Neurostimulation as an intervention for treatment resistant depression: From research on mechanisms towards targeted neurocognitive strategies

• The efficacy of neurostimulation for treatment resistant depression could not be sufficiently demonstrated.
• Research on the working mechanisms of neurostimulation is important to develop new neurocognitive interventions.
• A combination of neurostimulation and cognitive interventions holds promise to treat treatment resistant depression.

Despite the fact that several interventions for major depression have proven efficacy, a substantial number of patients are or become treatment resistant to various forms of pharmacotherapy and psychotherapy. Biological interventions that directly target brain activity such as electroconvulsive therapy are used to treat these patients, but some of these interventions are unlikely to be easily accepted because of their more invasive nature or side-effects. The efficacy of non-invasive neurostimulation with a favorable side effect profile, such as repetitive Transcranial Magnetic Stimulation, could not be sufficiently demonstrated for treatment resistant depressed patients (TRD). We argue that research on the working mechanisms of these neurostimulation techniques is necessary to develop more efficient treatment protocols. After an overview of current neurostimulation approaches to treatment resistance and the introduction of a neurobiological and a cognitive framework of depression, we provide an integrative review of research on both the neurobiological and cognitive working mechanisms of neurostimulation in TRD, with a specific emphasis on the work of our lab. Thereafter, we describe our own studies and studies from other labs on new neurocognitive interventions. Finally we discuss how all this knowledge can be used to further develop new strategies to deal with treatment resistance, in combining neurostimulation and cognitive interventions.