Serotonin research: contributions to understanding psychoses

This review (2008) summarizes convergent evidence in support of the serotonergic model of psychedelics, schizophrenia, and psychosis, and concludes that the serotonergic system contributes to psychotic states only by interacting with other neurotransmitter systems in the brain.

Abstract

“The history of serotonin research is closely related to the study of hallucinogenic drugs that function as agonists at serotonin-2A receptors. The fundamental idea that psychotic states seen in psychiatric disorders such as schizophrenia might be attributable, in part, to abnormalities in serotonergic systems began with the almost simultaneous discovery of lysergic acid diethylamide (LSD), psilocybin and serotonin. Sixty years of study have confirmed early speculations regarding the important relationship between serotonin and both drug-induced and disorder-based psychotic states. Now, modern biochemical, pharmacological, behavioral, neuroimaging, genetic and molecular biological sciences are converging to understand how serotonergic systems interact with other monoaminergic and glutamatergic systems to modulate states of consciousness and contribute to psychotic disorders such as the group of schizophrenias. This review summarizes experimental assessments of the serotonergic hallucinogen model psychosis in relation to the serotonin hypothesis of schizophrenia.”

Authors: Mark A. Geyer & Franz X. Vollenweider

Summary

Introduction

The history of research on serotonin is closely intertwined with modern studies of the neurobiological origins of psychotic states in general and the group of schizophrenia disorders in particular. The discovery of the psychotic-like effects of LSD and the identification of serotonin as an endogenous neurohormone led to the hypothesis that serotonin provides a model psychosis.

Psilocybin produces profound changes in mood, thought, intuition, sensory perception, the experience of time and space, and even the experience of self. These changes are dose dependent and can range from pleasure to bliss and feelings of oneness to fear and paranoid ideation.

Parallels between dose-related hallucinogen effects and the development of schizophrenia

Comparisons of symptom profiles of serotonergic hallucinogens and schizophrenia disorders have demonstrated that some hallucinogen-induced states share some common phenomenological features with early acute stages of the group of schizophrenia disorders. Despite some similarities, there are also some differences between hallucinogen-induced models and psychoses in schizophrenia. For example, tolerance develops rapidly to serotonergic hallucinogens whereas auditory rather than visual hallucinations are more characteristic of schizophrenia.

The progression of schizophrenia disorders may be similar to the progression of hallucinogenic drugs, in that the early phases are dominated by abnormalities in serotonin receptors, but the subsequent course involves a more complex evolution of compensatory alterations involving serotonergic systems and interacting dopaminergic and glutamatergic systems.

Experimental studies of the model psychosis induced by serotonin agonists

Many theoretical descriptions of the neuronal basis of the symptomatology in schizophrenia and other psychotic disorders involve deficits in early information processing mechanisms. These failures might lead to a breakdown of cognitive integrity and difficulty in distinguishing self from non-self.

The theoretical construct of gating has been operationalized successfully by using measures of behavioral plasticity, including prepulse inhibition and habituation of acoustic startle responses. Symptomatic schizophrenia patients exhibit deficits in both prepulse inhibition and habituation of startle, phenomena that are correlated with measures of thought disorder.

Serotonergic hallucinogens impair attention, working memory and associative learning, while leaving executive functions largely unaffected, and disrupt information processing in pathways implicated in sensory gating and the pathophysiology of schizophrenia.

In recent years, it has been demonstrated that 5-HT2A-receptor agonists such as LSD and psilocybin produce psychotomimetic effects through excessive 5-HT2A-receptor activation. Moreover, 5-HT2A-receptor abnormalities are evident in the brains of schizophrenic patients.

Psilocybin produces metabolic changes indicative of hyperfrontality in healthy humans, which parallel the hyperfrontality characteristic of the acute phase of schizophrenia. These findings contrast with the hypofrontality seen in chronic patients with deficit schizophrenia. Recent investigations have linked the 5-HT2A receptor gene to sensorimotor gating deficits in patients with schizophrenia and have also been associated with poor long-term outcome and poor response to antipsychotic treatments.

Serotonin receptors involved in psychotomimetic effects

The initial uncertainty in the mid-1950s as to whether serotonergic hallucinogens such as LSD or psilocybin function primarily as serotonin agonists or antagonists continued well through the 1980s. However, the accumulated evidence from biochemical, electrophysiological and behavioral studies in animals clearly demonstrate that 5-HT2A receptors contribute most substantially to the effects of hallucinogens.

Despite evidence that 5-HT2A receptor antagonists contribute to the clinical benefits of newer generation of antipsychotic drugs, clinical studies have not yet been conducted to evaluate the efficacy of 5-HT2A receptor antagonists in the treatment of schizophrenia.

Although 5-HT2A receptors seem to be the most important, 5-HT1A receptors might also influence many of the same behavioral endpoints and might contribute to or interact with the impact of hallucinogens on 5-HT2A receptors.

Serotonin circuits and interactions with other systems

Early research indicated that serotonergic hallucinogens and hallucinogenic anesthetics induce hallucinatory behavior along a continuum of excitation, with the characteristic evolution from sensory illusions to pseudo and true hallucinations in humans arising with the increasing impairment and disruption of sensory gating.

Functional neuroimaging studies in humans demonstrate that psilocybin produces hyperfrontality and divergent prefrontal – subcortical activation, and that ketamine produces a similar pattern of activation in cortical and subcortical structures. This pattern of activation is due to a common disruption of thalamic gating of sensory and cognitive information.

Serotonergic hallucinogens can alter thalamocortical transmission by stimulating 5-HT2A receptors located in several components of the CSTC loop. This inundation of the cortex with sensory and cognitive information can ultimately cause the sensory flooding, cognitive fragmentation and ego-dissolution seen in both drug-induced and disorder-based psychoses. Serotonergic hallucinogens may enhance thalamic transmission and support the view that deficient thalamic gating leads to sensory overload of the cortex and psychosis, but they may also disrupt cortico-thalamo-cortical or cortico-cortical integration of distributed neuronal activity.

New directions for research on serotonin and psychosis

Despite extensive research linking serotonin and psychosis over the past six decades, new findings indicate that the unifying principle of 5-HT2A-agonist actions as mediating the psychedelic and psychotomimetic effects of serotonergic hallucinogens is over-simplified.

The switch rate in a binocular rivalry paradigm was reduced by administration of psilocybin to healthy volunteers, but not by pretreatment with the 5-HT2A antagonist ketanserin. This suggests that non-5-HT2A serotonin receptors may be responsible for these effects.

New evidence indicates that important differential pharmacological functions might be evident even within the domain of 5-HT2A-receptor-agonist actions, and that functional selectivity at 5-HT2A receptors might be a potential mechanism underlying some actions of subclasses of 5-HT2A-receptor-agonists, including actions on cortical pyramidal cells.

Functional selectivity mechanisms could revitalize the study of serotonin and its relevance to the group of schizophrenia disorders. Recent findings indicate that serotonergic and glutamatergic models of psychosis are converging, and that a prodrug for an agonist at mGlu2 and mGlu3 receptors seems to be efficacious in the treatment of positive psychotic symptoms of schizophrenia.

Future research on serotonergic contributions to psychoses

Serotonergic systems are important in the genesis of drug-induced psychotic states and in the treatment and potentially the etiology of some psychotic disorders such as schizophrenia. The research into serotonin and psychosis remains an exciting opportunity for discovery.