Drug models of schizophrenia

This study (2014) reviews drug-based models of schizophrenia in order to evaluate their similarity to schizophrenia and help in understanding the pathogenesis of schizophrenia.

Abstract

“Schizophrenia is a complex mental health disorder with positive, negative and cognitive symptom domains. Approximately one third of patients are resistant to currently available medication. New therapeutic targets and a better understanding of the basic biological processes that drive pathogenesis are needed in order to develop therapies that will improve quality of life for these patients. Several drugs that act on neurotransmitter systems in the brain have been suggested to model aspects of schizophrenia in animals and in man. In this paper, we selectively review findings from dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic and kappa opioid pharmacological drug models to evaluate their similarity to schizophrenia. Understanding the interactions between these different neurotransmitter systems and their relationship with symptoms will be an important step towards building a coherent hypothesis for the pathogenesis of schizophrenia.”

Authors: Hannah Steeds, Robin L. Carhart-Harris & James M. Stone

Summary

Introduction

Current antipsychotic medications do not show significant differences in efficacy, and are primarily differentiated by their side-effect profiles. For those patients that do respond to treatment, long-term compliance is required, with attempts to discontinue medication generally leading to relapse.

There is a pressing need to develop novel treatments for schizophrenia that have more tolerable side effects and are effective in those patients who fail to respond to currently available antipsychotic drugs. Drug models of schizophrenia may assist in this development.

Pharmacological models of schizophrenia often fail to faithfully mimic the symptoms of schizophrenia, and some drugs induce schizophrenia-like symptoms only after continued administration, which makes them less suitable for experimental medicine studies.

Animal models of psychosis are useful for testing novel agents, but they are difficult to interpret unless they have been extensively cross-validated with human models. Furthermore, putative therapeutic agents do not always have the same effects in animals as in man.

Dopaminergic stimulants have been shown to induce stereotyped behaviours in rats, which may be related to the positive symptoms of psychosis. This behaviour is also associated with impaired prepulse inhibition, a marker of sensory gating impairment also seen in patients with schizophrenia. Amphetamine-induced sensitization is not thought to fully resemble the cognitive and negative symptom domains of schizophrenia and may lead to the development of more dopamine-targeting antipsychotic drugs.

Glutamatergic

NMDA receptor hypofunction has been suggested as an alternative or additional neurochemical model of schizophrenia to the dopamine hypothesis, and reduced NMDA receptor binding has been reported in medication free patients with schizophrenia.

Phencyclidine and ketamine are dissociative anaesthetics that are suggested to be pharmacological models of schizophrenia. They have been shown to increase gamma oscillations, functional connectivity, and prefrontal glutamate levels. Ketamine leads to a reduction in GABAergic interneuron function, possibly through preferential effects of ketamine on NMDA receptors expressed on cortical GABAergic interneurons, although this is unlikely to occur due to the preferential sensitivity of pyramidal cell NMDA receptors to ketamine.

Ketamine has been demonstrated to exacerbate positive and negative symptoms in pre-existing schizophrenia, and may also lead to impairments in cognition that resemble schizophrenia. Ketamine binding to NMDA receptors correlates with its effect on negative symptoms, whereas downstream effects correlate with ratings of positive psychotic symptoms.

Ketamine induces visual hallucinations, which are more common than auditory hallucinations in schizophrenia. This suggests that ketamine may induce a state closer to the prodrome/ early stages of schizophrenia.

Chronic PCP and ketamine users may have persistent schizophrenia-like symptoms and may be misdiagnosed as having schizophrenia. The neurobiological changes that occur over time in the schizophrenic brain may also persist after the acute effects of the drug have passed.

Models generated by dissociative anaesthetics demonstrate that NMDA receptor dysfunction could be a key factor in the pathogenesis of schizophrenia. These models may be useful in predicting the efficacy of therapies that target the cognitive and negative symptom domains of the illness.

Serotonergic

The serotonin (5-HT) system is also involved in psychotic symptom formation, and hallucinogens such as LSD and psilocybin are 5-HT2A receptor agonists. These drugs disrupt PPI and lead to downstream increases in glutamate release, closely resembling effects seen in patients with psychosis.

Atypical antipsychotics have higher affinity for 5-HT2A receptors than for dopamine D2 receptors, and may be useful in improving cognition or negative symptoms in patients with schizophrenia.

There are several differences between the symptoms of schizophrenia and the hallucinogenic state induced by serotonergic drugs, although schizophreniform symptoms can be observed in people while on these drugs, and altered activity in the prefrontal cortex results in mild thought disorder and altered perception similar to that seen in schizophrenia.

A recent study has shown that chronic administration of lower doses of LSD in rodents can induce a behavioural syndrome that persists after the drug is stopped.

Endocannabinoid

Manipulation of the endocannabinoid system may provide another way to model schizophrenic-like symptoms. This system plays a role in attention, learning and memory.

Acute cannabis or THC administration may induce positive and negative symptoms and cognitive impairments resembling those of schizophrenia in healthy individuals, and may also exacerbate the symptoms of schizophrenia in those already affected by the condition.

GABAergic, and dopaminergic, models of GABAergic dysfunction may help to unify our understanding of schizophrenia. Increased hippocampal glutamatergic outputs may drive increased striatal dopamine activity, and normalization of hippocampal GABAergic function might be a valid approach to antipsychotic drug development.

There is some evidence that GABA-A receptor manipulation affects psychotic symptoms on humans. However, results from existing compounds in patients have not been promising, and it is hoped that novel approaches to this system may yield additional benefit.

Cholinergic

Nicotinic neurotransmission has been studied in schizophrenia, and it has been hypothesized that patients with schizophrenia use tobacco to self-medicate and reduce negative and cognitive symptoms. Nicotinic agonists have been developed for use in patients with schizophrenia.

Although nicotinic antagonists are generally used as muscle relaxants, it is questionable whether nicotinic receptor antagonism is involved in the development of psychotic symptoms. Furthermore, nicotinic receptor antagonism does not reliably induce or worsen positive psychotic symptoms in patients with schizophrenia.

Blockade of acetylcholine receptors by atropine, scopolamine and other drugs can cause delirium and hallucinations, as well as cognitive impairments.

Patients with schizophrenia who are unmedicated have reduced muscarinic receptor availability. Clozapine, which has higher occupancy of muscarinic receptors than olanzapine, may be able to improve cognitive impairment in affected patients.

Kappa opioids

Salvia divinorum is a kappa opioid agonist that leads to potent symptoms of dissociation and complex and vivid hallucinations. However, the effects of salvia divinorum may not be particularly representative of schizophrenic region, and ketamine may increase glutamine levels in healthy volunteers.

Conclusion

Dopaminergic psychostimulants provide a good model of paranoid psychosis in schizophrenia, but do not accurately mimic cognitive or negative symptoms. NMDA receptor antagonists and THC provide a more complete model of schizophrenia.

Animal models of schizophrenia may also have value with further investigation into the role of dopamine, glutamate and cannabis in schizophrenia. Furthermore, drugs targeting GABA and acetylcholine receptors may still prove to be a promising avenue for novel treatments in schizophrenia.

Pharmacological models may never be able to accurately mimic all aspects of schizophrenia, but they may still be able to provide valuable insight into the neurobiological mechanisms underlying specific symptom domains.