Reviewing the ketamine model for schizophrenia

This review (2013) examines the psychotomimetic model of ketamine, with regard to its inhibitory glutaminergic transmission that causes similar abnormalities in cortical oscillations as observed in patients with schizophrenia. This similarity may be indicative of an early developmental stage leading up to acute schizophrenia, given that the hallucinatory profile of ketamine entails visual hallucinations, whereas chronic schizophrenia is marked almost exclusively by auditory hallucinations.

Abstract

“Introduction: The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory γ-aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value.

Discussion: We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia.”

Authors: Joel Frohlich & John D. Van Horn

Summary

Ketamine, a benzodiazepine, acts at the N-methyl-D-aspartate glutamate receptor and can be used to study the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia.

Introduction

Schizophrenia is a mental disorder characterized by both positive and negative symptoms, as well as social and occupational dysfunction. Patients with schizophrenia live 12 – 15 years shorter than the average lifespan.

The dopamine and glutamate systems are most frequently implicated in the pathogenesis of schizophrenia. The relationship between these neurotransmitter systems is complicated, and several theories have been proposed to explain why the striatal regions suffer from hyperdopaminergia while prefrontal cortical regions suffer from hypodopaminergia.

The dopamine hypothesis is supported by evidence that dopamine D1 and D2 receptors are involved in working memory and psychosis, respectively, and that dopamine D1 receptor antagonists reduce working memory performance.

The glutamate hypothesis of schizophrenia is a newer hypothesis that implicates glutamergic dysfunction as a mechanism underlying both positive and negative symptoms, as well as cognitive dysfunction, in schizophrenia. Ketamine is the safest human model for studying this hypothesis.

Molecular Physiology and Pharmacology of NMDAR

Glutamate is the principal excitatory neurotransmitter of the central nervous system. Glycine is a co-agonist required for activation of NMDAR, and glycine type 1 transporters and small neutral amino acid transporters regulate synaptic glycine and D-serine levels.

The NMDAR is a ion channel that is sensitive to heavy metal cations, polyamines, protons, and redox agents. The NMDAR is necessary for the induction of long-term potentiation (LTP), which is beyond the scope of this review.

NMDARs are heteromeric channels composed of an NR1 subunit and modulatory subunits of the NR2 (NR2A-D) family. The NR3 (NR3A-B) family of modulatory subunits confers interesting properties on NMDARs.

Uses and Properties of Ketamine

Ketamine is a PCP derivative, first synthesized by Calvin Stevens in 1962 and formally described in 1965. It is preferred over PCP in pharmacological challenge of human subjects in neuroimaging or neuropsychological studies. Ketamine is a dissociative anesthetic with additional analgesic, amnesic, and possible fast acting antidepressant properties. It is recognized by the World Health Organization as an essential medicine for any basic health care system, but is a Schedule III controlled substance in the United States.

Ketamine has been shown to cause hallucinations, blurred vision, delirium, floating sensations, and vivid dreams. These effects are most common in patients over 16 years of age and rarest in children.

Ketamine’s two enantiomers, (S)-ketamine and (R)-ketamine, have different pharmacological properties and differential effects on psychiatric symptoms and cerebral metabolism in healthy volunteers.

Ketamine Pharmacology

Ketamine is principally an NMDAR ligand, but also has varying affinities for many other receptors. Its partial agonism for the D2 dopamine receptor threatens the foundations of the glutamate hypothesis, but lack of replication elsewhere has rendered this finding contentious.

Ketamine is a ligand for many other receptors, including the sigma receptor, which is involved in mitochondrial Ca2+ signaling, neuroprotection, neuroplasticity, and neurite outgrowth. Schizophrenic patients have a deficit in sigma receptors, which may be relevant to the pathophysiology of schizophrenia.

SKF10047, an NMDAR antagonist, induces schizophrenia-like symptoms by binding to sigma-1 receptors. Moreover, sigma-1 receptors and the PCP binding site of NMDAR share common ligands, and more research is required to ascertain their role in the pathophysiology of schizophrenia.

Ketamine is an agonist of the kappa opioid receptor, which has been implicated in the pathophysiology of schizophrenia. Kappa receptor agonists have psychomimetic properties, and dynorphins, endogenous kappa receptor ligands, are increased in the cerebrospinal fluid of schizophrenia patients.

Ketamine has been shown to interact with several receptors, including NMDAR, sigma receptors, and kappa opioid receptors. It also triggers spontaneous action potentials in the frog peripheral nervous system, and blocks human central nervous system Na+ channels.

Evidence for NMDAR Dysfunction

Ketamine’s effects at NMDAR are complex and counterintuitive, as it induces excessive release of glutamate and acetylcholine, but attenuates many subjective effects and blood oxygen-level-dependent (BOLD) signal responses induced by ketamine. Olney and colleagues (1999) proposed that chronic over-release of excitatory neurotransmitters can explain both cognitive and behavioral symptoms of schizophrenia, as well as morphological changes and neurodegeneration in patients’ brains.

Much molecular evidence points to NDMAR dysfunction in schizophrenia. Reduced levels of a protein linked to NMDAR function and working memory, as well as increased interactions between erbB4 and PSD-95, have been found in schizophrenic brains.

Several single nucleotide polymorphisms (SNPs) in genes regulating the NMDAR co-agonist D-serine have been linked to schizophrenia, and supplementation of antipsychotic medication with D-serine alleviates negative, cognitive, and total symptoms of schizophrenia.

ISHH and SPECT imaging studies have directly established the presence of NMDAR hypofunction in schizophrenia patients, and a genome-wide meta-analysis has found associations between SNPs at the same four loci and five different psychiatric disorders, including the three disorders examined in the aforementioned postmortem study.

The evidence supports the ketamine model of schizophrenia over competing models, including adrenochrome and -9-tetrahydrocannabinol. However, it remains possible that other hypotheses of schizophrenia are compatible with the ketamine model and the glutamate hypothesis.

Neurotransmitter Effects and Impact on Cognition

The dopamine hypothesis is the main competitor to the glutamate hypothesis, and ketamine models of schizophrenia are distinct from the glutamate hypothesis due to ketamine’s affinity for many non-glutamate receptors. Pharmacological evidence suggests that NMDAR dysfunction underlies dopaminergic dysfunction in schizophrenia. PCP-induced effects in rats are treatable with glycine and NFPS, a glycine transport antagonist, and MK-801 increases dopaminergic activity in frontal cortex, nucleus accumbens, and striatum.

NMDARs are ubiquitous in the cortex and are necessary for long-term potentiation (LTP). Dysfunction of NMDARs can explain many cognitive symptoms of schizophrenia, including reduced mismatch negativity (MMN) generation in auditory oddball paradigms and reduced activation in sensory cortex.

Chronic PCP exposure induces hypofrontality in rats, and pharmacological fMRI studies have demonstrated that ketamine reduces ventromedial frontal activation. Increased glutamate release, induced by katamine, explains observed frontal deactivation.

Prefrontal hypodopaminergia models predict that schizophrenia patients should have increased switch costs, yet schizophrenia patients have switch costs equal to controls.

Disruptions to Connectivity

The glutamate hypothesis is an attractive model because it offers an explanation for schizophrenia’s age of onset in early adulthood. Synaptic pruning takes place in late adolescence, and the completion of synaptic pruning is the proverbial straw that breaks the camel’s back.

Recent research has examined the roles of brain rhythms and neural synchrony in neurodevelopment and schizophrenia. It has been suggested that pruning connections in neural network models increases the dimensional complexity of simulated electroencephalogram (EEG) and simulates hallucinations in speech perception networks.

In schizophrenia, brain networks are more sparsely connected, with fewer “hub” regions with very high interconnectivity and reduced efficiency of connections. This is consistent with a hypothesis that schizophrenic symptoms occur due to a lesion or developmental defect disconnecting a mesocortical-corticofugal feedback loop regulating dopamine activity.

In schizophrenia, the default mode network (DMN) has increased connectivity, and the extent of strengthened connectivity within the DMN is correlated with the severity of psychiatric symptoms. Furthermore, the excitation of GABAergic interneurons is longer and farther in schizophrenia patients than in controls.

Ketamine, PCP, and MK-801 increase GABA levels in the PFC, which inhibits pyramidal cells and synchronizes their oscillations. Schizophrenic patients have reduced numbers of GABAergic interneurons in the PFC and lower axon cartridge density.

Ketamine challenge alters functional connectivity in ways that mirror dysconnectivity in schizophrenia, including decoupling beginning at a spatial scale of 4 mm, a significant finding in 42% of slices, and increases and decreases in functional connectivity of a neural circuit composed of the dorsal reticular thalamus, anteroventral/mediodorsal thalamic nuclei, and PFC. Ketamine challenge increases global-based connectivity (GBC), reduces anticorrelated relationships between a task-positive network and the DMN, and increases connectivity between the cerebellum and visual cortex with the medial visual network in human resting-state fMRI.

Cortical Oscillations

Although fMRI is limited by slow temporal resolution, EEG has revealed abnormal oscillatory activity in schizophrenia, particularly in the gamma band (30 – 80 Hz). The gamma rhythm is principally generated by fast-spiking GABAergic interneurons, whose output induces GABAA receptor mediated inhibitory postsynaptic potentials in principal cells. Schizophrenia patients have decreased gamma rhythm, reduced phase locking, decreased interhemispheric phase coherence, and increased latency to coherence changes, all of which suggest a mechanism by which visual information is not integrated both within visual cortex and across cortical networks.

Schizophrenia patients have reduced auditory steady-state responses and evoked power, which suggest aberrant, gamma-mediated neural computations in faulty auditory processing, including auditory hallucinations.

In schizophrenia, frontal networks appear inflexible and inefficient, thus serving as weaker substrates for working memory. Facial emotion processing is also inefficient in schizophrenia patients, perhaps reflecting a disconnection with the external world and an inefficient use of resources. While this isomorphism between symptoms offers welcome simplicity, evidence from TMS studies suggests that faulty gamma rhythmogenesis is a problem rooted not in prefrontal hypodopaminergia, but rather in abnormal glutamatergic and GABAergic transmission at NMDAR and GABAA receptors, respectively. Cortical networks in schizophrenia appear rigid and inflexible, as judged from their gamma band activity. However, complex physiological systems often operate on the “edge of chaos”, and this may explain why schizophrenic pathology is due in part to reduced complexity and flexibility of gamma oscillations.

In addition to abnormal gamma band oscillations, abnormal oscillations have also been detected in high beta (20 – 29 Hz), alpha, theta, and delta bands in schizophrenia patients. These abnormalities suggest that schizophrenia is a neurodevelopmental disorder involving inappropriate neural synchrony.

Ketamine increases gamma power in rat neocortex and hippocampus in vivo, yet attenuates gamma rhythmogenesis in rat medial entorhinal cortex in vitro. This suggests that gamma rhythms are generated locally, and that this may explain the context dependent increases and reductions of gamma activity in schizophrenia. Ketamine administered to patients for general anesthesia prior to surgery increases the amplitude of the 40-Hz ASSR, whereas in schizophrenia patients the amplitude is instead reduced. Ketamine increases gamma oscillations and reduces delta oscillations in response to auditory clicks in both healthy subjects and rats.

High-frequency gamma oscillations are decelerated by NMDARs, and this may be a possible physiological basis for psychotic visual hallucinations.

Ketamine replicates the changes in gamma power observed in schizophrenia in healthy subjects, and also increases the power of 20 – 29 Hz oscillations in the beta band in association cortex and PFC.

Alterations of Brain Signaling Dynamics

After considering many lines of research, it is appropriate to take a step back and view the problem from a larger perspective. The balance of excitation and inhibition (E/I-balance) is an important parameter for understanding emergent properties of cortical networks in light of Turing instability. It has been postulated that schizophrenia is a dynamical disease resulting from the tuning of a control parameter past a critical value.

Conclusions, Limitations, and Future Directions

Ketamine is a good model for acute schizophrenia because it explains positive and negative symptoms, cognitive deficits, dopaminergic dysfunction, GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations in terms of NMDAR hypofunction and interactions with D2, opioid, and other receptors. The ketamine model of schizophrenia should be integrated with other compatible pharmacological models of schizophrenia, and more studies should look at nonlinearity and evidence of bifurcations after ketamine infusion in the EEG of healthy volunteers.

Figure 1. Pharmacology of NMDAR

The NMDAR is an ionotropic glutamate receptor and nonselective cation channel with many ligands. Ketamine, glycine/D-serine, polyamines, and heavy metal cations can all modulate the effects of other ligands.

The two enantiomers of ketamine share a binding site with phencyclidine within the pore of the NMDAR and induce similar effects.

Ketamine is a ligand of many diverse receptors. It is not clear which receptors mediate which of ketamine’s effects, but multiple pathways may converge to cause positive symptoms.