Effects of Transcranial Direct Current Stimulation (tDCS) and Approach Bias Modification (ABM) training on food cravings in people taking antipsychotic medication

Individuals taking antipsychotic medication show increased food craving, caloric intake and weight gain which puts them at elevated risk for obesity-related conditions, e.g. type 2 diabetes and cardiovascular disease [1]. People with schizophrenia have a higher mortality rate than the general population, mainly due to physical illnesses [2]. Reducing the weight-related side effects of antipsychotic medication has the potential to improve health outcomes for this population.

Antipsychotic drug-induced weight gain is well documented. A meta-analysis of 81 studies reported that, after 10 weeks of treatment, there was a mean weight increase of 4.45 kg in patients receiving clozapine and 4.15 kg for those receiving olanzapine [3]. Fountaine et al. [4] showed that olanzapine treatment resulted in an estimated 345 kcal/day (18%) excess energy intake in 30 healthy male volunteers and 2.65 kg increased body weight (over 15 days). Another study showed that four weeks of treatment with olanzapine was associated with an estimated increase of energy intake of 598 kcal/day (28%) in 10 male adolescents [5]. These reports are broadly consistent with another review which concluded that patients with schizophrenia are more likely than matched controls to consume a diet poor in fibre and fruit and rich in saturated fat [6].

Treatments for antipsychotic drug-induced weight gain include medication and behavioural interventions such as nutritional advice, cognitive behavioural therapy and exercise. Pharmacological interventions (e.g. fenfluramine, sibutramine, reboxetine, metformin, topiramate) are not very effective and can have significant side effects [7], whereas research on behavioural interventions has produced mixed results. In a five-year naturalistic study of 82 outpatients newly started on clozapine, weight gain occurred despite active weight loss programmes involving diet and exercise [8]. A meta-analysis of 20 trials of exercise interventions reported no significant effect on body mass index (BMI) [9], whereas a review of 13 studies investigating behavioural interventions reported a weight loss of 3.15% of initial weight, well below the 5%–10% threshold considered sufficient to improve weight-related complications [10]. Another meta-analysis of 17 studies concluded that behavioural interventions prevented and/or reduced antipsychotic-associated weight gain (3.12 kg less weight gain); however, weight was significantly improved only in outpatient trials (p < 0.0001) but not in inpatient or mixed samples (p = 0.09–0.96) [7]. On the basis of these findings, there is a need for new treatments that target weight gain in people who take antipsychotic medication, especially those who may find it hard to engage in exercise or therapy.

Human and animal studies suggest that antipsychotic drugs stimulate appetite by interacting with dopamine (D2), serotonin (5HT2a & 5HT2c) and histamine (H1, H2) receptors [1]. Changes in peripheral hormones, e.g. leptin, ghrelin and adiponectin, have been reported to be involved [11]. Fat deposition may be facilitated by stress induced activation of the hypothalamic-pituitary-adrenal axis [12]. Genetic predisposition may also play a part, e.g. antipsychotic drug-induced weight gain is reported to be correlated with polymorphisms in the common promoter region for 5HT2c receptors [13] and polymorphisms near the melanocortin 4 receptor gene (MC4R4) [14].

As a result of altered appetite and increased susceptibility to hunger, people taking antipsychotic medication may develop disordered dietary behaviours [15]. Brömel et al. [16] showed that out of 12 patients started on clozapine, nine reported increased appetite and two developed binge-eating episodes. In another study of 74 patients on either olanzapine or clozapine, 37 screened positively for binge eating, with nine fulfilling criteria for binge-eating disorder and five for bulimia nervosa [17]. Additionally, patients who screened positively for binge eating showed higher BMIs and higher BMI gains during treatment. These results suggest that modifying food cravings and/or food consumption may affect antipsychotic drug-induced weight gain.

The observations described above are consistent with evidence from neuroimaging studies. A functional magnetic resonance imaging (fMRI) study of 25 individuals after one week of olanzapine treatment showed enhanced anticipatory and consummatory responses to food rewards and decreased responsivity to food consumption [18]. Another study of 25 individuals after 16 weeks of olanzapine treatment reported increased sensitivity to appetitive stimuli in insular cortices, amygdala and cerebellum, compared with controls [19]. There was also an increased response to appetite-related stimuli from baseline to post treatment, in the frontal cortex, fusiform gyrus, amygdala and insula.

Neural activity in certain brain areas can be enhanced or reduced by neuromodulation procedures, e.g. repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). These non-invasive brain stimulation methods have demonstrated therapeutic potential in major depressive disorder [20], bipolar affective disorder [21], obsessive compulsive disorder, generalised anxiety disorder and substance use disorder [22]. They have also been trialled and well received in people with schizophrenia, helping to alleviate auditory verbal hallucinations and improving negative symptoms [22].

Brain stimulation may also be a promising tool for reducing food cravings [23] which could be used to treat antipsychotic-induced weight gain. The most common target of neuromodulation is the dorsolateral prefrontal cortex (dlPFC) which has been associated with control of eating via possible mechanisms of reward valuation, attention and inhibitory control [24]. For example, one session of high-frequency rTMS delivered to the left dlPFC lowered cue-induced food cravings in people with bulimic disorder [25, 26] and tDCS applied to the dlPFC reduced food cravings in healthy participants [27, 28] and the desire to eat in overweight and obese participants [29].

Another potential intervention for antipsychotic drug-induced weight gain is approach bias modification (ABM) training. ABM is a computer training aiming to modify implicit approach biases through teaching participants to avoid negative stimuli [30]. A review of 12 meta-analyses concluded that a course of ABM sessions can shift target biases in adults, with moderate effect sizes [31]. ABM can also be effective at re-training approach bias to appetitive cues such food and alcohol [32]. ABM significantly reduced approach tendencies and attention towards food cues in a sample of people who binge eat [33] and reduced eating disorders symptoms in a sample of people with either bulimia nervosa or binge-eating disorder [34].

TDCS has been proposed to modulate neural activity by changing the threshold for discharge of the stimulated neurons [35], i.e. it does not induce changes in neuronal firing in resting neuronal networks. Because tDCS does not alter resting networks, it has been proposed [36] that the potential therapeutic effects of tDCS are likely to be improved by pairing it with the behaviour (and associated changes in neuronal activity) that one is seeking to modify [36] (e.g. bias towards high-calorie foods). In this way, the effects of ABM may be enhanced by tDCS, i.e. it may increase neuroplasticity [37] and potentially aid learning aimed at avoiding high-calorie foods. In fact, this has been reported by Heeren et al. [38], who found that neuromodulation boosted the effects of cognitive training aimed at reducing cognitive bias and improving response inhibition. Den Uyl et al. [39] conducted four sessions of concurrent ABM and tDCS over seven days on alcohol-dependent inpatients. Although no enhanced effect of tDCS on ABM training was found, a reduced probability of relapse at the one-year follow-up was noted in the real tDCS group compared to sham. This indicates that combined tDCS and ABM can potentially have a stronger effect on reducing food cravings than either of the treatments alone.

In summary, research shows that dietary behaviours can be altered by neuromodulation methods as well as ABM training. To our knowledge, this will be the first time that both these interventions will be combined and applied in people taking antipsychotic medication. The proposed feasibility study is a randomised controlled trial (RCT) comparing ABM training combined with real (active) or sham (placebo) anodal tDCS to the right dlPFC in individuals with schizophrenia who take antipsychotic medication. We will assess recruitment, attendance, retention and follow-up rates that will inform the development of a large-scale RCT. Changes to food cravings and eating behaviours as well as other clinical outcomes (e.g. depression, anxiety, impulsiveness, schizophrenia symptoms) will be measured before and after the treatment intervention and at a two-week follow-up.

Antipsychotic drug-induced weight gain can affect the physical health of people with schizophrenia. Additionally, it can cause individuals to discontinue medication and hence predispose them to relapse [1]. Interventions to prevent weight gain have limited effectiveness in acutely unwell patients who may find it hard to engage in diet or exercise behaviours [7]. There is a need for treatments to prevent weight gain that are easily accessible and can be utilised in various settings.

Non-invasive brain stimulation methods, e.g. tDCS, can be used to target brain areas such as the dlPFC which are associated with cognitive control (including eating) [24]. These have the potential to reduce antipsychotic drug-induced weight gain, e.g. by decreasing food cravings. TDCS can be combined with ABM training to strengthen its effects on retraining approach bias towards high calorie foods. We have described the protocol for a feasibility trial that will inform future studies and add to the evidence of brain-directed interventions for antipsychotic drug-induced weight gain.

Strengths of the study include use of combined neuromodulation and cognitive training. It has been reported that behaviours and cognitions undertaken during or following the tDCS can impair or abolish the effects of stimulation [66]. Administering two interventions concurrently will remove any cognitive interferences and ensure uniform treatment. The protocol is also designed to measure the possible mechanisms of action, e.g. on approach bias and impulsiveness, as well as on clinical symptoms. The protocol adheres to guidance on the optimal conduct of neuromodulation trials [55, 56, 67].

Possible challenges relate to recruitment/attrition. People with schizophrenia may be ambivalent about receiving tDCS because they may associate it with electroconvulsive therapy. Additionally, people who experience persecutory delusions may not want to undergo the treatment. As participants will be recruited via clinical teams, the aforementioned beliefs may also apply to the clinicians (i.e. the perceived value and cost of the treatment) and this may affect recruitment. To mitigate this, special care will be taken to explain the practical and technical nature of the tDCS to both service users and clinicians. Previous neuromodulation studies in patients with schizophrenia have showed good recruitment rates and adherence to treatment; however, it is unclear whether this can be replicated in the context of weight management. There may be other challenges, e.g. if the participant believes they are receiving sham, or if the treatment is too uncomfortable or too tiring. It is not clear whether participants will be able to distinguish between the real and sham treatment and what impact this will have on attrition rates. TDCS blinding is generally good, e.g. in an RCT for major depressive disorder, tDCS blinding was comparable to that of sertraline [68]. Sensations felt during treatment may interfere with blinding, tDCS can occasionally result in mild discomfort during administration (i.e. tingling, itching or skin redness). However, based on the review of 209 studies, these side effects occur at a similar rate in both real and sham groups [54].

In summary, combined tDCS and ABM is a promising brain-directed treatment for reducing food cravings and food consumption. This innovative feasibility RCT will assess the acceptability and efficacy of this intervention in people with schizophrenia. It will provide a basis for development of future large-scale RCTs and, if results are positive, will provide support for the implementation of it as a treatment.

Participant recruitment and data collection for this study began in June 2019. Recruitment will be completed in May 2020 (approximately). The most recent version of the protocol (v1.0 dated 4 April 2019) was approved by the Oxford B REC (reference no. 19/SW/0095) on 4 June 2019. Any substantial protocol amendments will be communicated to investigators via email and to other parties as required. Amendments to the study protocol will be reported in publications reporting the study outcomes.