-frequency repetitive TMS administered to the left prefrontal cortex. The absence of psychosis, younger age, and certain brain physiologic markers might predict treatment success. Technical parameters possibly affecting treatment success include intensity and duration of treatment, but these suggestions require systematic testing. CONCLUSIONS: TMS shows promise as a novel antidepressant treatment. Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment parameters most likely to produce success. In addition to its potential clinical role, TMS promises to provide insights into the pathophysiology of depression through research designs in which the ability of TMS to alter brain activity is coupled with functional neuroimaging.

Transcranial magnetic stimulation: a new tool in the fight against depression.

Since its introduction to the clinical realm in 1985, transcranial magnetic stimulation (TMS) has rapidly developed into a tool for exploring central nervous system function in both health and disease. The antidepressant effects of TMS were initially observed in 1993. Since then, a solid body of evidence has accumulated suggesting antidepressant effects for both slow TMS (sTMS) and repetitive TMS (rTMS). This review is divided into four parts. First, it addresses the basic concepts governing TMS, and then, second, it discusses the technical parameters involved in administering TMS. Knowledge of these parameters is necessary for understanding how TMS is administered, and how manipulation of the technique impacts on the results obtained. Third, we review the most relevant studies on the antidepressant effects of sTMS and rTMS published to date. Finally, we discuss cortical excitability and how the understanding of this basic neurophysiological function of cortical neurons can be used for monitoring the effects of TMS. In our discussion, we conclude that the time has arrived for TMS to be offered to depressed patients as a treatment.