What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study's patient-level data with fidelity to the original research protocol.

OBJECTIVE: Reanalyse the patient-level data set of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study with fidelity to the original research protocol and related publications. DESIGN: The study was open label and semirandomised examining the effectiveness of up to four optimised and increasingly aggressive, antidepressant therapies in depressed adults. Patients who failed to gain adequate relief from their level 1 trial on the SSRI citalopram could receive up to three additional treatment trials in levels 2-4. SETTING: 41 North American psychiatry and primary care treatment centres. PARTICIPANTS: 4041 adults screened positive for major depressive disorder. In contrast to most clinical trials, STAR*D enrolled patients seeking care (vs recruited) and included patients with a wide range of common comorbid medical and psychiatric conditions to enhance the generalisability of findings to real-world clinical practice. INTERVENTIONS: STAR*D evaluated the relative effectiveness of 13 antidepressants therapies in treatment levels 2-4 for depressed patients who failed to gain adequate benefit from their level 1 medication trial. MAIN OUTCOME MEASURES: According to the STAR*D protocol, the primary outcome was remission, defined as a score <8 on the blinded Hamilton Rating Scale for Depression (HRSD). Response was a secondary outcome defined as ≥50% reduction in HRSD scores. STAR*D's protocol specifically excluded all non-blinded clinic-administered assessments from use as research outcome measures. RESULTS: STAR*D investigators did not use the protocol-stipulated HRSD to report cumulative remission and response rates in their summary article and instead used a non-blinded clinic-administered assessment. This inflated their report of outcomes, as did their inclusion of 99 patients who scored as remitted on the HRSD at study outset as well as 125 who scored as remitted when initiating their next-level treatment. These patients should have been excluded from data analysis. In contrast to the STAR*D-reported 67% cumulative remission rate after up to four antidepressant treatment trials, the rate was 35.0% when using the protocol-stipulated HRSD and inclusion in data analysis criteria. CONCLUSION: STAR*D's cumulative remission rate was approximately half of that reported.

The Fallacy of Sham-Controlled Neurofeedback Trials: A Reply to Thibault and Colleagues (2018).

Background: Sham-controlled neurofeedback (NFB) trials consistently find no separation on ADHD outcome measures leading many to conclude that NFB's beneficial effects are due to placebo. Method: We deconstruct the NFB training methodology and findings of six sham-controlled trials that assessed for evidence of learning. Results: All six studies found no evidence NFB subjects learned to self-modulate the targeted electroencephalogram (EEG). Careful analyses revealed these studies' training methodologies were antithetical to the established science of operant conditioning thereby preventing subjects from learning to self-modulate. These findings are in marked contrast to NFB studies whose methodology mirror the best practices of operant conditioning. Conclusion: The premise that NFB's beneficial effects are due to placebo phenomenon is unproven as these studies compared two forms of false-feedback, not operant conditioning of the EEG. Because these studies are highly cited and considered the gold standard in scientific rigor, a reappraisal of the evidence is urgently needed.

Multi-site six month outcome study of complex psychiatric patients evaluated with addition of brain SPECT imaging.

BACKGROUND: Psychiatric diagnoses are made primarily through clinical histories, with psychiatrists searching for DSM (Diagnostic and Statistical Manual of Mental Disorders)-driven symptom clusters, and outcomes for patients have not substantially improved in decades for many disorders. PRIMARY STUDY OBJECTIVE: In this study, the research team examined the outcome impact of the addition of single photon emission computed tomography (SPECT) to the assessment of complex patients. DESIGN: The research team designed a multisite, prospective, 6-mo outcome study. The study was completed after final outcome measures were obtained on 500 participants. SETTING: The study occurred in four psychiatric clinics, the Amen Clinics in Newport Beach and San Francisco, CA; Bellevue, WA; and Reston, VA. PARTICIPANTS: Participants were new outpatients at the four clinics who were entered into the study between January 2011 and August 2012. PRIMARY OUTCOME MEASURES: Evaluations included (1) histories, (2) mental-status examinations, (3) a Structured Clinical Interview for DSM-IV (SCID-IV), (4) the Beck Depression Inventory-II (BDI-II), (5) the Brief Symptom Inventory (BSI), (6) the Quality of Life Inventory (QOLI), and (7) brain SPECT scans during rest and concentration. At 6 mo, standardized outcome measurements were readministered (BDI-II, BSI, QOLI), and the research team asked questions about improvement and compliance. RESULTS: Seventy-five percent of participants reported significant clinical improvement; 55% reported being "very compliant," 41% "somewhat compliant," and 4% "noncompliant." Significant improvements were observed across all three assessments: (1) BDI, 360 out of 500 (72%) participants decreased, mean difference=-6.92; (2) BSI, 367 out of 461 (80%) participants decreased, mean difference=-0.39.; (3) QOLI, 427 (85%) of participants improved) at 6 mo (Hotelling T2=460; P<.0001), mean difference=+1.65. Net improvement was measured at 81% (n=405). CONCLUSIONS: To the research team's knowledge, this study is the first outcome study of complex psychiatric patients using SPECT as an additional diagnostic tool and demonstrating significant improvement. Further studies comparing the addition of brain SPECT to "treatment as usual" groups are warranted.

Specific ways brain SPECT imaging enhances clinical psychiatric practice.

Our objective was to ascertain in a prospective case series how often brain single photon emission computed tomography (SPECT) neuroimaging adds relevant information for diagnosis and/or treatment beyond current standard assessment tools in complex psychiatric cases. Charts of 109 consecutively evaluated outpatients from four psychiatrics clinics that routinely utilize SPECT imaging for complex cases were analyzed in two stages. In stage one, psychiatrists reviewed detailed clinical histories, mental status exams, and the structured clinical interview for DSM-IV, but not the results of SPECT studies, assigned a diagnosis based on DSM-IV criteria, and then developed a comprehensive treatment plan. In stage two, evaluators were given access to the SPECT studies for each patient. The addition of SPECT modified the diagnosis or treatment plan in 78.9% (n=86; rated level 2 or 3 change) of cases. The most clinically significant changes were undetected brain trauma (22.9%), toxicity patterns (22.9%) and the need for a structural imaging study (9.2%). Specific functional abnormalities were seen as follows that potentially could impact treatment: temporal lobe dysfunction (66.1%) and prefrontal hypoperfusion (47.7%). SPECT has the potential to add clinically meaningful information to enhance patient care beyond current assessment tools in complex or treatment resistant cases.

Efficacy and effectiveness of antidepressants: current status of research.

BACKGROUND: This paper examines the current status of research on the efficacy and effectiveness of antidepressants. METHODS: This paper reviews four meta-analyses of efficacy trials submitted to America's Food and Drug Administration (FDA) and analyzes STAR*D (Sequenced Treatment Alternatives to Relieve Depression), the largest antidepressant effectiveness trial ever conducted. RESULTS: Meta-analyses of FDA trials suggest that antidepressants are only marginally efficacious compared to placebos and document profound publication bias that inflates their apparent efficacy. These meta-analyses also document a second form of bias in which researchers fail to report the negative results for the pre-specified primary outcome measure submitted to the FDA, while highlighting in published studies positive results from a secondary or even a new measure as though it was their primary measure of interest. The STAR*D analysis found that the effectiveness of antidepressant therapies was probably even lower than the modest one reported by the study authors with an apparent progressively increasing dropout rate across each study phase. CONCLUSIONS: The reviewed findings argue for a reappraisal of the current recommended standard of care of depression.