Adjunct transcranial direct current stimulation improves cognitive function in patients with schizophrenia: A double-blind 12-week study

Abstract

Objectives

Cognitive impairment is a common symptom of schizophrenia that has significant effects on quality of life and the activities of daily living. The present study examined the ability of transcranial direct current stimulation (tDCS) to improve cognitive function and clinical symptoms in patients with schizophrenia.

Methods

Fifty-six patients with schizophrenia were randomized to real-tDCS and sham-tDCS groups. The participants were stable for a period of 3 months before study enrollment. Each group received 30 min of active 2-mA tDCS or sham stimulation over the left dorsolateral prefrontal cortex (anode F3, cathode F4) once per day for 10 consecutive weekdays. The Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) and Wisconsin Card Sorting Test (WCST) were used to evaluate cognitive function, and the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Schizophrenia scale (CGI-SCH), and Calgary Depression Scale for Schizophrenia (CDSS) were used to evaluate symptoms at baseline, after 10 sessions, and at 3-month follow-up.

Results

There was a significant time × group interaction, indicating that MCCB working memory (P = 0.008) and overall scores (P = 0.031) improved over time in the real-tDCS group compared to the sham-tDCS group. There was also a significant time × group interaction for depressive symptoms as evaluated by the CGI-SCH, which decreased over time in the real-tDCS group (P = 0.041). tDCS treatment combined with antipsychotic medication was generally well-tolerated and safe.

Conclusions

Adjunct tDCS treatment is safe and effective for improving cognitive status in patients with schizophrenia.

Introduction

Cognitive impairment is a common symptom of schizophrenia. It is estimated that 90% of patients have clinically meaningful deficits in at least 1 cognitive domain, and 75% have deficits in at least 2 domains (Palmer et al., 1997). Patients with schizophrenia generally exhibit impairments in attention, executive function, verbal and visuospatial working memory, and learning and memory (Sharma and Antonova, 2003). These cognitive impairments manifest stably from the onset of schizophrenia (Addington and Addington, 2002), although in some cases, patients with schizophrenia exhibit cognitive impairment from adolescence prior to the first episode of schizophrenia, with a more pronounced tendency in patients with a family history of schizophrenia (Seidman et al., 2013). Additionally, other clinical symptoms and neurodegenerative changes can manifest as a function of age (Heilbronner et al., 2016). Several literature reviews have shown that, across studies, cognitive deficits have highly consistent relationships with various types of functional outcomes, including community functioning and the ability to acquire skills in psychosocial rehabilitation (Green, 2007). Thus, cognitive decline in schizophrenia ultimately affects patient prognosis and quality of life (Bowie and Harvey, 2006, Katschnig, 2000).

Various strategies have been developed with the aim of restoring cognitive function in patients with schizophrenia. Some studies indicate that second-generation antipsychotic medications are associated with cognitive benefits compared to first-generation antipsychotics, but many patients treated with second-generation antipsychotics suffer from persistent cognitive impairment (Marder and Fenton, 2004). Therefore, pharmacotherapy for cognitive impairment represents a significant unmet medical need in patients with schizophrenia, and is a key focus of drug development by government health agencies, academic researchers, and the pharmaceutical industry (Haig et al., 2016). Despite studies of promising drug candidates, there are no options approved by the US Food and Drug Administration (FDA) for the treatment schizophrenia-associated cognitive decline (Opler et al., 2014).

Several non-pharmacological treatments have been explored as options for improving cognitive function, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). These methods are used to non-invasively alter regional brain activity to influence plasticity at the neural level (Pascual-Leone et al., 2005). In particular, tDCS is a noninvasive brain stimulation method that uses local electrical stimulation to achieve neuromodulation. From a clinical research perspective, tDCS is currently the most well-investigated technique for transcranial electric stimulation, with basic and clinical investigations highlighting its neuromodulatory efficacy, affordability, ease of use, low rate of adverse effects, and unique mechanism of action that theoretically permits its use in combination with behavioral techniques to enhance learning (Brunoni and Fregni, 2015). tDCS reduces cortical excitability via cathodal polarization, similar to rTMS, and increases cortical excitability through anodal polarization (Nitsche and Paulus, 2000). Although tDCS does not provide localized stimulation with the specificity of rTMS, it provides a better sham condition, which is advantageous for use in double-blind clinical trials. Additionally, tDCS is easier to use with cognitive training than rTMS, because it is less likely to influence attention and produces less scalp sensation (Miniussi et al., 2008).

In patients with schizophrenia, several lines of evidence implicate the involvement of the prefrontal cortex in specific cognitive deficits (e.g., working memory and executive control) (Owen et al., 2016). Thus, there is growing interest in tDCS for the treatment of schizophrenia symptoms, including auditory hallucinations and cognitive deficits. Typically, cathodal (inhibitory) tDCS over the temporoparietal cortex has been used to treat hallucinations, whereas anodal tDCS over the left prefrontal cortex has been used to enhance cognition (Loo and Martin, 2015). One study showed that tDCS improved cognitive function without affecting other clinical symptoms in patients with schizophrenia (Smith et al., 2015). Other attempts to use tDCS in patients with schizophrenia have yielded inconsistent results. On the whole, there is a lack of conclusive research on the continuity of effects after tDCS treatment in patients with schizophrenia (Fitzgerald et al., 2014, Mattai et al., 2011).

In a recent review of cognitive outcomes of tDCS over the DLPFC in schizophrenia, small positive effects were found for anodal stimulation on behavioral measures of attention and working memory, with tentative findings of positive results for cognitive ability and memory. The authors concluded, however, that due to the paucity of available data, much remains unknown regarding the clinical efficacy of tDCS in schizophrenia (Mervis et al., 2017).

The aim of this study was to evaluate the ability of tDCS treatment to positively affect cognitive function in patients with schizophrenia, and to determine whether the effects were maintained over time.