A theory on prefrontal dysfunction contributing to psychosis and other schizophrenia symptoms mediated by open potassium and hyperpolarization-activated cyclic nucleotide-gated channels

Schizophrenia includes positive, negative, and cognitive symptoms. Negative and cognitive symptoms do not benefit from current treatments and currently are the main determinants of functional outcome. In the European Union, where healthcare is widely accessible, 80%-90% of patients with schizophrenia are unemployed, while 10% of them die by suicide. Currently, it is believed that psychosis and schizophrenia’s positive symptoms stem from excessive dopamine D2 activity in the striatum, leading to ‘hyper-salience’ followed by delusions, and in the sensory cortex leading to ‘self-generated sensory activity’ followed by hallucinations. The reviewed evidence in this article suggests open potassium and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels leading to prefrontal cortex (PFC) dysfunction followed by ‘cognitive impairment’/’loss of insight’/’lack of deliberate reasoning’/’lack of reality monitoring’ to also be a contributing factor in psychosis and schizophrenia. This could explain how kappa-opioid agonists and potassium channel openers induce psychosis while lowering dopamine but opening potassium channels; how nicotine improves certain schizophrenia symptoms while increasing dopamine but closing potassium/HCN channels; how insightfulness is maintained with 5HT2A psychedelics which increase dopamine but close potassium channels; why guanfacine which closes potassium/HCN channels is the best treatment in delirium psychosis which is characterized by prominent cognitive dysfunction; and why clozapine which closes potassium/HCN channels is superior to other antipsychotics. This article concludes that having a cognitive deficit in the first place may make someone more susceptible to developing all schizophrenia symptoms and that potassium/HCN channel blockers would improve that. They would especially ameliorate the neglected cognitive and negative symptoms. This article also notes the importance of norepinephrine and NMDA. Lastly, it proposes treatment perspectives, summarizes the reviewed findings in Table 1, and presents theorized pathways behind schizophrenia and psychosis in Figure 1.