A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience
Issue link: https://innovationscns.epubxp.com/i/555782
[ V O L U M E 1 2 , N U M B E R 7 – 8 , J U L Y – A U G U S T 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 13 medication. 4 Medication nonadherence is also a significant issue in the treatment of schizophrenia, with nonadherence r ates of over 70 percent during the course of one year. 5 There is also a significant side effect burden with antipsychotic medications, including extrapyramidal symptoms, weight gain, and metabolic abnormalities, which may make antipsychotic medications less acceptable to patients and their families. Due to the limitations of antipsychotic pharmacological agents, we are in need of alternate modalities for treating schizophrenia or augmenting the antipsychotic medications currently employed. Neuromodulation is a new frontier in the investigation of effective treatment options for schizophrenia. Among the different methods of neuromodulation, transcranial magnetic stimulation (TMS) is one that has been investigated the most thoroughly in randomized, controlled trials over the past 15 years. The purpose of this article is to review the literature with regard to the efficacy and safety of TMS on the treatment of positive and negative symptoms in schizophrenia. TMS BACKGROUND TMS is a noninvasive neurostimulation technique that uses alternating magnetic fields to induce electrical current in the cortex of the brain. In 2008, a TMS device from Neuronetics (Malvern, Pennsylvania) was the first to be approved by the United States Food and Drug Administration (FDA) for its use in the treatment of patients who have had a major depressive episode and who failed to respond to a single adequate antidepressant trial. The device was approved using the following stimulation parameters: 120-percent motor threshold, 10Hz, 4 seconds on, 26 seconds off. In 2014, the FDA expanded its approval of this device to include treatment of adult patients with MDD who have failed to benefit from any number of antidepressant medications. In 2013, a TMS device from Brainsway (Jerusalem, Israel) was approved by the FDA, also for its use in the t reatment of adult patients with MDD who have failed to benefit from any number of antidepressant medications. TMS is considered safe and well tolerated. 6 The use of alternating magnetic fields to induce electrical current in the brain is based on Faraday's principle. During application of TMS, an electromagnetic coil is placed on the scalp that transforms electrical activity to pulsed magnetic energy, which passes through the cranium unimpeded to induce an electrical field in the cortex. As a result, neurons depolarize and generate action potentials. 7 If the frequency of the pulse is low (i.e., 1Hz or less), TMS has an inhibitory effect on neural circuits (through gabaergic effects or long- term neuronal depression [LTD]). 8 Conversely, if the pulse frequency is high (i.e., greater than 1Hz), an excitatory effect will be generated (through glutamergic effects or long term potentiation [LTP]). Pulses can be administered as single, paired, or in a series, called a train. TMS delivered in a train is termed repetitive TMS (rTMS). While single and paired pulse TMS are used for neurodiagnostic purposes, it is rTMS that has therapeutic benefit in psychiatric disorders. 9 Unlike electroconvulsive therapy, no anesthesia is required when administering TMS; patients are awake and alert during treatment and can leave immediately following their session. Adverse reactions can include post-treatment mild and self- limited headache, scalp pain at the site of stimulation, and potential transient adverse effects on hearing due to the clicking sound of the machine, which can be prevented with the use of earplugs. The most serious potential adverse effect of TMS is induction of seizure, which is rare, with none reported in the pivotal trial that led to FDA approval and in which 10,000 sessions were delivered without seizure induction. Patients should be carefully screened for organic brain disease, personal history of seizure, or family h istory of epilepsy. 9 According to a case series by Stanford et al 2 that examined the use of high frequency prefrontal rTMS for treatment of negative symptoms of schizophrenia, negative symptoms appear to be associated with hypoactivity of the dorsolateral prefrontal cortex of the brain, while positive symptoms appear to be associated with hyperactivity in the left temporo-parietal cortex. Stanford et al 2 also suggest that auditory hallucinations may be due to aberrant activation of language perception areas (i.e., Wernicke's area) in the left temporo-parietal cortex. Studies have investigated the use of low frequency TMS to target positive symptoms, in theory by decreasing cortical excitability and possibly inhibiting dopamine release. 10,11 Conversely, high frequency TMS can target negative symptoms by increasing cortical excitation and inducing dopamine release. 2 Negative symptoms of schizophrenia may be reduced by the use of high-frequency TMS to the left dorsolateral prefrontal cortex, while positive symptoms are reduced by applying low-frequency TMS to the left temporo-parietal cortex. 2,10,11 Based on our literature review, research over the past 15 years supports the use of TMS as an safe and efficacious means of treating positive and negative symptoms of schizophrenia, with the most notable body of evidence supporting the reduction of auditory hallucinations. However, not all of the studies we examined showed efficacy of TMS, and a number of the studies we examined had negative results. METHODOLOGY Literature review for this article was conducted via Ovid Medline and PubMed databases. The search was carried out using the terms TMS, repetitive transcranial magnetic