The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder.

BACKGROUND: Prefrontal Transcranial Magnetic Stimulation (TMS) therapy repeated daily over 4-6 weeks (20-30 sessions) is US Food and Drug Administration (FDA) approved for treating Major Depressive Disorder in adults who have not responded to prior antidepressant medications. In 2011, leading TMS clinical providers and researchers created the Clinical TMS Society (cTMSs) (www.clinicaltmssociety.org, Greenwich, CT, USA), incorporated in 2013. METHODS: This consensus review was written by cTMSs leaders, informed by membership polls, and approved by the governing board. It summarizes current evidence for the safety and efficacy of the use of TMS therapy for treating depression in routine clinical practice. Authors systematically reviewed the published TMS antidepressant therapy clinical trials. Studies were then assessed and graded on their strength of evidence using the Levels of Evidence framework published by the University of Oxford Centre for Evidence Based Medicine. The authors then summarize essentials for using TMS therapy in routine clinical practice settings derived from discussions and polls of cTMSs members. Finally, each summary clinical recommendation is presented with the substantiating peer-reviewed, published evidence supporting that recommendation. When the current published clinical trial evidence was insufficient or incomplete, expert opinion was included when sufficient consensus was available from experienced clinician users among the membership of the cTMSs, who were polled at the Annual Meetings in 2014 and 2015. CONCLUSIONS: Daily left prefrontal TMS has substantial evidence of efficacy and safety for treating the acute phase of depression in patients who are treatment resistant or intolerant. Following the clinical recommendations in this document should result in continued safe and effective use of this exciting new treatment modality.

Can Medication Free, Treatment-Resistant, Depressed Patients Who Initially Respond to TMS Be Maintained Off Medications? A Prospective, 12-Month Multisite Randomized Pilot Study.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is efficacious for acute treatment of resistant major depressive disorder (MDD), but there is little information on maintenance TMS after acute response. OBJECTIVE/HYPOTHESIS: This pilot feasibility study investigated 12-month outcomes comparing two maintenance TMS approaches--a scheduled, single TMS session delivered monthly (SCH) vs. observation only (OBS). METHODS: Antidepressant-free patients with unipolar, non-psychotic, treatment-resistant MDD participated in a randomized, open-label, multisite trial. Patients meeting protocol-defined criteria for improvement after six weeks of acute TMS were randomized to SCH or OBS regimens. TMS reintroduction was available for symptomatic worsening; all patients remained antidepressant-free during the trial. RESULTS: Sixty-seven patients enrolled in the acute phase, and 49 (73%) met randomization criteria. Groups were matched, although more patients in the SCH group had failed ≥ 2 antidepressants (p = .035). There were no significant group differences on any outcome measure. SCH patients had nonsignificantly longer time to first TMS reintroduction, 91 ± 66 days, vs. OBS, 77 ± 52 days; OBS patients were nonsignificantly more likely to need reintroduction (odds ratio = 1.21, 95% CI .38-3.89). Reintroduction lasted 14.3 ± 17.8 days (SCH) and 16.9 ± 18.9 days (OBS); 14/18 (78%) SCH and 17/27 (63%) OBS responded to reintroduction. Sixteen patients (32.7%) completed all 53 weeks of the study. CONCLUSIONS: Maintaining treatment-resistant depressed patients off medications with periodic TMS appears feasible in some cases. There was no statistical advantage of SCH vs. OBS, although SCH was associated with a nonsignificantly longer time to relapse. Those who initially respond to TMS have a strong chance of re-responding if relapse occurs.

Transcranial magnetic stimulation for the treatment of major depression.

Major depression is often difficult to diagnose accurately. Even when the diagnosis is properly made, standard treatment approaches (eg, psychotherapy, medications, or their combination) are often inadequate to control acute symptoms or maintain initial benefit. Additional obstacles involve safety and tolerability problems, which frequently preclude an adequate course of treatment. This leaves an important gap in our ability to properly manage major depression in a substantial proportion of patients, leaving them vulnerable to ensuing complications (eg, employment-related disability, increased risk of suicide, comorbid medical disorders, and substance abuse). Thus, there is a need for more effective and better tolerated approaches. Transcranial magnetic stimulation is a neuromodulation technique increasingly used to partly fill this therapeutic void. In the context of treating depression, we critically review the development of transcranial magnetic stimulation, focusing on the results of controlled and pragmatic trials for depression, which consider its efficacy, safety, and tolerability.

A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period.

OBJECTIVE: Transcranial magnetic stimulation (TMS) is an effective and safe acute treatment for patients not benefiting from antidepressant pharmacotherapy. Few studies have examined its longer term durability. This study assessed the long-term effectiveness of TMS in naturalistic clinical practice settings following acute treatment. METHOD: Adult patients with a primary diagnosis of unipolar, nonpsychotic major depressive disorder (DSM-IV clinical criteria), who did not benefit from antidepressant medication, received TMS treatment in 42 clinical practices. Two hundred fifty-seven patients completed a course of acute TMS treatment and consented to follow-up over 52 weeks. Assessments were obtained at 3, 6, 9, and 12 months. The study was conducted between March 2010 and August 2012. RESULTS: Compared with pre-TMS baseline, there was a statistically significant reduction in mean total scores on the Clinical Global Impressions-Severity of Illness scale (primary outcome), 9-Item Patient Health Questionnaire, and Inventory of Depressive Symptoms-Self Report (IDS-SR) at the end of acute treatment (all P < .0001), which was sustained throughout follow-up (all P < .0001). The proportion of patients who achieved remission at the conclusion of acute treatment remained similar at conclusion of the long-term follow-up. Among 120 patients who met IDS-SR response or remission criteria at the end of acute treatment, 75 (62.5%) continued to meet response criteria throughout long-term follow-up. After the first month, when the majority of acute TMS tapering was completed, 93 patients (36.2%) received reintroduction of TMS. In this group, the mean (SD) number of TMS treatment days was 16.2 (21.1). CONCLUSIONS: TMS demonstrates a statistically and clinically meaningful durability of acute benefit over 12 months of follow-up. This was observed under a pragmatic regimen of continuation antidepressant medication and access to TMS retreatment for symptom recurrence. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01114477.

Long-term efficacy and safety of iloperidone: an update.

Schizophrenia is a devastating neuropsychiatric disease with a worldwide prevalence of approximately 0.5%-1%. Since many patients do not achieve adequate symptom relief from available agents, alternate pharmacotherapeutic approaches are needed. In this context, iloperidone was recently approved by the US Food and Drug Administration for the treatment of schizophrenia. This paper first reviews its pharmacodynamic and pharmacokinetic profiles, emphasizing their clinical relevance. Next, it summarizes the literature on its acute and maintenance efficacy, safety, and tolerability. It then considers pharmacogenetic data which may help to predict response and risk of cardiac arrhythmias with this agent. Finally, it critically positions iloperidone relative to other first- and second-generation antipsychotics.

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of quality of life outcome measures in clinical practice.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective and safe therapy for major depressive disorder (MDD). This study assessed quality of life (QOL) and functional status outcomes for depressed patients after an acute course of TMS. METHODS: Forty-two, U.S.-based, clinical TMS practice sites treated 307 outpatients with a primary diagnosis of MDD and persistent symptoms despite prior adequate antidepressant pharmacotherapy. Treatment parameters were based on individual clinical considerations and followed the labeled procedures for use of the approved TMS device. Patient self-reported QOL outcomes included change in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the EuroQol 5-Dimensions (EQ-5D) ratings from baseline to end of the acute treatment phase. RESULTS: Statistically significant improvement in functional status on a broad range of mental health and physical health domains was observed on the SF-36 following acute TMS treatment. Similarly, statistically significant improvement in patient-reported QOL was observed on all domains of the EQ-5D and on the General Health Perception and Health Index scores. Improvement on these measures was observed across the entire range of baseline depression symptom severity. CONCLUSION: These data confirm that TMS is effective in the acute treatment of MDD in routine clinical practice settings. This symptom benefit is accompanied by statistically and clinically meaningful improvements in patient-reported QOL and functional status outcomes.

Pharmacological and clinical profile of recently approved second-generation antipsychotics: implications for treatment of schizophrenia in older patients.

Antipsychotics are frequently used in elderly patients to treat a variety of conditions, including schizophrenia. While extensively studied for their impact in younger populations, there is comparatively limited evidence about the effectiveness of these agents in older patients. Further complicating this situation are the high comorbidity rates (both psychiatric and medical) in the elderly; age-related changes in pharmacokinetics that lead to a heightened proclivity for adverse effects; and the potential for multiple, clinically relevant drug interactions. With this background in mind, we review diagnostic and treatment-related issues specific to elderly patients suffering from schizophrenia. We then focus on the potential role of the most recently approved second-generation antipsychotics, paliperidone (both the extended-release oral formulation and the long-acting injectable formulation), iloperidone, asenapine and lurasidone, given the limited clinical experience with these agents in the elderly. While there is limited data to support their safety, tolerability and efficacy in older patients with schizophrenia, each has unique characteristics that should be considered when used in this population.

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.

BACKGROUND: Few studies have examined the effectiveness of transcranial magnetic stimulation (TMS) in real-world clinical practice settings. METHODS: Forty-two US-based clinical TMS practice sites treated 307 outpatients with Major Depressive Disorder (MDD), and persistent symptoms despite antidepressant pharmacotherapy. Treatment was based on the labeled procedures of the approved TMS device. Assessments were performed at baseline, week 2, at the point of maximal acute benefit, and at week 6 when the acute course extended beyond 6 weeks. The primary outcome was change in the Clinician Global Impressions-Severity of Illness from baseline to end of acute phase. Secondary outcomes were change in continuous and categorical outcomes on self-report depression scales (9-Item Patient Health Questionnaire [PHQ-9], and Inventory of Depressive Symptoms-Self Report [IDS-SR]). RESULTS: Patients had a mean ± SD age of 48.6 ± 14.2 years and 66.8% were female. Patients received an average of 2.5 (± 2.4) antidepressant treatments of adequate dose and duration without satisfactory improvement in this episode. There was a significant change in CGI-S from baseline to end of treatment (-1.9 ± 1.4, P < .0001). Clinician-assessed response rate (CGI-S) was 58.0% and remission rate was 37.1%. Patient-reported response rate ranged from 56.4 to 41.5% and remission rate ranged from 28.7 to 26.5%, (PHQ-9 and IDS-SR, respectively). CONCLUSION: Outcomes demonstrated response and adherence rates similar to research populations. These data indicate that TMS is an effective treatment for those unable to benefit from initial antidepressant medication.

Quetiapine for the treatment of acute bipolar mania, mixed episodes and maintenance therapy.

INTRODUCTION: Bipolar disorder is characterized by mood instability, which can be challenging to manage. First-line pharmacological approaches usually involve lithium, anticonvulsants and antipsychotics. Over the past fifteen years, several second-generation antipsychotics have demonstrated benefits for various phases of this disorder. AREAS COVERED: This article examines the pharmacodynamics and pharmacokinetics of quetiapine ; its evidence base as an acute and maintenance monotherapy or adjunctive therapy for bipolar manic or mixed episodes is also discussed, along with the related issues of its safety and tolerability. EXPERT OPINION: In the context of bipolar disorder, quetiapine is the only agent approved as a monotherapy or adjunct therapy for acute manic/mixed episodes in adults and adolescents; as a monotherapy for acute depressive episodes in adults; and as an adjunctive maintenance therapy for bipolar I and II disorder in adults. In addition to its antipsychotic properties, this broad mood-stabilizing potential may simplify the management of select patients.

Adjunctive use of repetitive transcranial magnetic stimulation in depressed adolescents: a prospective, open pilot study.

OBJECTIVE: Depression is often a serious and debilitating illness in adolescents. Unfortunately, a significant number of adolescents do not respond to antidepressant medications or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment intervention shown to benefit depression in adults. This study considered rTMS as an adjunctive treatment in adolescents with major depressive disorder. METHOD: This prospective, open, multicenter trial of active adjunctive rTMS was conducted with 8 adolescents with DSM-IV-TR major depressive disorder (MDD) that had not responded sufficiently to 2 adequate antidepressant medication trials. All subjects were maintained on a stable dose of a selective serotonin reuptake inhibitor during the trial. Thirty daily rTMS treatments were given 5 days per week over 6 to 8 weeks. rTMS was applied to the left dorsolateral prefrontal cortex (120% of motor threshold; 10 Hz; 4-second trains; 26-second intertrain interval; 75 trains) for a total of 3,000 stimulations per treatment session. RESULTS: Seven of 8 adolescents completed all 30 treatments. rTMS was well tolerated, and no significant safety issues were identified. Suicidal ideation was present at baseline in 3 of the adolescents, and it improved during treatment. The primary outcome measure was the Children's Depression Rating Scale-Revised (CDRS-R); results improved significantly from baseline (mean [SD]) (65.9 [6.6]) to treatment 10 (50.9 [12]), P < .02. The CDRS-R scores continued to improve through the rTMS treatment series at treatment 20 (40.1 [14]), P < .01; treatment 30 (32.6 [7.3]), P < .0001; and at 6-month follow-up (32.7 [3.8]), P < .0001. CONCLUSIONS: This prospective open trial suggests that rTMS is a safe, feasible, and potentially effective adjunctive therapy for treatment-resistant MDD in adolescents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00587639.

Quetiapine monotherapy for bipolar depression.

INTRODUCTION: Depression, in the context of bipolar disorder, is more prevalent than hypomania or mania and accounts for most of the disability. Furthermore, the treatment of bipolar depression is more complicated than the treatment of unipolar major depression. Finally, the evidence base for pharmacotherapy of bipolar depression is much smaller than for unipolar depression or hypomania/mania. AREAS COVERED: The article examines the mechanism of action and pharmacokinetics of quetiapine, its evidence base as a treatment for bipolar depression and related issues of safety and tolerability. EXPERT OPINION: In the context of bipolar disorder, quetiapine is the only monotherapy approved for the treatment of hypomania/mania, depression and as an adjunctive maintenance therapy. In addition to its antipsychotic properties, this broad mood stabilizing potential may uniquely benefit and simplify the management of some bipolar patients who can tolerate this agent.

Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study.

BACKGROUND: Although transcranial magnetic stimulation (TMS) can be an effective acute antidepressant treatment, few studies systematically examine persistence of benefit. OBJECTIVE: We assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. METHODS: Three hundred one patients were randomly assigned to active or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure. RESULTS: Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. CONCLUSIONS: These initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse.

Aripiprazole for late-life schizophrenia.

Antipsychotics are frequently used in elderly patients to treat a variety of conditions, including schizophrenia. While extensively studied for their impact in younger populations, there is comparatively limited evidence about the effectiveness of these agents in older patients. Further complicating this situation are the high co-morbidity rates (both psychiatric and medical) in the elderly; age-related changes in pharmacokinetics leading to a heightened proclivity for adverse effects; and the potential for multiple, clinically relevant drug interactions. With this background in mind, we review diagnostic and treatment-related issues specific to elderly patients suffering from schizophrenia and other psychotic conditions, focusing on the potential role of aripiprazole.

Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder.

OBJECTIVE: To determine the relative effects of risperidone and divalproex in pediatric mania. METHODS: This is a double-blind, randomized, outpatient clinical trial with 66 children and adolescents (mean age= 10.9 ± 3.3 years; age range= 8-18 years) with mania who were randomly assigned to either risperidone (0.5-2 mg/day, n= 33) or divalproex (60-120 µg/mL, n= 33) for a six-week period. Measures included the Young Mania Rating Scale (YMRS) and Child Depression Rating Scale-Revised (CDRS-R). RESULTS: Mixed-effects regression models, with interaction between time and the active drug as predictors, found that the risperidone group had more rapid improvement than the divalproex group (p < 0.05), although final scores did not differ significantly between groups. Mixed models using only those subjects who completed the six-week study found similar results. The response rate on YMRS was 78.1% for risperidone and 45.5% for divalproex (p < 0.01). The remission rate for risperidone was 62.5%, compared with 33.3% for divalproex (p < 0.05). Improvement on the CDRS-R was significantly higher for the risperidone group relative to the divalproex group (p < 0.05). There were no significant differences between groups in safety, but subject retention was significantly higher at study endpoint in the risperidone group (p < 0.01). Dropout rate was 24% in the risperidone group and 48% in the divalproex group, with increased irritability being the most common reason for dropout in the latter. There was no significant weight gain in either group. CONCLUSION: Results suggest that risperidone was associated with more rapid improvement and greater reduction in manic symptoms compared to divalproex. Although the results suggest that both drugs are safe, risperidone's lower attrition rate and lower rate of adverse events may suggest better toleration. Clinical trials with larger samples are required to confirm these preliminary findings.

Iloperidone for schizophrenia.

IMPORTANCE OF THE FIELD: No existing antipsychotic adequately controls all symptoms associated with schizophrenia. Also, no antipsychotic adequately benefits most patients with this disorder. Finally, the safety and tolerability of each antipsychotic frequently dictate the choice of agent. AREAS COVERED IN THE REVIEW: The mechanism of action of iloperidone, its efficacy and its safety and tolerability when used to treat patients with schizophrenia. WHAT THE READER WILL GAIN: An appreciation of the potential advantages and disadvantages of iloperidone when used for the treatment of schizophrenia. TAKE HOME MESSAGE: Iloperidone is a recent addition to the current group of second-generation antipsychotics. While it may share many qualities with other agents in this class, its unique neuroreceptor signature and adverse-effect profile may prove beneficial in clinical practice.

The acute efficacy of aripiprazole across the symptom spectrum of schizophrenia: a pooled post hoc analysis from 5 short-term studies.

OBJECTIVE: To evaluate the efficacy of aripiprazole across a range of symptoms-positive, negative, disorganized thought, depression/anxiety, and hostility-in schizophrenia and schizoaffective disorder. METHOD: Pooled data were analyzed from 5 short-term, double-blind, multicenter studies (published between 1997 and 2007) involving patients hospitalized with acute exacerbation of schizophrenia (5 studies) or schizoaffective disorder (2 studies) and randomly assigned to aripiprazole (N = 875), haloperidol (N = 193), risperidone (N = 95), or placebo (N = 406). Aripiprazole doses ranged from 2 to 30 mg/day. Patients receiving the ineffective 2-mg dose were excluded from the primary analyses presented here. Factor analysis of Positive and Negative Syndrome Scale (PANSS) data was used to evaluate changes from baseline with aripiprazole on 5 symptom factors-positive, negative, disorganized thought, depression/anxiety, and hostility-in 2 population subsets-schizophrenia and schizoaffective disorder. Pairwise comparisons were made as follows for schizophrenia: aripiprazole versus placebo in all 5 studies; aripiprazole, haloperidol, and placebo in 3 studies; and aripiprazole, risperidone, and placebo in 1 study. Patients with schizoaffective disorder in 2 studies were included in the comparison of aripiprazole and placebo. RESULTS: Aripiprazole was significantly better than placebo in improving all 5 PANSS factor scores from baseline (each p < .001) in the schizophrenia dataset. In schizoaffective disorder, aripiprazole was significantly better than placebo for the improvement of positive (p

An fMRI study of visual attention and sensorimotor function before and after antipsychotic treatment in first-episode schizophrenia.

While much is known about receptor affinity profiles of antipsychotic medications, less is known about their impact on functional brain systems in patients with schizophrenia. We conducted functional magnetic resonance imaging (fMRI) studies with first-episode schizophrenia patients as they made saccades to unpredictable visual targets before and after 4-6 weeks of antipsychotic treatment. Matched healthy individuals were scanned at similar time intervals. Pretreatment, patients had less activation in frontal and parietal eye fields and cerebellum. After treatment these disturbances were not present, suggesting improved function in attentional and sensorimotor systems. Other pretreatment abnormalities were noted in sensory and ventromedial prefrontal cortex, but after treatment these abnormalities were absent or less prominent, in line with improved function in attentional systems. In addition, although not abnormal at baseline, there was reduced activity after treatment in dorsal prefrontal cortex, dorsal striatum, and dorsomedial thalamus, suggesting a potential adverse effect of treatment on frontostriatal systems, perhaps related to dopamine blockade in the caudate. These findings provide evidence for a complex impact of antipsychotic medication on functional brain systems in schizophrenia and illustrate the potential of neuroimaging biomarkers for both adverse and beneficial drug effects on functional brain systems.