Efficacy of high-frequency repetitive transcranial magnetic stimulation in schizophrenia patients with treatment-resistant negative symptoms treated with clozapine

Wagner, Elias; Wobrock, Thomas; Kunze, Birgit; Langguth, Berthold; Landgrebe, Michael; Eichhammer, Peter; Frank, Elmar; Cordes, Joachim; Wölwer, Wolfgang; Winterer, Georg; Gäebel, Wolfgang; Hajak, Göran; Ohmann, Christian; Verde, Pablo Emilio; Rietschel, Marcella; Ahmed, Rayaz; Honer, William G.; Siskind, Dan; Malchow, Berend; Strube, Wolfgang; Schneider‐Axmann, Thomas; Falkai, Peter; Hasan, Alkomiet

doi:10.1016/j.schres.2019.01.021

Cited by 19 publications

(16 citation statements)

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“…In fact, individual patient-data meta-analysis in clozapine-exposed TRS patients failed to replicate the beneficial effect reported in RESIS trial [50]. Unlike subjects in Wagner et al's report [51], our subjects were not treatment resistant and were not exposed to clozapine. Treatment resistance status, especially clozapine resistance, is linked to a specific lack of striatal hyperdopaminergic state [34].…”

Section: Discussioncontrasting

confidence: 59%

“…Interestingly, an exploratory re-analysis showed improvement in non-specific factors including excitement and general psychopathology [13]. Furthermore, a subsequent sub-group analysis in clozapine-exposed patients revealed a surprising beneficial effect on positive symptoms, as well as general and total psychopathology but not negative symptoms [51]. In fact, individual patient-data meta-analysis in clozapine-exposed TRS patients failed to replicate the beneficial effect reported in RESIS trial [50].…”

Section: Discussionmentioning

confidence: 97%

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Frontal–striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS

Limongi

Mackinley

Dempster

et al. 2020

Eur Arch Psychiatry Clin Neurosci

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Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high-frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)-increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal-striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling of resting state fMRI in a sample of 19 first episode psychosis subjects. We found that the total score of positive symptoms of schizophrenia is strongly associated with the frontostriatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as decreased bidirectional excitatory influence between the LDLPFC and the LSTR is related to the severity of positive symptoms, especially delusions. We interpret that an increase in striatal dopaminergic tone that underlies positive symptoms is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal 'brake'. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low-frequency (1 Hz) rTMS of the prefrontal area.

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 97%

Frontal–striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS

Limongi

Mackinley

Dempster

et al. 2020

Eur Arch Psychiatry Clin Neurosci

View full text Add to dashboard Cite

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“…It would have been better to include patients with the same treatment to improve the comparability and to better explore potentiation effects. For instance, Wagner and colleagues 38 found that rTMS and clozapine could have a good potentiation effect on NSS. Moreover, the sex proportion was skewed towards males, thereby, contributing to the limitation of generalizability of current results.…”

Section: Discussionmentioning

confidence: 99%

Intermittent theta burst stimulation for negative symptoms of schizophrenia—A double-blind, sham-controlled pilot study

et al. 2021

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Optimal noninvasive brain stimulation parameters for the treatment of negative symptoms of schizophrenia remain unclear. Here, we aimed to investigate the clinical and biological effects of intermittent theta burst transcranial magnetic stimulation (iTBS) in patients with treatment-resistant negative symptoms of schizophrenia (NCT00875498). In a randomized sham-controlled 2-arm study, 22 patients with schizophrenia and treatment-resistant negative symptoms received 20 sessions of either active (n = 12) or sham (n = 10) iTBS. Sessions were delivered twice a day on 10 consecutive working days. Negative symptom severity was assessed 5 times using the Scale for the Assessment of Negative Symptoms (SANS): before iTBS, after iTBS, and 1, 3, and 6 months after iTBS. As a secondary objective, we explored the acute effects of iTBS on functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) using seed-based resting-state functional connectivity MRI (rsFC fMRI) images acquired before and after iTBS. Active iTBS over the left DLPFC significantly decreased negative symptoms severity compared to sham iTBS (F(3,60) = 3.321, p = 0.026). Post hoc analyses revealed that the difference between groups was significant 6 months after the end of stimulation sessions. Neuroimaging revealed an increase in rsFC between the left DLPFC and a brain region encompassing the right lateral occipital cortex and right angular gyrus and a right midbrain region that may encompass dopamine neuron cell bodies. Thus, iTBS over the left DLPFC can alleviate negative symptoms of schizophrenia. The effect might be driven by significant modulation of dopamine transmission.

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“…Therefore, though the evidence is still inconclusive, the effects of ECT augmentation certainly merit further examination. On the other hand, augmentation with recurrent transcranial magnetic stimulation appears to be largely ineffective in CRS despite promising results from recent trials[ 66 , 67 ].…”

Section: Augmentation Strategies For Crs: a Brief Reviewmentioning

confidence: 99%

Clozapine resistant schizophrenia: Newer avenues of management

Chakrabarti¹

2021

WJP

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About 40%-70% of the patients with treatment-resistant schizophrenia have a poor response to adequate treatment with clozapine. The impact of clozapine-resistant schizophrenia (CRS) is even greater than that of treatment resistance in terms of severe and persistent symptoms, relapses and hospitalizations, poorer quality of life, and healthcare costs. Such serious consequences often compel clinicians to try different augmentation strategies to enhance the inadequate clozapine response in CRS. Unfortunately, a large body of evidence has shown that antipsychotics, antidepressants, mood stabilizers, electroconvulsive therapy, and cognitive-behavioural therapy are mostly ineffective in augmenting clozapine response. When beneficial effects of augmentation have been found, they are usually small and of doubtful clinical significance or based on low-quality evidence. Therefore, newer treatment approaches that go beyond the evidence are needed. The options proposed include developing a clinical consensus about the augmentation strategies that are most likely to be effective and using them sequentially in patients with CRS. Secondly, newer approaches such as augmentation with long-acting antipsychotic injections or multi-component psychosocial interventions could be considered. Lastly, perhaps the most effective way to deal with CRS would be to optimize clozapine treatment, which might prevent clozapine resistance from developing. Personalized dosing, adequate treatment durations, management of side effects and non-adherence, collaboration with patients and caregivers, and addressing clinician barriers to clozapine use are the principal ways of ensuring optimal clozapine treatment. At present, these three options could the best way to manage CRS until research provides more firm directions about the effective options for augmenting clozapine response.

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Efficacy of high-frequency repetitive transcranial magnetic stimulation in schizophrenia patients with treatment-resistant negative symptoms treated with clozapine

Cited by 19 publications

References 50 publications

Frontal–striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS

Frontal–striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS

Intermittent theta burst stimulation for negative symptoms of schizophrenia—A double-blind, sham-controlled pilot study

Clozapine resistant schizophrenia: Newer avenues of management

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