Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

A Clinical Case Series of Acute and Maintenance Home Administered Transcranial Direct Current Stimulation in Treatment-Resistant Depression.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a noninvasive neurostimulation technique being translated clinically for the treatment of depression. There is limited research documenting the longer-term effectiveness and safety of tDCS treatment. This case series is the first report of remotely supervised, home-administered tDCS (HA-tDCS) for depression in a clinical setting. METHODS: We report clinical, cognitive, and safety outcomes from 16 depressed patients who received acute and/or maintenance HA-tDCS. We retrospectively examined clinical data from up to 2.5 years of treatment. Descriptive statistics are reported to document patient outcomes. RESULTS: Twelve patients received acute treatment for a current depressive episode and 4 commenced tDCS maintenance therapy after responding to ECT or repetitive transcranial magnetic stimulation (rTMS). The cohort was highly treatment-resistant wherein 15 of 16 patients failed 3 trials or more of antidepressant medication in the current episode, and 6 patients failed to gain significant benefit from prior ECT or rTMS. Five of 12 patients responded to acute tDCS within 6 weeks, and 9 patients who received tDCS for more than 12 weeks maintained improvements over several months. Cognitive tests showed no evidence of impairments in cognitive outcomes after up to 2 years of treatment. Two patients were withdrawn from treatment because of blurred vision or exacerbation of tinnitus. Transcranial direct current stimulation was otherwise safe and well tolerated. CONCLUSIONS: Transcranial direct current stimulation given for at least 6 weeks may be of clinical benefit even in treatment-resistant depression. Results provide support for long-term effectiveness, safety, and feasibility of remotely supervised HA-tDCS and suggest a role for maintenance tDCS after acute treatment with tDCS, rTMS, or ECT.

Ketamine treatment for depression: A model of care.

OBJECTIVE: Ketamine and related compounds are emerging as rapidly acting therapies for treatment-resistant depression. Ketamine differs from standard antidepressants in its speed of action, specific acute and cumulative side effects, risk of dependence and regulatory requirements. However, there is currently little guidance offering translation from research studies into clinical practice. We therefore detail a comprehensive model of care for ketamine treatment of depression. METHOD: We formulated a set of policies and procedures for a 'compassionate use' ketamine programme that developed out of our clinical research in ketamine. These policies and procedures were formulated into a detailed model of care. RESULTS: The current Australian and New Zealand regulatory frameworks and professional bodies' recommendations regarding ketamine are detailed along with clinical governance and infrastructure considerations. We next describe a four-step model comprising initial assessment, pre-treatment, treatment and post-treatment phases. The model comprises thorough psychiatric and medical assessments examining patient suitability, a rigorous consenting process and structured safety monitoring across an acute treatment course or maintenance therapy. Our ketamine dose-titration method is detailed allowing flexible dosing of patients across a treatment course enabling individualised treatment. CONCLUSION: The model of care aims to bridge the gap between efficacy studies and clinical care outside of research settings as ketamine and related compounds become increasingly important therapies for treatment-resistant depression.

Transcranial Random Noise Stimulation for the Acute Treatment of Depression: A Randomized Controlled Trial.

BACKGROUND: Transcranial electrical stimulation has broad potential as a treatment for depression. Transcranial random noise stimulation, which delivers randomly fluctuating current intensities, may have greater cortical excitatory effects compared with other forms of transcranial electrical stimulation. We therefore aimed to investigate the antidepressant efficacy of transcranial random noise stimulation. METHODS: Depressed participants were randomly assigned by computer number generator to receive 20 sessions of either active or sham transcranial random noise stimulation over 4 weeks in a double-blinded, parallel group randomized-controlled trial. Transcranial random noise stimulation was delivered for 30 minutes with a direct current offset of 2 mA and a random noise range of 2 mA. Primary analyses assessed changes in depression severity using the Montgomery-Asperg Depression Rating Scale. Neuroplasticity, neuropsychological, and safety outcomes were analyzed as secondary measures. RESULTS: Sixty-nine participants were randomized, of which 3 discontinued treatment early, leaving 66 (sham n = 34, active n = 32) for per-protocol analysis. Depression severity scores reduced in both groups (Montgomery-Asperg Depression Rating Scale reduction in sham = 7.0 [95% CI = 5.0-8.9]; and active = 5.2 [95% CI = 3.2-7.3]). However, there were no differences between active and sham groups in the reduction of depressive symptoms or the number of participants meeting response (sham = 14.7%; active = 3.1%) and remission criteria (sham = 5.9%; active = 0%). Erythema, paresthesia, fatigue, and dizziness/light-headedness occurred more frequently in the active transcranial random noise stimulation group. Neuroplasticity, neuropsychological, and acute cognitive effects were comparable between groups. CONCLUSION: Our results do not support the use of transcranial random noise stimulation with the current stimulation parameters as a therapeutic intervention for the treatment of depression. CLINICAL TRIAL REGISTRATION AT CLINICALTRIALS: gov/NCT01792414.

Neurocognitive effects of transcranial direct current stimulation (tDCS) in unipolar and bipolar depression: Findings from an international randomized controlled trial.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been found to have antidepressant effects and may have beneficial neurocognitive effects. However, prior research has produced an unclear understanding of the neurocognitive effects of repeated exposure to tDCS. The study's aim was to determine the neurocognitive effects following tDCS treatment in participants with unipolar or bipolar depression. METHOD: The study was a triple-masked, randomized, controlled clinical trial across six international academic medical centers. Participants were randomized to high dose (2.5 mA for 30 min) or low dose (0.034 mA, for 30 min) tDCS for 20 sessions over 4 weeks, followed by an optional 4 weeks of open-label high dose treatment. The tDCS anode was centered over the left dorsolateral prefrontal cortex at F3 (10/20 EEG system) and the cathode over F8. Participants completed clinical and neurocognitive assessments before and after tDCS. Genotype (BDNF Val66Met and catechol-o-methyltransferase [COMT] Val158Met polymorphisms) were explored as potential moderators of neurocognitive effects. RESULTS: The study randomized 130 participants. Across the participants, tDCS treatment (high and low dose) resulted in improvements in verbal learning and recall, selective attention, information processing speed, and working memory, which were independent of mood effects. Similar improvements were observed in the subsample of participants with bipolar disorder. There was no observed significant effect of tDCS dose. However, BDNF Val66Met and COMT Val158Met polymorphisms interacted with tDCS dose and affected verbal memory and verbal fluency outcomes, respectively. CONCLUSIONS: These findings suggest that tDCS could have positive neurocognitive effects in unipolar and bipolar depression. Thus, tDCS stimulation parameters may interact with interindividual differences in BDNF and COMT polymorphisms to affect neurocognitive outcomes, which warrants further investigation.

Comparison of Site Localization Techniques for Brain Stimulation.

OBJECTIVES: The dorsolateral prefrontal cortex (DLPFC) is a commonly targeted site using noninvasive brain stimulation techniques. Methods used to localize this site commonly rely on the International 10-20 electroencephalography (EEG) system, including elastic EEG caps, which stretch to accommodate varying head sizes, as well as the Beam F3 algorithm, which uses scalp measurements to calculate the location of the DLPFC. Both methods have been validated against magnetic resonance imaging-based DLPFC localization and are regularly used in research centers and clinics, but an in vivo comparison of reliability has not yet been conducted. This study examines whether Beam F3 and EEG cap methods differ in DLPFC localization, when applied by different practitioners (measurers) on a range of subjects. Further, whether measurer experience or subject head characteristics influence localization. METHODS: Measurers (n = 5) of varying levels of experience identified the location of the left DLFPC on subjects (n = 6) with varying head sizes, using both Beam F3 and EEG cap methods. An independent assessor recorded the measurers' placements along the anterior-posterior and medial-lateral planes. Values were normalized to the subjects' mean nasion-inion and tragus-tragus distances and examined using a mixed effects repeated measures analysis. RESULTS: The Beam F3 method resulted in significantly more anterior placements (~11.5 mm) compared with the EEG cap. Subjects with smaller head sizes had more anterior placements, compared with medium and large heads, regardless of the method used. There was no significant difference between methods along the medial-lateral plane. Measurer experience did not significantly influence DLPFC localization. CONCLUSIONS: Beam F3 and EEG cap methods resulted in similar DLPFC placements, with a small difference along the anterior-posterior plane. Measurer experience did not affect either method, suggesting that 2 weeks of training is sufficient to achieve competency. Training and reliability of DLPFC placement therefore do not represent substantial barriers to application of either method. Special care should be taken with subjects with small heads as both methods resulted in more anterior DLPFC placements.

Increase in PAS-induced neuroplasticity after a treatment course of intranasal ketamine for depression. Report of three cases from a placebo-controlled trial.

BACKGROUND: Animal studies suggest that neural plasticity may play a role in the antidepressant effects of a single ketamine dose. However, the potential effects of repeated ketamine treatments on human neuroplasticity are unknown. METHODS: This pilot RCT study measured plasticity-induced changes before and after a ketamine course, in three treatment-resistant depressed subjects, who were randomized to receive 8 intranasal treatments of 100mg ketamine or 4.5mg midazolam. Mood ratings were performed by a trained blinded rater at baseline and 24h-48h after the ketamine course, using the Montgomery Asberg Depression Rating Scale (MADRS). Neuroplasticity was assessed in the motor cortex using a paired associative stimulation (PAS) paradigm at baseline and 24h-48h after the treatment course. No changes in current psychotropic medication or dosage were permitted for 4weeks prior to trial entry and throughout the trial. RESULTS: The subject receiving ketamine, but not those receiving midazolam, presented a marked increase in neural plasticity after the treatment course. However, mood changes were not associated with changes in neural plasticity. LIMITATIONS: Pilot study with small sample size. Concomitant antidepressant medications taken. Plasticity was tested in the motor cortex only, thus the generalizability of these findings to other brain areas cannot be assumed. CONCLUSIONS: These results suggest that a course of intranasal ketamine may enhance synaptic plasticity in subjects with depression, but this was not associated with antidepressant effects. Further research on this topic is warranted.

Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-pharmacological intervention for depression. It has mixed results, possibly caused by study heterogeneity. AIMS: To assess tDCS efficacy and to explore individual response predictors. METHOD: Systematic review and individual patient data meta-analysis. RESULTS: Data were gathered from six randomised sham-controlled trials, enrolling 289 patients. Active tDCS was significantly superior to sham for response (34% v. 19% respectively, odds ratio (OR) = 2.44, 95% CI 1.38-4.32, number needed to treat (NNT) = 7), remission (23.1% v. 12.7% respectively, OR = 2.38, 95% CI 1.22-4.64, NNT = 9) and depression improvement (B coefficient 0.35, 95% CI 0.12-0.57). Mixed-effects models showed that, after adjustment for other predictors and confounders, treatment-resistant depression and higher tDCS 'doses' were, respectively, negatively and positively associated with tDCS efficacy. CONCLUSIONS: The effect size of tDCS treatment was comparable with those reported for repetitive transcranial magnetic stimulation and antidepressant drug treatment in primary care. The most important parameters for optimisation in future trials are depression refractoriness and tDCS dose.

Transcranial direct current stimulation to enhance cognition in euthymic bipolar disorder.

OBJECTIVES: To investigate the use of transcranial direct current stimulation (tDCS) for enhancing working memory and sustained attention in euthymic patients with bipolar disorder. METHODS: Fifteen patients with bipolar disorder received anodal left prefrontal tDCS with an extracephalic cathode (prefrontal condition), anodal left prefrontal and cathodal cerebellar tDCS (fronto-cerebellar condition), and sham tDCS given 'online' during performance on a working memory and sustained attention task in an intra-individual, cross-over, sham-controlled experimental design. Exploratory cluster analyses examined responders and non-responders for the different active tDCS conditions on both tasks. RESULTS: For working memory, approximately one-third of patients in both active tDCS conditions showed performance improvement. For sustained attention, three of 15 patients showed performance improvement with prefrontal tDCS. Responders to active tDCS for working memory performed more poorly on the task during sham tDCS compared to non-responders. CONCLUSIONS: A single session of active prefrontal or fronto-cerebellar tDCS failed to improve working memory or sustained attention performance in euthymic patients with bipolar disorder. Several important considerations are discussed in relation to future studies investigating tDCS for enhancing cognition in patients with bipolar disorder.

Neuromodulation therapies for geriatric depression.

Depression is frequent in old age and its prognosis is poorer than in younger populations. The use of pharmacological treatments in geriatric depression is limited by specific pharmacodynamic age-related factors that can diminish tolerability and increase the risk of drug interactions. The possibility of modulating cerebral activity using brain stimulation techniques could result in treating geriatric depression more effectively while reducing systemic side effects and medication interactions. This may subsequently improve treatment adherence and overall prognosis in the older patient. Among clinically available neuromodulatory techniques, electroconvulsive therapy (ECT) remains the gold standard for the treatment of severe depression in the elderly. Studies have proven that ECT is more effective and has a faster onset of action than antidepressants in the treatment of severe, unipolar, geriatric depression and that older age is a predictor of rapid ECT response and remission. The application of novel and more tolerable forms of ECT for geriatric depression is currently being examined. Preliminary results suggest that right unilateral ultrabrief ECT (RUL-UB ECT) is a promising intervention, with similar efficacy to brief-pulse ECT and fewer adverse cognitive effects. Overall findings in repetitive transcranial magnetic stimulation (rTMS) suggest that it is a safe intervention in geriatric depression. Higher rTMS stimulation intensity and more treatments may need to be given in the elderly to achieve optimal results. There is no specific data on vagus nerve stimulation in the elderly. Transcranial direct current stimulation, magnetic seizure therapy and deep brain stimulation are currently experimental, and more data from geriatric samples is needed.

Clinical Pilot Study and Computational Modeling of Bitemporal Transcranial Direct Current Stimulation, and Safety of Repeated Courses of Treatment, in Major Depression.

OBJECTIVES: This study aimed to examine a bitemporal (BT) transcranial direct current stimulation (tDCS) electrode montage for the treatment of depression through a clinical pilot study and computational modeling. The safety of repeated courses of stimulation was also examined. METHODS: Four participants with depression who had previously received multiple courses of tDCS received a 4-week course of BT tDCS. Mood and neuropsychological function were assessed. The results were compared with previous courses of tDCS given to the same participants using different electrode montages. Computational modeling examined the electric field maps produced by the different montages. RESULTS: Three participants showed clinical improvement with BT tDCS (mean [SD] improvement, 49.6% [33.7%]). There were no adverse neuropsychological effects. Computational modeling showed that the BT montage activates the anterior cingulate cortices and brainstem, which are deep brain regions that are important for depression. However, a fronto-extracephalic montage stimulated these areas more effectively. No adverse effects were found in participants receiving up to 6 courses of tDCS. CONCLUSIONS: Bitemporal tDCS was safe and led to clinically meaningful efficacy in 3 of 4 participants. However, computational modeling suggests that the BT montage may not activate key brain regions in depression more effectively than another novel montage--fronto-extracephalic tDCS. There is also preliminary evidence to support the safety of up to 6 repeated courses of tDCS.

Use of transcranial direct current stimulation (tDCS) to enhance cognitive training: effect of timing of stimulation.

The capacity for transcranial direct current stimulation (tDCS) to increase learning and cognition shows promise for the development of enhanced therapeutic interventions. One potential application is the combination of tDCS with cognitive training (CT), a psychological intervention which aims to improve targeted cognitive abilities. We have previously shown that tDCS enhanced performance accuracy, but not skill acquisition, on a dual n-back working memory (WM) CT task over repeated sessions. In the current study, we investigated the optimal timing for combining tDCS with the same CT task to enhance within and between session performance outcomes across two daily CT sessions. Twenty healthy participants received in a randomised order 30 min of anodal tDCS to the left dorsolateral prefrontal cortex immediately before ('offline' tDCS) and during performance ('online' tDCS) on a dual n-back WM CT task, in an intra-individual crossover design. Analyses examined within and between session consolidation effects of tDCS on CT performance outcomes. Results showed that 'online' tDCS was associated with better within session skill acquisition on the CT task, with a significant difference found between conditions the following day. These results suggest that 'online' tDCS is superior to 'offline' tDCS for enhancing skill acquisition when combining anodal tDCS with CT. This finding may assist with the development of enhanced protocols involving the combination of tDCS with CT and other rehabilitation protocols.

Transcranial direct current stimulation treatment protocols: should stimulus intensity be constant or incremental over multiple sessions?

Interest in transcranial direct current stimulation (tDCS) as a new tool in neuropsychiatry has led to the need to establish optimal treatment protocols. In an intra-individual randomized cross-over design, 11 healthy volunteers received five tDCS sessions to the left primary motor cortex on consecutive weekdays at a constant or gradually increasing current intensity, in two separate weeks of testing. Cortical excitability was assessed before and after tDCS at each session through peripheral electromyographic recordings of motor-evoked potentials. Both conditions led to significant cumulative increases in cortical excitability across the week but there were no significant differences between the two groups. Motor thresholds decreased significantly from Monday to Friday in both conditions. This study demonstrated that, in the motor cortex, administration of tDCS five times per week whether at a constant intensity or at a gradually increasing intensity was equally effective in increasing cortical excitability.

Anodal transcranial direct current stimulation increases brain intracellular pH and modulates bioenergetics.

Transcranial direct current stimulation is an emerging treatment for brain disorders but its mode of action is not well understood. We applied 10 min 1 mA anodal transcranial direct current stimulation (tDCS) inside the bore of a 3 T MRI scanner to the left dorsolateral prefrontal cortex of 13 healthy volunteers (aged 19-28 yr) in a blinded, sham-controlled, cross-over design. Brain bioenergetics were measured from the left temporo-frontal region using 31P magnetic resonance spectroscopy before, during and for 20 min following tDCS. Brain pH rose during tDCS and remained elevated afterwards. Phosphomonoesters were significantly decreased while inorganic phosphate (Pi) also fell. Partial-least squares discriminant analysis of the data revealed two significantly different subject groups: one where phosphocreatine (PCr), ATP and Pi fell along with a larger increase in pH and one where PCr and ATP increased along with a smaller increase in pH and a slower and more sustained decrease in Pi. Group membership was predicted by baseline pH and ATP. We interpreted the effects of tDCS as driving two biochemical processes: cellular consumption of ATP causing hydrolysis of PCr via the creatine kinase reaction driving the increase in pH; synthesis of ATP and PCr by mitochondria with concomitant drop in Pi and phosphomonoester levels.

Can transcranial direct current stimulation enhance outcomes from cognitive training? A randomized controlled trial in healthy participants.

Computer-administered cognitive training (CT) tasks are a common component of cognitive remediation treatments. There is growing evidence that transcranial direct current stimulation (tDCS), when given during cognitive tasks, improves performance. This randomized, controlled trial explored the potential synergistic effects of CT combined with tDCS in healthy participants. Altogether, 60 healthy participants were randomized to receive either active or sham tDCS administered during training on an adaptive CT task (dual n-back task), or tDCS alone, over 10 daily sessions. Cognitive testing (working memory, processing speed, executive function, reaction time) was conducted at baseline, end of the 10 sessions, and at 4-wk follow-up to examine potential transfer effects to non-trained tasks. Altogether, 54 participants completed the study. Over the 10 'online' sessions, participants in the active tDCS+CT condition performed more accurately on the CT task than participants who received sham tDCS+CT. The performance enhancing effect, however, was present only during tDCS and did not result in greater learning (i.e. improvement over sessions) on the CT task. These results confirm prior reports of enhancement of cognitive function during tDCS stimulation. At follow-up, the active tDCS+CT group, but not the sham tDCS+CT group, showed greater gains on a non-trained test of attention and working memory than the tDCS-only group (p < 0.01). Although this gain can mainly be attributable to training, this result suggests that active tDCS may have a role in further enhancing outcomes.

Augmenting transcranial direct current stimulation with (D)-cycloserine for depression: a pilot study.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that causes changes in cortical excitability. Recent double-blind placebo-controlled clinical trials suggest that tDCS may be efficacious in the treatment of depression. Pharmacological agents that prolong the effects of tDCS could lead to greater cumulative changes in cortical excitability, producing greater and more prolonged efficacy. One agent shown to prolong the excitability-enhancing effects of tDCS in healthy subjects is D-Cycloserine, a partial agonist at the glycine-binding site of N-methyl-D-aspartate receptors. We investigated whether combining prefrontal tDCS with D-Cycloserine could enhance and/or prolong the antidepressant effect of tDCS. METHODS: Five depressed subjects who had relapsed or failed to achieve remission after receiving a previous course of prefrontal tDCS were recruited. In this open-label pilot study, subjects ingested 100-mg D-Cycloserine 2 hours before tDCS sessions. Subjects received 20 minutes of tDCS at 2 mA on consecutive weekdays for a total of 20 sessions. The anode was placed at pF3 and the cathode at F8 (10/20 system). Clinical response was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: The change in Montgomery-Åsberg Depression Rating Scale scores was not greater with the combination of D-Cycloserine and tDCS than had previously been produced by tDCS alone. No significant additional adverse effects were reported. CONCLUSIONS: This pilot open-label study found that pretreatment with 100-mg D-Cycloserine 2 hours before tDCS was well tolerated but did not enhance the antidepressant efficacy of anodal prefrontal tDCS.

Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial.

BACKGROUND: Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy. AIMS: To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230). METHOD: Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed. RESULTS: There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3-6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS. CONCLUSIONS: Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.

Processes of self-management in chronic illness.

PURPOSE: Self-management is a dynamic process in which individuals actively manage a chronic illness. Self-management models are limited in their specification of the processes of self-management. The purpose of this article is to delineate processes of self-management in order to help direct interventions and improve health outcomes for individuals with a chronic illness. DESIGN: Qualitative metasynthesis techniques were used to analyze 101 studies published between January 2000 and April 2011 that described processes of self-management in chronic illness. METHODS: Self-management processes were extracted from each article and were coded. Similar codes were clustered into categories. The analysis continued until a final categorization was reached. FINDINGS: Three categories of self-management processes were identified: focusing on illness needs; activating resources; and living with a chronic illness. Tasks and skills were delineated for each category. CONCLUSIONS: This metasynthesis expands on current descriptions of self-management processes by specifying a more complete spectrum of self-management processes. CLINICAL RELEVANCE: Healthcare providers can best facilitate self-management by coordinating self-management activities, by recognizing that different self-management processes vary in importance to patients over time, and by having ongoing communication with patients and providers to create appropriate self-management plans.

Hypomania induction in a patient with bipolar II disorder by transcranial direct current stimulation (tDCS).

OBJECTIVES: To report a case of hypomania induced by transcranial direct current stimulation (tDCS) given with an extracephalic reference electrode. Transcranial direct current stimulation is a noninvasive brain stimulation technique in which a weak current is applied through the scalp to produce changes in neuronal excitability in the underlying cerebral tissue. Recent clinical trials have shown promising results with left anodal prefrontal tDCS in treating depression. When the reference cathodal electrode in tDCS is moved from the cranium to an extracephalic position, larger areas of both cerebral hemispheres are stimulated, with potential implications for both efficacy and safety. METHODS: We report the case of a 33-year-old female with bipolar II disorder, on mood stabilizer medication, who had previously participated in a clinical trial of tDCS given with a bifrontal electrode montage for the treatment of major depression without incident, but became hypomanic when she received a later course of tDCS given with a frontoextracephalic configuration. Factors contributing to the development of hypomania in the second course of tDCS are examined. RESULTS: No substantial differences were found in the patient's clinical presentation between the 2 tDCS courses to explain the emergence of hypomania only after the second course. The different montage used in the second course appeared to be the main contributory factor in the induction of hypomania. CONCLUSIONS: The reported case suggests that frontoextracephalic tDCS has antidepressant properties and the potential to induce hypomanic symptoms. In particular, it raises the question of whether frontoextracephalic tDCS requires additional precautions when administered to bipolar patients compared to bifrontal tDCS.