Reviewing the ketamine model for schizophrenia

Abstract

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. 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.

Keywords: Ketamine; N-methyl-D-aspartate receptor; glutamate; schizophrenia.

Figure 1. Pharmacology of NMDAR

The NMDAR is an ionotropic glutamate receptor and nonselective cation channel with many ligands. Ketamine is one of several uncompetitive antagonists that block the channel at a PCP binding site within the pore. Glycine/D-serine and glutamate are coagonists that bind to the extracellular domain of the receptor. Both are necessary for channel opening; however, the NMDAR is rarely considered a glycine receptor because it is glutamate that is released from the presynaptic terminal, with micromolar background levels of glycine sufficing for channel activation. Polyamines, which modulate the effects of other ligands, and heavy metal cations, which can block or potentiate the channel, also have distinct binding sites. Mg²⁺ is a voltage dependent channel blocker that mediates the Hebbian mechanism of LTP.

Figure 2. Chemical Structures of (S)-ketamine and Phencyclidine

(S)-ketamine, left, is the more potent of ketamine’s two enantiomers. It is known as 2-chlorphenyl-2-methylamino-cyclohexanone by International Union of Pure and Applied Chemists (IUPAC) nomenclature. Phencyclidine (PCP, right) and ketamine share a binding site within the pore of the NMDAR and induce similar effects. Both chemicals are dissociative anesthetics and share structural similarities such as aromaticity.

Figure 3. Diverse effects of ketamine at many receptors

Ketamine is a ligand of many diverse receptors. Ascertaining which receptors mediate which of ketamine’s effects is a challenge for a ketamine model of schizophrenia. Above, we have mapped out speculative, causal relationships between receptors and the effects of ketamine, underscoring the multi-transmitter nature of the ketamine model of schizophrenia. Note that multiple pathways may converge to cause positive symptoms. Effects of D1 dopamine receptors and NMDAR may also converge to cause cognitive symptoms; however, only receptors that interact directly with ketamine are pictured here.