The treatment of Schizophrenia and Schizoaffective Disorder poses a significant challenge to psychiatry. Despite advancements in psychiatric medication, which remains the primary treatment approach, efficacy often extends only to alleviating positive symptoms and leaves nearly a third of patients with partial or no relief (1, 2). Furthermore, pharmacological interventions often entail therapy that lasts years or even is lifelong, increasing the burden on patients for side effects like extrapyramidal symptoms and metabolic syndrome. Acknowledging this therapeutic gap, non-pharmacological interventions such as Transcranial Magnetic Stimulation (TMS) and Transcranial Electrical Stimulation (tES) are gaining prominence in both research and clinical practice, offering promising alternatives for patients with these conditions (3).

rTMS and tES are safe and non-invasive techniques that utilize alternating magnetic fields and electrical currents respectively, to modulate electrical currents in the brain (4). TMS, uses electromagnetic pulses to create an electrical field in specific areas of the cortical brain parenchyma. This can either stimulate or inhibit the neuronal activity, depending on if the stimulus is high frequency (ie 20Hz) or low frequency (ie 1Hz) respectively. When used repetitively, as in rTMS, many pulses of electromagnetism are provided in ~30 minute sessions, typically daily, over the course of many weeks. More recent research has utilized theta burst stimulation (TBS), in which higher frequency (50 Hz) bursts are provided intermittently to mimic endogenous theta wave stimulation.

tES instead utilizes a constant weak electric stimulus either with direct (Transcranial Direct Current Stimulation or tDCS) or alternating (Transcranial Alternating Current Stimulation or tACS) currents to achieve a similar goal of effecting cortical excitability (5). Both TMS and tES approaches have shown promise in the treatment of conditions like depression as well as the positive and negative symptoms of psychosis (6–10). For auditory hallucinations (AH), targeting of the Left Temporoparietal Junction (L-TPJ) consistently has shown improvement in patients already being treated with antipsychotic medication (11, 12).

Recent research has introduced accelerated protocols, where tES or rTMS sessions are administered multiple times per day. This approach has the advantage of delivering more bursts over a shorter time period. In conditions like Major Depressive Disorder, condensing TMS protocols which are typically several weeks down to as little as five days, achieved faster and stronger treatment outcomes (9). Accelerated protocols offer the practical advantage of requiring less time commitment compared to standard protocols, potentially improving the practicality and adherence patients have with these interventions.

The benefit of accelerated protocols for psychotic symptoms is still unclear. While previous meta-analyses have suggested a dose-dependent relationship for both rTMS and tDCS, the benefit of more stimulation appears to diminish beyond a certain point (10). This is similar to the dose response pattern observed for antipsychotic medication (13), suggesting that more treatment cannot be assumed to yield more response. Therefore, there is a clear need to determine the efficacy and feasibility of accelerated approaches for psychotic symptoms.

The present study examines the array of accelerated neurostimulation protocols employed in addressing psychotic symptoms, in particular AHs. Focus has been made to draw attention to differences in scheduling, stimulus location, frequency of stimulus, and total volume of stimulus given.

This review compares accelerated neurostimulation protocols for the treatment of psychosis. Unlike previous meta-analyses (10, 12, 34, 35), the present study focused specifically on accelerated protocols, defined as protocols that provided neurostimulation more than once per day. Our analysis showed that both TMS and tES protocols improved AHs and PPS, while not meaningfully changing NPS. TMS protocols had a more pronounced but similar effect to tES overall. This aligns with prior research of non-accelerated protocols showing consistent improvement for patients treated with rTMS (35), whereas tDCS has shown more modest or mixed results (34).

For AHs, the rTMS groups that used fMRI guidance showed by far the most improvement. This is in line with prior research, suggesting the superiority of localization using fMRI vs TTIS (33). Cap-based targeting, as is done in TTIS, has been shown to decrease the accuracy and precision of targeting DLPFC in TMS (36). Due to the impracticality of fMRI guidance, the clinical setting typically relies on cap-based methods.

Localization of sites other than the L-TPJ, like the bilateral TPJs, STS, and Broca’s area showed similar or worse responses. This is in line with current research that prioritizes the L-TPJ (37) as it has been consistently demonstrated to play a role in the physiopathology of AHs (38, 39).

High and low frequency rTMS performed roughly the same, with a small priority for low frequency. Prior research has been mixed with which approach is more efficacious, with superiority typically being seen in low frequency rTMS (3, 35). Studies using high frequency bursts were able to shorten the total treatment duration, often to only two or three days in total, without decreasing the total number of bursts provided. This provides another possible opportunity, along with the accelerated scheduling, to expedite treatment outcomes.

cTBS demonstrated a stronger effect on AHs than TMS overall. cTBS, like low Frequency rTMS, produces a Long-Term Depression (LTD) effect on neurons rather than a Long Term Potentiation (LTP) effect like iTBS and HF-rTMS, possibly pointing to why these protocols have yielded the most benefit (40). TBS protocols are shorter and more efficient than TMS as they provide stimulation at a much higher frequency. X. Liu’s Study provided roughly ten times the total number of pulses as the other TMS studies, while providing treatment for 59 fewer minutes than the LF-rTMS studies. This is especially important considering a dose dependent relationship has been demonstrated for these interventions (10, 41).

TBS has also shown promise as a tool for the use of other positive and negative symptoms of schizophrenia, especially considering its strong effects on neuronal plasticity (42). In this study cTBS groups elicited the strongest response to PPS, but no clear effect on NPS.

Regarding NPS, all of the treatment types yielded only modest improvements, with very little difference between one another. This may be because the stimulus locations were focused on improving AH. Other intervention sites like the DLPFC have been utilized in the past in order to improve negative symptoms more substantially (43). This also may be because many of the treatment groups, ie LF-rTMS or cTBS, provided an inhibitory stimulus. Excitatory neurostimulation, like in the case of iTBS, has shown potential (10).

tDCS studies were more consistent in their approach, generally placing the anode over the DLPFC and the cathode over the left TPJ, with a twice-daily (BID) stimulation schedule over multiple consecutive days. One study utilizing transcranial alternating current stimulation (tACS) showed results comparable to the tDCS group as a whole.

Overall, this study points to accelerated approaches having a comparable effect on AH and PPS to non-accelerated approaches. The SMD of 0.34 yielded in the between-group analysis of AHs suggests a small to moderate effect size. Previous meta-analyses of non-accelerated protocols have yielded comparable effect sizes (10, 44) including 0.29 (95%CI = 0.02, 0.57) (6) for LFrTMS, 0.44(p <0.01) (45) for rTMS, and 0.50 (95%CI -0.09,1.09) for tDCS (12).

There are many limitations to this study. First, the heterogeneity in stimulation protocols and outcome measures among the studies complicates direct comparisons. Furthermore, many of the studies evaluated are single-arm studies or have small sample sizes which limits the generalizability of these findings. Additionally, the metaanalysis contains data from both cohort and RCT studies, which may yield different results. Another limitation is that this study only reviewed one database and did not include data from case studies or from studies published before 2014, meaning it is not an exhaustive look at the data.

Future research should prioritize randomized controlled trials with standardized protocols and larger sample sizes to better understand the optimal way to deliver these interventions. Direct comparisons in efficacy and practicality between accelerated and non-accelerated protocols would also be very useful. Additionally, long-term studies are needed to assess the sustainability of these effects and potential adverse outcomes, ultimately informing clinical practices and improving patient care.