The Placebo Effect in Psychosis: Why It Matters and How to Measure It.

Psychosis is characterized by unusual percepts and beliefs in the form of hallucinations and delusions. Antipsychotic medication, the primary treatment for psychosis, is often ineffective and accompanied by severe side effects, but research has not identified an effective alternative in several decades. One reason that clinical trials fail is that patients with psychosis tend to show a significant therapeutic response to inert control treatments, known as the placebo effect, which makes it difficult to distinguish drug effects from placebo effects. Conversely, in clinical practice, a strong placebo effect may be useful because it could enhance the overall treatment response. Identifying factors that predict large placebo effects could improve the future outlook of psychosis treatment. Biomarkers of the placebo effect have already been suggested in pain and depression, but not in psychosis. Quantifying markers of the placebo effect would have the potential to predict placebo effects in psychosis clinical trials. Furthermore, the placebo effect and psychosis may represent a shared neurocognitive mechanism in which prior beliefs are weighted against new sensory information to make inferences about reality. Examining this overlap could reveal new insights into the mechanisms underlying psychosis and indicate novel treatment targets. We provide a narrative review of the importance of the placebo effect in psychosis and propose a novel method to assess it.

Prevalence of Neuroradiological Abnormalities in First-Episode Psychosis: A Systematic Review and Meta-analysis.

Importance: Individuals presenting with first-episode psychosis (FEP) may have a secondary ("organic") etiology to their symptoms that can be identified using neuroimaging. Because failure to detect such cases at an early stage can have serious clinical consequences, it has been suggested that brain magnetic resonance imaging (MRI) should be mandatory for all patients presenting with FEP. However, this remains a controversial issue, partly because the prevalence of clinically relevant MRI abnormalities in this group is unclear. Objective: To derive a meta-analytic estimate of the prevalence of clinically relevant neuroradiological abnormalities in FEP. Data Sources: Electronic databases Ovid, MEDLINE, PubMed, Embase, PsychINFO, and Global Health were searched up to July 2021. References and citations of included articles and review articles were also searched. Study Selection: Magnetic resonance imaging studies of patients with FEP were included if they reported the frequency of intracranial radiological abnormalities. Data Extraction and Synthesis: Independent extraction was undertaken by 3 researchers and a random-effects meta-analysis of pooled proportions was calculated. Moderators were tested using subgroup and meta-regression analyses. Heterogeneity was evaluated using the I2 index. The robustness of results was evaluated using sensitivity analyses. Publication bias was assessed using funnel plots and Egger tests. Main Outcomes and Measures: Proportion of patients with a clinically relevant radiological abnormality (defined as a change in clinical management or diagnosis); number of patients needed to scan to detect 1 such abnormality (number needed to assess [NNA]). Results: Twelve independent studies (13 samples) comprising 1613 patients with FEP were included. Of these patients, 26.4% (95% CI, 16.3%-37.9%; NNA of 4) had an intracranial radiological abnormality, and 5.9% (95% CI, 3.2%-9.0%) had a clinically relevant abnormality, yielding an NNA of 18. There were high degrees of heterogeneity among the studies for these outcomes, 95% to 73%, respectively. The most common type of clinically relevant finding was white matter abnormalities, with a prevalence of 0.9% (95% CI, 0%-2.8%), followed by cysts, with a prevalence of 0.5% (95% CI, 0%-1.4%). Conclusions and Relevance: This systematic review and meta-analysis found that 5.9% of patients presenting with a first episode of psychosis had a clinically relevant finding on MRI. Because the consequences of not detecting these abnormalities can be serious, these findings support the use of MRI as part of the initial clinical assessment of all patients with FEP.

Speech Illusions in People at Clinical High Risk for Psychosis Linked to Clinical Outcome.

BACKGROUND AND HYPOTHESIS: Around 20% of people at clinical high risk (CHR) for psychosis later develop a psychotic disorder, but it is difficult to predict who this will be. We assessed the incidence of hearing speech (termed speech illusions [SIs]) in noise in CHR participants and examined whether this was associated with adverse clinical outcomes. STUDY DESIGN: At baseline, 344 CHR participants and 67 healthy controls were presented with a computerized white noise task and asked whether they heard speech, and whether speech was neutral, affective, or whether they were uncertain about its valence. After 2 years, we assessed whether participants transitioned to psychosis, or remitted from the CHR state, and their functioning. STUDY RESULTS: CHR participants had a lower sensitivity to the task. Logistic regression revealed that a bias towards hearing targets in stimuli was associated with remission status (OR = 0.21, P = 042). Conversely, hearing SIs with uncertain valence at baseline was associated with reduced likelihood of remission (OR = 7.72. P = .007). When we assessed only participants who did not take antipsychotic medication at baseline, the association between hearing SIs with uncertain valence at baseline and remission likelihood remained (OR = 7.61, P = .043) and this variable was additionally associated with a greater likelihood of transition to psychosis (OR = 5.34, P = .029). CONCLUSIONS: In CHR individuals, a tendency to hear speech in noise, and uncertainty about the affective valence of this speech, is associated with adverse outcomes. This task could be used in a battery of cognitive markers to stratify CHR participants according to subsequent outcomes.

Dopamine and reward-related vigor in younger and older adults.

Vigor reflects how motivated people are to respond to stimuli. We previously showed that, on average, humans are more vigorous when a higher rate of reward is available, and that this relationship is modulated by the dopamine precursor levodopa. Dopamine signaling and probabilistic reward learning deteriorate across the adult life span, and thus, the relationship between vigor and reward may also change in aging. We tested this assertion and assessed whether it correlates with D1 dopamine receptor availability, measured using Positron Emission Tomography. We registered response times of 30 older and 30 younger participants during an oddball discrimination task where rewards varied systematically between trials. The average reward rate had a similar impact on vigor in both age groups. There was a weak positive association between ventral striatal dopamine receptor availability and the effect of average reward rate on response time. Overall, the effect of reward on response vigor was similar in younger and older adults, and weakly correlated with dopamine D1 receptor availability.

Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function.

Preclinical rodent models suggest that psychosis involves alterations in the activity and glutamatergic function in the hippocampus, driving dopamine activity through projections to the striatum. The extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and 1H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (ppeakFWE = 0.003, t = 4.4, z = 4.19) and a poor functional outcome (ppeakFWE < 0.001, t = 5.52, z = 4.81 and ppeakFWE < 0.001, t = 5.25, z = 4.62) were associated with a negative correlation between the hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (ppeakFWE = 0.016, t = 3.73, z = 3.39, ppeakFWE = 0.014, t = 3.78, z = 3.42, ppeakFWE = 0.011, t = 4.45, z = 3.91, ppeakFWE = 0.003, t = 4.92, z = 4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function.

Aberrant Salience, Information Processing, and Dopaminergic Signaling in People at Clinical High Risk for Psychosis.

The aberrant salience hypothesis proposes that striatal dopamine dysregulation causes misattribution of salience to irrelevant stimuli leading to psychosis. Recently, new lines of preclinical evidence on information coding by subcortical dopamine coupled with computational models of the brain's ability to predict and make inferences about the world (predictive processing) provide a new perspective on this hypothesis. We review these and summarize the evidence for dopamine dysfunction, reward processing, and salience abnormalities in people at clinical high risk of psychosis (CHR) relative to findings in patients with psychosis. This review identifies consistent evidence for dysregulated subcortical dopamine function in people at CHR, but also indicates a number of areas where neurobiological processes are different in CHR subjects relative to patients with psychosis, particularly in reward processing. We then consider how predictive processing models may explain psychotic symptoms in terms of alterations in prediction error and precision signaling using Bayesian approaches. We also review the potential role of environmental risk factors, particularly early adverse life experiences, in influencing the prior expectations that individuals have about their world in terms of computational models of the progression from being at CHR to frank psychosis. We identify a number of key outstanding questions, including the relative roles of prediction error or precision signaling in the development of symptoms and the mechanism underlying dopamine dysfunction. Finally, we discuss how the integration of computational psychiatry with biological investigation may inform the treatment for people at CHR of psychosis.