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Repetitive transcranial magnetic stimulation (rTMS) protocols increasingly use subgenual anterior cingulate cortex (sgACC) functional connectivity to individualize treatment targets. However, the efficacy of this approach is unclear, with conflicting findings and varying effect sizes across studies. Here, the authors investigated the effect of the stimulation site's functional connectivity with the sgACC (sgACC-StimFC) on treatment outcome to rTMS in 295 patients with major depression. The reliability and accuracy of estimating sgACC functional connectivity were validated with data from individuals who underwent extensive functional MRI testing. Electric field modeling was used to analyze associations between sgACC-StimFC and clinical improvement using standardized assessments and to evaluate sources of heterogeneity. An imputation-based method provided reliable and accurate sgACC functional connectivity estimates. Treatment responses weakly but robustly correlated with sgACC-StimFC (r=−0.16), but only when the stimulated cortex was identified using electric field modeling. Surprisingly, this association was driven by patients with strong global signal fluctuations stemming from a specific periodic respiratory pattern (r=−0.49). Functional connectivity between the sgACC and the stimulated cortex was correlated with individual differences in treatment outcomes, but the association was weaker than those observed in previous studies and was accentuated in a subgroup of patients with distinct, respiration-related signal patterns in their scans. These findings indicate that in a large representative sample of patients with major depressive disorder, individual differences in sgACC-StimFC explained only ∼3% of the variance in outcomes, which may limit the utility of existing sgACC-based targeting protocols. However, these data also provide strong evidence for a true—albeit small—effect and highlight opportunities for incorporating additional functional connectivity measures to generate models of rTMS response with enhanced predictive power. [ABSTRACT FROM AUTHOR]

An editorial is presented on findings on a new treatment protocol developing for rapidly and effectively treating individuals with treatment-resistant depression. Topics include placebo control in the latest study being important giving the relatively high likelihood of a placebo response in treatment-resistant depression; and limiting the generalizability and full adoption of the treatment innovation in the treatment-resistant depression population.

Objective: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics.Methods: This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics.Results: Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory.Conclusions: Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols. [ABSTRACT FROM AUTHOR]

Objective: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.Method: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus.Results: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients.Conclusions: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation. [ABSTRACT FROM AUTHOR]

Objective: Postmortem and structural imaging studies suggest that patients with schizophrenia have disrupted cerebellar activity. It has been speculated that these abnormalities mediate disorganized thought processes and psychosis. The authors' goal was to use transcranial magnetic stimulation to measure cerebellar inhibition, a proxy of cerebellar activity, as the principal output of the cerebellum is inhibitory. Method: Cerebellar inhibition was accomplished by delivering a magnetic cerebellar conditioning stimulus 5-15 msec before a magnetic test stimulus to the motor cortex. The cerebellar conditioning stimulus inhibits the size of the motor evoked potential produced by the test stimulus by approximately 50%. Ten patients with schizophrenia and 10 healthy comparison subjects completed the cerebellar inhibition protocol. Results: Patients with schizophrenia demonstrated significant deficits in cerebellar inhibition compared with healthy subjects. Conclusions: The authors conclude that deficits in cerebellar inhibitory activity in schizophrenia may be the result of an abnormality in the cerebellum or disrupted cerebellar-thalamic.. cortical connectivity. [ABSTRACT FROM AUTHOR]