When the drugs don’t work: treatment-resistant schizophrenia, serotonin and serendipity

Abstract

Treatment-resistant schizophrenia is a serious clinical problem. We adopt a systems-level approach positing a greater role for cognitive control mechanisms in the development of psychotic symptoms and illustrate the clinical application of this via a case report of treatment-resistant patients treated successfully with adjunct pro-cognitive serotonergic medication.

The role of cognitive control in the positive symptoms of psychosis

“…However, our findings suggest that cognitive control could be an important avenue for novel interventional approaches to the treatment of persistent positive symptoms and prevention of chronic illness. Preliminary work using psychological approaches, neuromodulation and pro-cognitive psychopharmacology ( Cella et al, 2020 , Lowe et al, 2018 , Orlov et al, 2017 ) demonstrate some promise.…”

Cognitive control network connectivity differentially disrupted in treatment resistant schizophrenia

“…Instead, self-inhibitory connectivity within the ACC was increased in resistant patients, and ACC-striatal ‘hyper’-drive was associated with both increased psychotic symptoms and aberrant salience. This suggests that ACC function may be inefficient in resistant patients and that symptoms may persist if top-down regulation of the reward network is impaired – a mechanism that is not targeted by current antipsychotic medication ( Lowe et al, 2018 ). The specificity of this finding would be best addressed using a prospective longitudinal design, with larger numbers of patients, to test the potential of these effective connectivity measures to predict treatment resistance.…”

Examination of the Neural Basis of Psychoticlike Experiences in Adolescence During Reward Processing

“…The pattern of decreased striatal activation and increased prefrontal activation supports the suggestion that the evolution of clinically relevant psychotic symptoms requires not only a deficit in striatal reward processing, but also a putative failure of compensatory frontal executive processes. 24,25 Thus, this increase in right frontal activation in PLEs may serve as a proxy of executive function-a compensatory mechanism to ensure that any unusual experiences secondary to reward processing deficits do not become incorrectly represented given the current context. The lack of any neuropsychological performance differences in executive functioning between the low and high PLE adolescent groups also lends additional support to this view.…”