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International Study to Predict Optimized Treatment in Depression 



Why Depression?

Globally, depression is the leading cause of disability. In the United States alone, annual costs of depression related illnesses and lost workplace productivity exceed $210 billion. One in five people experience a mood or anxiety disorder. These disorders affect young people in their most productive years and can have a chronic impact across the entire lifespan.

Advancing precise and personalized treatment for depression

The current diagnosis and treatment process is one of 'guess and check' relying on observed symptoms.  It is insufficient to guide people to the right treatment sooner than is currently the case. On average, it takes 11 years for people to find treatment. The process of trying one treatment, waiting and seeing, then trying another, can be overwhelmingly frustrating and, all too often, life-threatening.

Depression is incredibly heterogenous but the ‘guess and check’ approach considers everyone to be the same.  There are no tests available to personalize diagnoses. Treatments are selected as ‘one-size-fits’ all.  

Taking up the challenge of personalized treatment in iSPOT-D

The international Study to Predict Optimized Treatment in Depression (iSPOT-D) took up the challenge to identify biomarkers for personalizing treatments. Led by academic principal investigator Leanne Williams and an incredible iSPOT-D investigator group spanning 20 sites in 5 countries, iSPOT-D was among the first multi-site biomarker studies of depression to assess multiple markers of depression in relation to multiple treatments. A large sample of 1008 people with depression and 336 healthy peers were assessed before and after treatment on clinical symptoms, psychological function, behavioral tests of general and emotional cognition, resting and task EEG and genetics. A subsample of iSPOT-D participants also completed structural brain imaging, task-free and task evoked functional brain imaging.








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Who, What and How of iSPOT-D

iSPOT-D is among the largest biomarkers trials of depression, involving 20 sites across 5 countries.  The first wave of enrollment, involving 1008 people with depression and 336 healthy peers, was undertaken in 2008 through 2013. In 2023 we celebrate the 10th anniversary of ‘wrapping’ enrollment and the large body of published outcomes to date. In the coming years we look forward to delivering outcomes that integrate across the multiple makers assessed in iSPOT-D.


The aim of iSPOT-D is to improve outcomes for depression. iSPOT-D is grounded in personalized neuroscience. Using tests and markers we can identify meaningful subgroups of depression and ultimately personalized diagnoses, that break apart the heterogeneity of the broad diagnoses.  These markers can determine which treatment might be most effective for each subgroup and each individual, to improve outcomes sooner – instead of the wait and see approach that can take so many years. In iSPOT-D we focused on predictive biomarkers that determine pre-treatment which people will go on to respond to treatments and which people may not. We also focused on response biomarkers that quantify which processes change with clinical improvement over the course of treatment.

What treatments were studied?

We assessed three of the most commonly prescribed antidepressants across the 5 countries involved in iSPOT-D.

These were:  Escitalopram, Sertraline and Venlafaxine-extended release (XR)

Patients were randomized to one of these three treatments. At the end of the pre-treatment baseline testing session, patients were given a letter addressed to their treating clinician with their randomized medication.

How were clinical treatment outcomes assessed?

Primary treatment outcomes were assessed by clinical ratings of the 17-item Hamilton Depression Rating Scale at 8-weeks post treatment.

Secondary outcomes included the following:

  • Self-reports of symptom severity on the Quick Inventory of Depressive Symptoms- Self Report (QIDS-SR) at baseline and 8-weeks post-treatment, as well as weeks 1, 2, 4, and 6 with the acute evaluation period.

  • Ratings of side effects using the Frequency and Intensity Burden of Side Effects Rating (FIBSER)

  • Quality of Life assessed using the World Health Organization Quality Of Life (WHOQoL) scale

  • Social Functioning and Adjustment Scale (SOFAS)

  • Satisfaction With Life Scale (SWLS)

  • Emotion regulation assessed using the Emotion Regulation Questionnaire (ERQ) 

What biomarker measures were used?

Biomarkers were assessed across psychological, neurocognitive, physiological, autonomic and neural circuit domains of function pre- and post-treatment. 

  • Temperament and psychological factors, assessed using the Brief Risk-resilience Index for Screening (BRISC), a brief pan-diagnostic web-based screen for emotional health, the Depression Anxiety and Stress Scale (DASS), and the NEO-five factor inventory.

  • General and social emotional cognition, assessed using computerized behavioral performance tests with established psychometric properties and norms.

  • Electrical brain function, assessed using electroencephalography (EEG) under both resting conditions and with Event Related Potentials (ERPs) evoked by a battery of multiple tasks, spanning a startle task, Oddball attention, N-back working memory, GoNoGo response inhibition and Facial Expressions of Emotion Task (FEET).  

  • Autonomic function, assessed using heart rate and skin conductance measures acquired during the same resting and task-evoked conditions.

  • Functional brain circuits assessed using functional MRI during task-free and task conditions designed to match those used with ERPs: Oddball attention, N-back working memory, GoNoGo response inhibition and Facial Expressions of Emotion Task under both conscious explicit and nonconscious implicit conditions.

At the pre-treatment baseline we also assessed brain structure and genetic markers.

  • Structural brain anatomy and white matter connectivity assessed using magnetic resonance imaging (MRI) with high temporal resolution T1, T2 and diffusion imaging scans

  • Genetics, focusing initially on targeted SNPs taken from a blood sample

Who Took Part?

A total of 1008 adult patients meeting DSM-IV criteria for nonpsychotic Major Depressive Disorder and 336 age and sex-matched healthy controls completed the first wave of the iSPOT-D study. Approximately 20% of participants completed the structural and functional brain imaging sessions at the Sydney site.

What was the interaction with usual care physicians?

Reflecting the pragmatic biomarker design of the iSPOT-D trial, patient treatment was supported by a partnership with ongoing care providers. Each patient’s referring doctor understood the process of randomization and saw the benefit of obtaining objective measures within a trial design for eligible patients.  Physicians received the randomized medication following each patient’s baseline testing. They were also sent a detailed, evidence-based pre- and post-treatment  feedback report comparing their patient’s profile within clinical domains of depression diagnosis and symptom severity and within the performance domains of general and emotional cognition compared to age and sex-matched norms. Participants who complete the MRI scan also received a radiologist read of their structural MRI scan.

iSPOT-D and Registration

Sponsor:  Brain Resource Company Operations Pty Ltd. 
Registry Name:
Registration Number: NCT00693849

Investigators Group & Sites

Australia and New Zealand

Swinburne University, Melbourne, Australia - Con Stough, PhD 

University of Auckland, New Zealand - Bruce Russell, PhD


Nijmegen, Netherlands - Martijn Arns, PhD 

United States

Cornell University, New York - XiaoLei Yu Baran, MD 

Stanford University, California - Charles Debattista, MD

University of Missouri, St.Louis - Steven Bruce, PhD

Center for Healing the Human Spirit, California - Barbara A. Cohen, PhD

Skyland Behavioral Health Associates, North Carolina - Roger deBeus, PhD

Brain Resource Center, New York - Kamran Fallahpour, PhD

Neurodevelopmental Center, Providence - Lawrence Hirshberg, PhD

Shanti Clinical Trials, California - Harbans Multani, MD

Miami University, Florida - Radu Saveanu, MD

Ohio State University, Ohio - Subhdeep Virk, MD

Brain Health Lab, Medical University of South Carolina, South Carolina - Elizabeth Wallis, PhD

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