Beyond Dopamine: treatment of schizophrenia using novel targets

Dopamine antagonism is not enough, stated Prof Rachel Upthegrove, UK. Current antipsychotics based on this mechanism of action are effective for about 60% of patients, mainly managing positive symptoms of schizophrenia, but patients struggle with the other symptoms and often relapse over time.1,2 Various unmet needs in the treatment of schizophrenia were outlined by Prof Ingrid Melle, Norway, and novel treatments designed to meet those needs were discussed by Prof Upthegrove and Prof Oliver Howes, UK.

Unmet needs in schizophrenia

A proportion of patients will show some treatment resistance from their first episode of psychosis, and some patients develop persistent psychotic symptoms.3,4 Even for those patients who respond to treatment, negative and cognitive symptoms may be relatively unchanged, producing pronounced deficits in social and instrumental functioning.5,6 Substance misuse is also twice as common in patients with schizophrenia as in the general population, and is associated with poorer outcomes.7 Finally, patients with schizophrenia have a reduced life expectancy compared with the general population, which is partly attributable to a high risk for suicide, particularly in the first few years after diagnosis.8,9 Co-morbid physical disorders, such as cardiovascular disease, and a higher risk of dying from any disease, also contribute to the early mortality of patients with schizophrenia.

Treatment resistance, negative and cognitive symptoms, substance misuse and reduced life expectancy are all key targets for new treatment development


Dopamine plus serotonin approach

Antipsychotics developed with efficacy not only at dopamine receptors, but also at serotonin receptor subtypes and at the sigma receptor have all shown efficacy in the treatment of schizophrenia, and against negative and cognitive symptoms.10–12 Alongside these newer antipsychotics, novel treatment targets outside of the dopaminergic and serotonergic systems are also being identified and tested.


Novel targets for schizophrenia

Elevated tone in the endocannabinoid system is seen at all stages in schizophrenia, making this system a target for treatment with cannabidiol. In addition, muscarinic M1/M4 receptor agonists act on the medium spiny neurons, stimulating endocannabinoid release, which can down-regulate firing of dopaminergic neurons. This treatment strategy has shown efficacy,13 albeit the peripheral tolerability of these drugs requires additional management. 

The proinflammatory cytokine interleukin-6 has a role in many downstream systems that are relevant to schizophrenia, such as effects on microglia, oxidative stress and signal transduction pathways that impact dopaminergic and glutamatergic systems. Immune modulators may therefore be a target for the management of treatment-resistant schizophrenia, negative symptoms and in the management of comorbid disorders, such as depression.14–16

Immune modulators have effects on many downstream systems relevant in the pathophysiology of schizophrenia

The D-amino acid oxidase (DAAO) inhibitors increase the levels of D-serine. This is a co-antagonist at the NMDA receptor, so can boost the NMDA hypofunctioning that is seen in schizophrenia.17 Early evidence indicates that these drugs have positive treatment effects in schizophrenia.18 Trace amine type 1 receptors are found presynaptically in dopaminergic neurons, and downregulate firing of these neurons. Agonists of these receptors may therefore be able to reduce the dopaminergic hyperactivity seen in schizophrenia, and therefore may have a positive effect on symptoms.19,20

In conclusion, a number of novel drugs have been developed for various target systems for treatment of schizophrenia. These drugs all appear to have downstream effects on relevant dopaminergic and/or glutamatergic pathways. These drugs may provide more specific effects on particular symptomology of schizophrenia, and reduce the adverse event burden on patients. They also pave the way to a personalized-medicine approach to patients.


Educational financial support was provided for this session by Global Medical Education / Sunovion and Sumitomo Dainippon Pharma


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