Principles of designing a clinical trial: optimizing chances of trial success.

PURPOSE OF REVIEW: Clinical trials are essential to advance health care and develop new therapies. In this review we discuss the underlying principles of clinical trial design with an emphasis on assessing design risks that lead to trial failure as well as negative trials. While of general interest, this is perhaps particularly timely for the neuromodulation community, given the paucity of well-designed trials in the field. We give some examples from the phantom limb pain (PLP) literature. RECENT FINDINGS: It is critical to gather as much preliminary data as possible and to know how to interpret it in order to choose an appropriate trial design. Therefore, the investigator needs to effectively assess the likely trial design risk/benefit ratio with a view to maximizing the chance of a meaningful outcome, whether this outcome rejects or fails to reject the null hypothesis. This analysis is especially important in a complex and heterogeneous disorder such as PLP, which has had many negative trials. SUMMARY: We discuss the factors pertaining to a strong trial design benefit/risk assessment, how late trial phases require greater support from preliminary data, how to design trials to minimize risks, maximize benefits, and optimize internal validity as well as the chances of a positive outcome. We highlight the need for investigators to incorporate best practice in trial design to increase the chances of success, to always anticipate unexpected challenges during the trial.

Structural brain abnormalities in patients with type I bipolar disorder and suicidal behavior.

Some studies have identified brain morphological changes in the frontolimbic network (FLN) in bipolar subjects who attempt suicide (SA). The present study investigated neuroanatomical abnormalities in the FLN to find a possible neural signature for suicidal behavior in patients with bipolar disorder type I (BD-I). We used voxel-based morphometry to compare euthymic patients with BD-I who had attempted suicide (n=20), who had not attempted suicide (n=19) and healthy controls (HCs) (n=20). We also assessed the highest medical lethality of their previous SA. Compared to the participants who had not attempted suicide, the patients with BD-I who had attempted suicide exhibited significantly increased gray matter volume (GMV) in the right rostral anterior cingulate cortex (ACC), which was more pronounced and extended further to the left ACC in the high-lethality subgroup (p<0.05, with family-wise error (FWE) correction for multiple comparisons using small-volume correction). GMV in the insula and orbitofrontal cortex was also related to suicide lethality (p<0.05, FWE-corrected). The current findings suggest that morphological changes in the FLN could be a signature of previous etiopathogenic processes affecting regions related to suicidality and its severity in BD-I patients.

Gray matter brain volumes in childhood-maltreated patients with bipolar disorder type I: A voxel-based morphometric study.

BACKGROUND: Childhood maltreatment (CM) may be related to clinical expression and outcome of bipolar disorder (BD). Several neuroimaging studies have detected brain morphological changes in specific neural networks of adults who suffered maltreatment in their childhood. We investigated alterations in gray matter volume (GMV) to determine a possible neuroanatomical basis of vulnerability in patients with CM having type I BD (BD-I). METHODS: We assessed 39 euthymic DSM-IV BD-I patients with (n=20) and without (n=19) a history of CM and 20 healthy controls without maltreatment as defined by the Childhood Trauma Questionnaire (CTQ). Voxel-based morphometry (VBM) was used to compare GMV differences between patients and controls and perform linear correlations in overall BD group between GMV and CTQ scores. RESULTS: BD-I patients had significant negative correlations between CTQ total score and GMV in the right dorsolateral prefrontal cortex (PFC) and the right thalamus; between physical abuse and GMV in the right dorsolateral PFC; between physical neglect and GMV in the thalamus bilaterally; and between emotional neglect and GMV in the right thalamus. LIMITATIONS: Pharmacological treatment could have altered GMV findings. Results emerged only when using SVC approach. CTQ, a retrospective self-report, has the risk of potential recall bias. The cross-sectional design limits longitudinal and neurodevelopmental inferences. CONCLUSIONS: The severity of self-reported CM in BD-I patients is associated with morphological changes in GMV of specific neural networks relevant to responses to stress and to modulate emotional behavior.

Neural correlates of hallucinations in bipolar disorder

Objective: Approximately one-half of all patients affected by bipolar disorder present with psychotic features on at least one occasion. Several studies have found that alterations in the activity of mesolimbic and prefrontal regions are related to aberrant salience in psychotic patients. The aim of the present study was to investigate the structural correlates of a history of hallucinations in a sample of euthymic patients with bipolar I disorder (BD-I). Methods: The sample consisted of 21 euthymic patients with BD-I and no comorbid axis I DSM-IV-TR disorders. Voxel based morphometry (VBM) was used to compare patients with and without a lifetime history of hallucinations. Preprocessing was performed using the Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) algorithm for VBM in SPM8. Images were processed using optimized VBM. Results: The main finding of the present study was a reduction in gray matter volume in the right posterior insular cortex of patients with BD-I and a lifetime history of hallucinations, as compared to subjects with the same diagnosis but no history of hallucinations. Conclusions: This finding supports the presence of abnormalities in the salience network in BD patients with a lifetime history of hallucinations. These alterations may be associated with an aberrant assignment of salience to the elements of one’s own experience, which could result in psychotic symptoms.

Neural correlates of hallucinations in bipolar disorder.

OBJECTIVE: Approximately one-half of all patients affected by bipolar disorder present with psychotic features on at least one occasion. Several studies have found that alterations in the activity of mesolimbic and prefrontal regions are related to aberrant salience in psychotic patients. The aim of the present study was to investigate the structural correlates of a history of hallucinations in a sample of euthymic patients with bipolar I disorder (BD-I). METHODS: The sample consisted of 21 euthymic patients with BD-I and no comorbid axis I DSM-IV-TR disorders. Voxel based morphometry (VBM) was used to compare patients with and without a lifetime history of hallucinations. Preprocessing was performed using the Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) algorithm for VBM in SPM8. Images were processed using optimized VBM. RESULTS: The main finding of the present study was a reduction in gray matter volume in the right posterior insular cortex of patients with BD-I and a lifetime history of hallucinations, as compared to subjects with the same diagnosis but no history of hallucinations. CONCLUSIONS: This finding supports the presence of abnormalities in the salience network in BD patients with a lifetime history of hallucinations. These alterations may be associated with an aberrant assignment of salience to the elements of one's own experience, which could result in psychotic symptoms.