Cariprazine for treating psychosis: an updated meta-analysis.

PURPOSE: Early treatment of psychotic illness improves outcomes, reduces relapse rates and should not be delayed. Cariprazine is a promising antipsychotic drug and may be a valuable resource when clinicians are in doubt if psychotic symptoms are due to schizophrenia or bipolar disorder. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis that included seven studies (n = 2896) analyzing the effect of cariprazine in psychotic symptoms assessed by the positive and negative symptoms scale (PANSS). RESULTS: We found cariprazine to be significantly superior to placebo (Hedges' g = 0.40; 95% CI 0.32-0.49) for acute psychosis independently of primary psychiatric diagnosis and also to be superior to placebo for both schizophrenia (Hedges' g = 0.39; 95% CI 0.29-0.50) and bipolar patients (Hedges' g = 0.43; 95% CI 0.27-0.58). CONCLUSIONS: We propose that cariprazine may be useful in treating psychosis independently of nosological differentiation at the beginning of the treatment Key pointsEarly treatment of psychotic illness with antipsychotic medications improves outcomes and reduces relapse rates.Cariprazine was found to be significantly superior to placebo for acute psychosis independently of primary psychiatric diagnosis.Cariprazine may be useful in treating psychosis independently of nosological differentiation between schizophrenia and bipolar disorder at the beginning of the treatment.

Screening for Dementia and Cognitive Decline in Adults With Down Syndrome: A Novel Approach Using the Informant Questionnaire on Cognitive Decline in the Elderly.

OBJECTIVE: The aim was to examine the psychometric properties of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) as a diagnostic tool to screen for dementia in aging individuals with Down syndrome (DS). METHODS: This was a cross-sectional study of 92 individuals with DS 30 y or above of age) evaluated with the IQCODE. Using the informant questionnaire of the Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities, we divided the subjects into 3 diagnostic groups: stable cognition; prodromal dementia; and dementia. The ability of the IQCODE to discriminate between diagnostic groups was analyzed by calculating the areas under the receiver operator characteristic curves (AUCs). RESULTS: The optimal IQCODE cutoffs were 3.14 for dementia versus stable cognition (AUC=0.993; P<0.001) and 3.11 for prodromal dementia+dementia versus stable cognition (AUC=0.975; P<0.001), with sensitivity/specificity/accuracy of 100%/96.8%/97.3%, and 93.3%/91.9%/92.4%, respectively. The IQCODE showed a weak-to-moderate correlation with cognitive performance (P<0.05). CONCLUSION: The IQCODE is a useful tool to screen for cognitive decline in individuals with DS and is suitable for use in a primary care setting.

Effect of a 10-day transcutaneous trigeminal nerve stimulation (TNS) protocol for depression amelioration: A randomized, double blind, and sham-controlled phase II clinical trial.

BACKGROUND: Major depressive disorder (MDD) is one of the leading causes of disability in the world. However, treatment options are still limited, and marked by high refractoriness rates, new approaches are needed to optimize clinical improvement. Trigeminal nerve stimulation (TNS) is an innovative neuromodulation strategy consisting on the application of an electric current over the trigeminal nerve that propagates stimuli towards brain areas involved in mood control. OBJECTIVE: We examined the effects of TNS in MDD after a 10-day experimental protocol. METHODS: This was a randomized, double blind, and sham-controlled phase II study with 24 patients with severe MDD. Patients underwent a 10-day intervention protocol and were assessed with the 17-item Hamilton Depression Rating Scale (HDRS-17) at following three observation points: baseline (T1), after 10 days (T2), and after one month of the last stimulation session (T3). Main clinical outcome analysis of variance (ANOVA) was performed. RESULTS: Patients in the active group presented a mean reduction of 36.15% in depressive symptoms after the stimulation protocol. There was a significant interaction between group and time regarding HDRS-17 scores (F = 3.18; df = 2; p = 0.0456). Post hoc analyses exhibited a statistically significant difference between active and sham group symptoms at T2 (p = 0.040) and T3 (p = 0.026), which highlights the sustained amelioration of depressive symptoms. CONCLUSION: The present study found amelioration of depressive symptoms for patients undergoing a 10-day stimulation protocol of TNS, and this was sustained after one month of follow-up.

Establishing an effective TMS protocol for craving in substance addiction: Is it possible?

BACKGROUND AND OBJECTIVES: Repetitive transcranial magnetic stimulation (TMS) is a non-invasive tool with known therapeutic efficacy in various neuropsychiatric disorders, such as depression, schizophrenia, mania, and anxiety disorders. We hereby, briefly present a brief review and meta-analysis on the use of TMS for craving in substance addiction. METHODS: We present our brief review and meta-analysis following the recommendations of the Cochrane group. A total of eight randomized controlled trials fulfilled eligibility criteria and were selected. A total of 199 patients were studied. RESULTS: We found active stimulation to be superior than sham protocols only for trials focused on right DLPFC (with Hedge's g = 1.48; ES (95%CI: 0.126-2.834), p = 0.032. DISCUSSION AND SCIENTIFIC SIGNIFICANCE: Main meta-analysis limitations include small number of studies, high heterogeneity among studies, and high publication bias. However challenging, our exploratory analysis underscored the amelioration of craving in substance addiction for trials using high frequency TMS protocols over the right DLPFC. We hereby, propose the use of this particular TMS protocol as a promising tool in clinical research.

Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: An Updated Systematic Review and Meta-analysis.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a promising noninvasive brain stimulation intervention. Transcranial magnetic stimulation has been proposed for obsessive-compulsive disorder (OCD) with auspicious results. OBJECTIVE: To assess the efficacy of TMS for OCD in randomized clinical trials (RCTs). METHODS: Systematic review using MEDLINE and EMBASE from the first RCT available until March 11, 2016. The main outcome was the Hedges g for continuous scores for Yale-Brown Obsessive Compulsive Scale in a random-effects model. Heterogeneity was evaluated with the I and the χ test. Publication bias was evaluated using the Begg funnel plot. Metaregression was performed using the random-effects model modified by Knapp and Hartung. RESULTS: We included 15 RCTs (n = 483), most had small-to-modest sample sizes. Comparing active versus sham TMS, active stimulation was significantly superior for OCD symptoms (Hedges g = 0.45; 95% confidence interval, 0.2-0.71). The funnel plot showed that the risk of publication bias was low and between-study heterogeneity was low (I = 43%, P = 0.039 for the χ test). Metaregression showed no particular influence of any variable on the results. CONCLUSIONS: Transcranial magnetic stimulation active was superior to sham stimulation for the amelioration of OCD symptoms. Trials had moderate heterogeneity results, despite different protocols of stimulation used. Further RCTs with larger sample sizes are fundamentally needed to clarify the precise impact of TMS in OCD symptoms.

Vagus nerve stimulation in neuropsychiatry: Targeting anatomy-based stimulation sites.

The vagus nerve (VN) is the longest cranial nerve, extending from the brain to the abdominal cavity. The VN consists of both afferent and efferent fibers (respectively 80% and 20%). Vagus nerve stimulation (VNS) is a neuromodulation strategy first developed in the 1980s for epilepsy. More recently, growing efforts in clinical research have been underscoring possible clinical benefits of VNS for different medical conditions such as epilepsy, major depression, anxiety disorders, and Tourette syndrome. Following the rational of VN anatomy and cranial innervation presented above, we hereby hypothesize that transcutaneously placing electrodes over the mastoid process could be a useful study protocol for future tVNS trials.

Effect of a 10-day trigeminal nerve stimulation (TNS) protocol for treating major depressive disorder: a phase II, sham-controlled, randomized clinical trial.

BACKGROUND: Considering both the burden determined by major depressive disorder (MDD) itself and the high refractoriness and recurrence index, alternative strategies, such as trigeminal nerve stimulation (TNS), are the cutting edge instruments to optimize clinical response and to avoid treatment discontinuation and relapse of symptoms. Trigeminal nerve stimulation is an incipient simple, low-cost interventional strategy based on the application of an electric current over a branch of the trigeminal nerve with further propagation of the stimuli towards brain areas related to mood symptoms. METHOD: The study was a phase II, randomized, sham-controlled trial with 40 patients with MDD. Patients with moderate or severe depressive symptoms as assessed by adequate clinical scales underwent a 10-day intervention protocol. Regarding main clinical outcome, analysis of variance (ANOVA) was performed to evaluate mean change scores in depressive symptoms as assessed by the HDRS-17 between baseline (t1), after intervention protocol (t2), and during one-month follow-up (t3). RESULTS: There was a significant interaction between the mean percentage changes in depressive symptoms according to the HDRS in the two groups across the three assessments (F=6.38, df=2, p=0.0033). Post hoc analyses (Bonferroni method) demonstrated a statistically significant difference between depressive symptoms at baseline and t1 (p=0.01) and between depressive symptoms at baseline and t2 (p=0.009). No severe adverse effects were reported. DISCUSSION: Our results in the present controlled trial highlight the possibility of more practical treatment protocols for clinical research, which are similar to those for different neuromodulation strategies such as transcranial direct current stimulation (tDCS). The in-office administration of TNS in our protocol is similar to the schedule for repetitive transcranial magnetic stimulation (rTMS), though over fewer treatment sessions. CONCLUSION: Further controlled studies will contribute to the establishment of the clinical relevance of this new treatment strategy for MDD.

Transcranial Direct Current Stimulation for Treating Depression in a Patient With Right Hemispheric Dominance: A Case Study.

We report the case of a 66-year-old male patient with major depressive disorder for the last 6 months. The patient had been diagnosed with dyslexia during childhood and was left-handed. The intervention protocol consisted in 10 consecutive daily transcranial direct current stimulation sessions. However, after 5 days of stimulation, the patient presented with intensification of depressive symptoms and panic attacks. It was hypothetized that the intensification of symptoms may have been due to stimulation protocol itself. Considering the patient was left-handed and presented comorbidity with dyslexia, there was a plausible hypothesis of right hemispheric dominance. This was corroborated by the Edinburgh Handedness Scale. In fact, dyslexic patients present right hemisphere dominance more frequently. The patient also presented a single photon emission computed tomography with a hypoperfusion area over the left posterior parietal lobe. After the patients agreement, a 10-day experimental repetitive transcranial magnetic stimulation low-frequency protocol over the left dorsolateral prefrontal cortex was started to inhibit the area, which was hypothetically hyperactivated following the rationale of right dominance. The patient presented amelioration of depressive and anxious symptoms. Given the hemispheric reversal we show in the present case study, however, it seems that therapies that are beneficial to right-handers could be detrimental to left-handers.

Reducing transcranial direct current stimulation-induced erythema with skin pretreatment: considerations for sham-controlled clinical trials.

OBJECTIVES: Transcranial direct current stimulation (tDCS)-induced erythema (skin reddening) has been described as an adverse effect that can harm blinding integrity in sham-controlled designs. To tackle this issue, we investigated whether the use of topical pretreatments could decrease erythema and other adverse effects associated with tDCS. MATERIALS AND METHODS: Thirty healthy volunteers were recruited, and four interventions were applied 30 min prior to tDCS in a Latin square design: placebo, ketoprofen 2%, hydroxyzine 1%, and lidocaine 5%. TDCS was applied for 30 min (2 mA, anode and cathode over F3 and F4, respectively) in two active sessions with a minimum 1-week interval. The Draize erythema scoring system scale was used to assess erythema intensity; a tDCS questionnaire was used to assess other adverse effects (e.g., tingling, itching, burning sensation, and pain). RESULTS: We found that ketoprofen (but not hydroxyzine or lidocaine) significantly attenuated tDCS-induced erythema regarding intensity and duration, with a medium effect compared with placebo. Erythema was overall mild, short-lived (lasting 18-24 min after tDCS ending), and more intense under the anode. Subjects with darker skin color also tended to present less intense tDCS-induced erythema. The prevalence of other adverse effects was low and did not differ between dermatological groups. CONCLUSIONS: Ketoprofen 2% topical pretreatment might be an interesting strategy to reduce tDCS-induced erythema and might be useful for blinding improvement in further sham-controlled tDCS trials.

A systematic review and meta-analysis of the use of repetitive transcranial magnetic stimulation for auditory hallucinations treatment in refractory schizophrenic patients.

BACKGROUND: The use of repetitive transcranial magnetic stimulation (rTMS) remains a promising therapeutic tool in the treatment of schizophrenia. Symptoms such as auditory hallucinations (AH) find contradictory results in many studies. Here we present an up-to-date systematic review and meta-analysis of rTMS in the treatment of AH in schizophrenia. METHODS: We searched Pubmed-MEDLINE from 1999 to 2013 for double-blinded randomized sham-controlled trials that applied slow rTMS on the left temporoparietal cortex and assessed the outcome results using Hallucination Change Scale or Auditory Hallucination Rating Scale or Scale for Auditory Hallucinations (SAH). We identified 10 studies suitable for the meta-analysis. RESULTS: We found a positive sized effect in favor of rTMS [random-effects model Hedges' g = 0.011, I-squared = 58.1%]. There was some variability between study effect sizes, but the sensitivity analysis concluded that none of them had sufficient weight to singularly alter the results of our meta-analysis. DISCUSSION: rTMS appears to be an effective treatment for AH. The left temporoparietal cortex seems to be the area in which rTMS is effective. Although meta-analysis is a powerful analytical tool, more studies must be conducted in order to obtain a more expressive sample size to perform a more accurate analytical approach.

Transcranial direct current stimulation for major depression: an updated systematic review and meta-analysis.

Transcranial direct cranial stimulation (tDCS) is a promising non-pharmacological intervention for treating major depressive disorder (MDD). However, results from randomized controlled trials (RCTs) and meta-analyses are mixed. Our aim was to assess the efficacy of tDCS as a treatment for MDD. We performed a systematic review in Medline and other databases from the first RCT available until January 2014. The main outcome was the Hedges' g for continuous scores; secondary outcomes were the odds ratio (ORs) to achieve response and remission. We used a random-effects model. Seven RCTs (n = 259) were included, most with small sample sizes that assessed tDCS as either a monotherapy or as an add-on therapy. Active vs. sham tDCS was significantly superior for all outcomes (g = 0.37; 95% CI 0.04-0.7; ORs for response and remission were, respectively, 1.63; 95% CI = 1.26-2.12 and 2.50; 95% CI = 1.26-2.49). Risk of publication bias was low. No predictors of response were identified, possibly owing to low statistical power. In summary, active tDCS was statistically superior to sham tDCS for the acute depression treatment, although its role as a clinical intervention is still unclear owing to the mixed findings and heterogeneity of the reviewed studies. Further RCTs with larger sample sizes and assessing tDCS efficacy beyond the acute depressive episode are warranted.

Trigeminal nerve stimulation (TNS) protocol for treating major depression: an open-label proof-of-concept trial.

BACKGROUND: Major depressive disorder (MDD) is an incapacitating mental disorder associated with significant personal, social, and economic impairment. Patients with MDD present lower quality of life and higher prevalence of medical conditions, including epilepsy. Noninvasive brain stimulation (NIBS) is a technique that might aid in overcoming some of the current challenges related to pharmacotherapy. Trigeminal nerve stimulation is an incipient, simple, low-cost interventional strategy based on the application of an electric current over a branch of the trigeminal nerve with further propagation of the stimuli toward brain areas related to mood symptoms. METHODS: We performed an open-label proof-of-concept trial using TNS for MDD. To the best of our knowledge, we present a TNS interventional protocol that has not been evaluated for MDD hitherto. RESULTS: A total of 11 patients were studied, with a mean age of 50.36 years (sd: 11.8 from 30 to 60). Only one patient was male. Regarding the main outcome, there was a reduction of depressive symptoms with a mean score of 5.72 (sd: 2.24) (p<0.001) on the HDRS-17. Considering a categorical analysis, all patients presented clinical response defined as a reduction of scores of at least 50%. Only one patient did not reach a remission score (defined as an HDRS score lower than 8). DISCUSSION: In the current neuromodulation scenario, clinical results have been working as truly hypothesis-driven forces, i.e., empirical observation and data analysis from different studies have been highlighting possible mechanisms related to the neurobiological functioning of neuromodulation strategies. The present results, however significant, need to be taken as hypothesis-driven given the study design. Data generalization is jeopardized due to the present study lacking a control group. Our results, therefore, may be overestimated due to intrinsic characteristics such as the placebo effect and Hawthorne effect. CONCLUSION: We present a proof-of-concept trial evaluating a new TNS protocol for depression. Data analysis underscores a significant participation of TNS in ameliorating depressive symptoms of patients with moderate or severe depressive episode. Further controlled studies will contribute to establish the clinical relevance of this new strategy for MDD.

Impact of two or less missing treatment sessions on tDCS clinical efficacy: results from a factorial, randomized, controlled trial in major depression.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a neuromodulatory intervention with recent clinical trials showing promising results in major depression treatment. Although tDCS has some appealing characteristics (e.g., low cost, ease of use, and relatively benign profile of adverse effects), one important drawback of the technique is the need to deliver consecutive, repeated sessions for several weekdays. However, no study investigated whether absences during this acute treatment phase impact on tDCS efficacy, and, if so, whether absences should be considered dropouts, therefore increasing attrition. MATERIAL AND METHODS: To examine this issue, we used data from a randomized, factorial, sham-controlled tDCS study that recruited 120 depressed patients. In this trial, the acute treatment phase consisted of ten consecutive sessions delivered once daily from Monday to Friday; two nonconsecutive missed visits were allowed, with extra tDCS sessions being performed to complete the original number of sessions. RESULTS: Our main finding was that the procedure of granting one to two absences during the acute treatment phase did not impact on tDCS antidepressant efficacy. Moreover, out of 103 completers, only 41 (39.8%) patients presented no missing visits and 25 (24.3%) presented two absences. These patients did not differ in clinical and demographic characteristics; thus, absences were probably circumstantial (e.g., traffic congestion, personal obligations). CONCLUSIONS: Absences during the acute tDCS treatment phase are common, which support the use of flexible schedules in future tDCS trials as to minimize attrition. Also, further studies should access whether higher number of absences can compromise optimal tDCS efficacy.

Safety of repeated transcranial direct current stimulation in impaired skin: a case report.

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique based on the application of a weak, direct electric current via 2 or more electrodes (anode and cathode) over the scalp. One concern when applying tDCS is skin burn. It has been suggested that skin lesions are related to changes in the local dermal homeostasis, and therefore, caution is warranted in patients with skin diseases (Loo et al [Int J Neuropsychopharmacol. 2011;14:425-426]). In this context, we believe that it would be useful for this emerging field of tDCS to report the preliminary safety of repeated application of tDCS in a patient with vitiligo, an autoimmune disorder characterized by depigmentation sites of the skin or mucous membranes. We report the case of a 31-year-old male patient with schizophrenia who underwent 10-daily tDCS sessions. He has had generalized vitiligo since childhood, and despite previous treatment, no current dermatologic follow-up was being carried out. Depigmentation sites were evident in different areas, particularly under the anodal area. We found that repeated anodal tDCS in 1 patient did not lead to skin lesions when applied over a vitiligo skin area. Some of the procedures that we used to buffer changes in skin temperature may have contributed to prevent tDCS-induced skin damage. Nevertheless, the exact conditions that lead to skin lesion are still unknown. Given the growing use and testing of tDCS, continuous assessment and reporting of local adverse effects are still warranted especially in conditions with increased risk of skin lesions such as in dermatologic conditions, skin burns, and previous skin damage.