Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology

Kaar, Stephen; Natesan, Sridhar; McCutcheon, Robert; Howes, Oliver

doi:10.1016/j.neuropharm.2019.107704

Cited by 235 publications

(201 citation statements)

References 334 publications

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“…On the basis of preclinical work using a model of striatal D2 overexpression, it has also been proposed that excessive striatal dopamine signalling may lead to reductions in cortical dopamine and associated cognitive symptoms. Therefore, it appears that both reduced and excessive dopamine signalling can have deleterious effects on cognition, which may contribute to the fact that there has been minimal success in developing dopamine modulating treatments for cognitive symptoms of schizophrenia.…”

Section: Dopaminementioning

confidence: 99%

“…Apomorphine was shown to be an efficacious treatment in an early clinical trial. Although later studies did not consistently replicate this finding, a recent investigation suggested that this drug may normalize dopaminergic activity, potentially via agonism of presynaptic autoreceptors. Another upstream approach involves agonism of trace amine type 1 receptors.…”

Section: Treatmentmentioning

confidence: 99%

“…Antipsychotics were serendipitously discovered over fifty years ago, but it took another decade or so until dopamine antagonism was demonstrated as central to their clinical effectiveness. Further evidence implicating the dopamine system in the pathophysiology of schizophrenia has subsequently accumulated, and it remains the case that all licensed first‐line treatments for schizophrenia operate primarily via antagonism of the dopamine D2 receptor.…”

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confidence: 99%

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Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

2020

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Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.

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Section: Dopaminementioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

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confidence: 99%

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Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

2020

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“…This is consistent with proposals that D2 blockade produces acute effects on cognition (Mehta et al 1999). While we cannot be certain of the brain regions underpinning our observed effects on social cognition, it is notable that striatal D2 receptors are associated with treatment effects of D2 antagonists in psychosis (Kaar et al 2019), although dopaminergic agents provide important modulatory function in the prefrontal cortex.…”

Section: Discussionmentioning

confidence: 85%

“…Given the role of dopamine in paranoia and paranoid delusions, we predicted that haloperidol would reduce attributions of harmful intent and salience of paranormal beliefs based on the observation that dopamine antagonism is the primary therapeutic mechanism of antipsychotics in the treatment of psychosis (Kaar et al, 2019). We predicted that potentiation of dopamine transmission using L-DOPA in healthy participants would increase attributions of harmful intent and the salience of paranormal beliefs, given increased presynaptic dopamine in those at risk of psychosis (Howes & Kapur, 2009).…”

Section: Introductionmentioning

confidence: 99%

Dopamine manipulations modulate paranoid social inferences in healthy people

Barnby

Bell

Deeley

et al. 2019

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Altered dopamine transmission is thought to influence the formation of persecutory delusions. However, despite extensive evidence from clinical studies there is little experimental evidence on how modulating the dopamine system changes social attributions related to paranoia, and the salience of beliefs more generally. 27 healthy male participants received 150mg L-DOPA, 3mg haloperidol, or placebo in a double blind, randomised, placebo-controlled study, over three within-subject sessions. Participants completed a multi-round Dictator Game modified to measure social attributions, and a measure of belief salience spanning themes of politics, religion, science, morality, and the paranormal. We preregistered predictions that altering dopamine function would affect i) attributions of harmful intent and ii) salience of paranormal beliefs. As predicted, haloperidol reduced attributions of harmful intent across all conditions compared to placebo. L-DOPA reduced attributions of harmful intent in fair conditions compared to placebo. Unexpectedly, haloperidol increased attributions of self-interest for opponents' decisions. There was no change in belief salience within any theme. These results could not be explained by scepticism or subjective mood. Our findings demonstrate the selective involvement of dopamine in social inferences related to paranoia in healthy individuals.

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Schizophrenia—An Overview

2020

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he Clinical Challenge 1 in this issue of JAMA Psychiatry describes a patient who clinicians will be familiar with: a young woman who develops auditory hallucinations, unusual beliefs, and a deterioration in cognitive abilities and social function and is diagnosed with schizophrenia in early adulthood. The diagnosis of schizophrenia is based on a clinical assessment. In response to concerns regarding diagnostic reliability, early narrative descriptions of the disorder have been replaced with codified criteria (Box). Positive symptoms, such as delusions and hallucinations, are often the reason the patient presents to the clinician. However, the disorder is also associated with negative symptoms, such as amotivation and social withdrawal, and cognitive symptoms, including deficits in working memory, executive function, and processing speed. While more recent descriptions emphasize positive symptoms (Box), earlier conceptualizations saw negative symptoms as core features of the disorder, 2 and negative and cognitive symptoms contribute substantially to the long-term burden associated with the disorder. 3 The disorder typically appears in early adulthood, and a prodromal period frequently precedes the first psychotic episode (Figure 1).Schizophrenia has a lifetime prevalence of about 1% 4 and accounts for a huge health care burden, with annual associated costs in the United States estimated to be more than $150 billion. 5 The fact that a disorder affecting around 1% of the population is associated with such costs is attributable to the fact that typical onset is in early adulthood and the long-term impairments in social and occupational function associated with the disease (Figure 1). 6 The disorder is also associated with reduced life expectancy: someone with schizophrenia has a mean life expectancy about 15 years shorter than the general population and a 5% to 10% lifetime risk of death by suicide. 7 In this review, we discuss findings from epidemiological, genetic, neuroimaging, and preclinical research to provide an overview of schizophrenia and consider the gaps in knowledge that remain. Theme 1: Convergence of Genetic and Early Environmental Risk Factors on NeurodevelopmentThe patient in the Clinical Challenge 1 case has a history of perinatal complications. Although schizophrenia typically appears in early adulthood, multiple strands of evidence indicate that its pathogenesis begins early in neurodevelopment. 8 This evidence includes increased rates of in utero adversity, such as maternal infections and starvation during pregnancy, and obstetric complications, including preterm birth and preeclampsia. [9][10][11] There is also evidence consistent with disrupted early neurodevelopment, such as skin markers of altered ectodermal development and mild cognitive and motor impairments in childhood. 9,12 Such impairments may manifest as IMPORTANCE Schizophrenia is a common, severe mental illness that most clinicians will encounter regularly during their practice. This report provides an overview of the clinical...

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Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology

Cited by 235 publications

References 334 publications

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

Dopamine manipulations modulate paranoid social inferences in healthy people

Schizophrenia—An Overview

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