Significant improvement in treatment resistant auditory verbal hallucinations after 5 days of double-blind, randomized, sham controlled, fronto-temporal, transcranial direct current stimulation (tDCS): A replication/extension study

Abstract

Background: Transcranial direct current stimulation (tDCS) is a potentially novel treatment for antipsychotic-resistant auditory verbal hallucinations (AVH) in schizophrenia. Nevertheless, results have been mixed across studies.

Methods: 89 schizophrenia/schizoaffective subjects (active: 47; Sham: 42) were randomized to five days of twice-daily 20-min active tDCS vs. sham treatments across two recruitment sites. AVH severity was assessed using the Auditory Hallucination Rating Scale (AHRS) total score. To assess target engagement, MRI was obtained in a sub sample.

Results: We observed a statistically significant, moderate effect-size change in AHRS total score across one-week and one-month favoring active treatment following covariation for baseline symptoms and antipsychotic dose (p = 0.036; d = 0.48). Greatest change was observed on the AHRS loudness item (p = 0.003; d = 0.69). In exploratory analyses, greatest effects on AHRS were observed in patients with lower cognitive symptoms (d = 0.61). In target engagement analysis, suprathreshold mean field-strength (>0.2 V/m) was seen within language-sensitive regions. However, off-target field-strength, which correlated significantly with less robust clinical response, was observed in anterior regions.

Conclusions: This is the largest study of tDCS for persistent AVH conducted to date. We replicate previous reports of significant therapeutic benefit, but only if medication dosage is considered, with patients receiving lowest medication dosage showing greatest effect. Response was also greatest in patients with lowest levels of cognitive symptoms. Overall, these findings support continued development of tDCS for persistent AVH, but also suggest that response may be influenced by specific patient and treatment characteristics. CLINICALTRIALS.GOV: NCT01898299.

Keywords: Auditory hallucinations; Clinical trial; Schizophrenia; Target engagement; tDCS.

Copyright © 2019 Elsevier Inc. All rights reserved.

Figures

Fig. 1.

Consort chart.

Fig. 2.

Line graph showing marginal means, co-varied for Baseline scores and CPZE, for percent (±SEM) improvement from baseline (100%) in the Auditory Hallucination Rating Scale (AHRS) total score for subjects with available data through one month.

Fig. 3.

Line graph showing marginal means, co-varied for Baseline scores and CPZE, for percent (±SEM) improvement from baseline (100%) in (A) the Positive and Negative Symptom Scale Hallucination item (PANSS P3) and (B) the Auditory Hallucination Rating Scale (AHRS) loudness item for subjects with available data through one month. (C–D) Line graphs showing marginal means, co-varied for Baseline scores and CPZE, for percent improvement in PANSS P3 (C) and AHRS loudness (D) for subjects recruited from outpatient settings.

Fig. 4.

Line graphs showing percent (±SEM) marginal means, co-varied for Baseline scores and CPZE, for percent improvement from baseline (100%) [47] in Auditory Hallucination Rating Scale (AHRS) total (A) or Reality (B) subjects meeting proxy criteria for intact low cognitive-symptom (early auditory processing) (n = 60).

Fig. 5.

Local tDCS field strength relative to clinical response. A. Field strength map calculated using Realistic vOlumetric-Approach to Simulate Transcranial Electric Stimulation” (ROAST) [46]. Cathodal and anodal electrodes are as indicated. Direction of current flow is indicated by arrows. Circles represent regions where field strength is inversely correlated with treatment response. Right panels represent sagittal and coronal views at the level of auditory cortex. B. Field strength by parcel within TPOJ and auditory association regions. Reference line represents threshold-level current flow. C. Scatterplots of field strength vs. clinical response for indicated parcels. Reference lines represent 0% change (horizontal) and threshold-level field strength (vertical).