(1) Background: The lack of reliable biomarkers remains a significant barrier to improving outcomes for patients with schizophrenia. While metabolomic analyses of blood, urine, and feces have been explored, results have been inconsistent. Compared to peripheral compartments, cerebrospinal fluid (CSF) more closely reflects the chemical composition of brain extracellular fluid. Given that brain dysregulation may be more pronounced during the first episode of psychosis (FEP), we hypothesized that metabolomic analysis of CSF from FEP patients could reveal disease-associated biomarkers. (2) Methods: We recruited 15 patients within 24 months of psychosis onset (DSM-4 criteria) and 14 control participants through the Johns Hopkins Schizophrenia Center. CSF samples were analyzed using both non-targeted and targeted liquid chromatography-mass spectrometry. (3) Results: The non-targeted analysis identified lower levels of N-acetylneuraminic acid and N-acetyl-L-aspartic acid in the FEP group, while levels of uric acid were elevated. The targeted analysis focused on indolic and phenolic molecules previously linked to neuropsychiatric disorders. Notably, L-phenylalanine and 4-hydroxycinnamic acid levels were lower in the FEP group, and this difference remained significant after adjusting for age and sex. However, none of the significant differences in analyte levels between the groups survived an adjustment for multiple comparisons. (4) Conclusions: Our intriguing but preliminary associations align with results from other investigational approaches and highlight potential CSF analytes that warrant further study in larger samples.

Psychotic disorders are known to be associated with elevated dopamine synthesis; yet, nondopamine factors may underlie the manifestation of some psychotic symptoms that are nonresponsive to dopamine-blocking agents. One under-explored nondopamine mechanism is neuroplasticity. We propose an account of the course of psychotic symptoms based on the extensive evidence for dopamine facilitation of Hebbian synaptic plasticity in cortical and subcortical memory systems. The encoding of psychotic experiences in autobiographical memory (AM) is expected to be facilitated in the hyperdopaminergic state associated with acute psychosis. However, once such 'spurious AM of psychosis' (SAMP) is encoded, its persistence may become dependent more on synaptic factors than dopamine factors. Under this framework, the involuntary retrieval of residual SAMP is postulated to play a key role in mediating the reactivation of symptoms with similar contents, as often observed in patients during relapse. In contrast, with active new learning of normalizing experiences across diverse real-life contexts, supported by intact dopamine-mediated salience, well-integrated SAMP may undergo 'extinction', leading to remission. The key steps to the integration of SAMP across psychotic and nonpsychotic memories may correspond to one's 'recovery style', involving processes similar to the formation of 'non-believed memory' in nonclinical populations. The oversuppression of dopamine can compromise such processes. We synthesize this line of evidence into an updated dopamine-gated memory framework where neuroplasticity processes offer a parsimonious account for the recurrence, persistence, and progression of psychotic symptoms. This framework generates testable hypotheses relevant to clinical interventions.

Learning whom to trust is integral for healthy relationships and social cohesion, and atypicalities in trust learning are common across a range of clinical conditions, including schizophrenia spectrum disorders, Parkinson's disease, and depression. Persecutory delusions - rigid, unfounded beliefs that others are intending to harm oneself - significantly impact affected individuals' lives as they are associated with a range of negative health outcomes, including suicidal behaviour and relapse. Recent advances in computational modelling and psychopharmacology have significantly extended our understanding of the brain bases of dynamic trust learning, and the neuromodulator dopamine has been suggested to play a key role in this. However, the specifics of this role on a computational and neurobiological level remain to be fully established. The current review article provides a comprehensive summary of novel conceptual developments and empirical findings regarding the computational role of dopamine in social learning processes. Research findings strongly suggest a conceptual shift, from dopamine as a reward mechanism to a teaching signal indicating which information is relevant for learning, and shed light on the neurocomputational mechanisms via which antipsychotics may alleviate symptoms of aberrant social learning processes such as persecutory delusions. Knowledge gaps and inconsistencies in the extant literature are examined and the most pressing issues highlighted, laying the foundation for future research that will further advance our understanding of the neuromodulation of social belief updating processes.

The dopamine hypothesis of schizophrenia posits that elevated striatal dopamine functioning underlies the development of psychotic symptoms. Chronic exposure to social stressors increases psychosis risk, possibly by upregulating striatal dopamine functioning. Here we systematically review single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies that examined the relationship between chronic social stress exposure and in vivo striatal dopamine functioning in humans. We searched the scientific databases PubMed and PsycINFO from inception to August 2023. The quality of the included studies was evaluated with the ten-item Observational Study Quality Evaluation (PROSPERO: CRD42022308883). Twenty-eight studies were included, which measured different aspects of striatal dopamine functioning including dopamine synthesis capacity (DSC), vesicular monoamine transporter type 2 binding, dopamine release following a pharmacological or behavioral challenge, D2/3 receptor binding, and dopamine transporter binding. We observed preliminary evidence of an association between childhood trauma and increased striatal DSC and dopamine release. However, exposure to low socioeconomic status, stressful life events, or other social stressors was not consistently associated with altered striatal dopamine functioning. The quality of available studies was generally low. In conclusion, there is insufficient evidence that chronic social stressors upregulate striatal dopamine functioning in humans. We propose avenues for future research, in particular to improve the measurement of chronic social stressors and the methodological quality of study designs.

Psychotic symptoms and delusional beliefs have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (n = 48, n = 19 female) in a double-blind placebo-controlled within-subjects design (see preregistration at https://osf.io/a4k9j/). We predicted individuals on versus off ʟ-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that ʟ-DOPA compared with placebo increased false alarm rates. Further, ʟ-DOPA did not reliably modulate measures of accuracy, discrimination sensitivity, and response bias. In all cases, Bayesian statistics revealed strong evidence in favor of the null hypothesis. The task design followed previous work on illusory pattern perception and comprised a limited number of items per condition. The results therefore need to be interpreted with caution, as power was limited. Future studies should address illusory pattern perception using more items and take into account potential dose-dependent effects and differential effects in healthy versus clinical samples.

While duration of the psychosis prodrome (DPP) attracts attention in relation to the developmental trajectory of psychotic illness and service models, fundamental issues endure in the context of dimensional-spectrum models of psychosis. Among 205 epidemiologically representative subjects in the Cavan-Monaghan First Episode Psychosis Study, DPP was systematically quantified and compared, for the first time, across all 12 DSM-IV psychotic diagnoses. DPP was also compared with duration of untreated psychosis (DUP) and each was then analysed in relation to premorbid features across three age ranges: <12, 12-15 and 16-18 years. For each diagnosis, medians for both DPP and DUP were shorter than means, indicating common right-skewed distributions. Rank orders for both DPP and DUP were longest for schizophrenia, intermediate for other schizophrenia-spectrum psychoses, psychotic depression and psychotic disorder not otherwise specified, and shortest for brief psychotic disorder, bipolar disorder and substance-induced psychotic disorder, though with overlapping right-skewed distributions. DPP was longer than DUP for all diagnoses except substance-induced psychotic disorder. Across functional psychotic diagnoses, longer DPP was predicted by higher premorbid intelligence and better premorbid adjustment during age 16-18 years. These findings indicate that, trans-diagnostically, DPP and DUP share right-skewed continuities, in accordance with a dimensional-spectrum model of psychotic illness, and may reflect a unitary process that has been dichotomized at a subjective threshold along its trajectory. Better premorbid functioning during age 16-18 years appears to confer resilience by delaying progression to overt psychotic symptoms and may constitute a particular target period for psychosocial interventions.

Schizophrenia is a severe psychological disorder in which reality is interpreted abnormally by the patient. The symptoms of the disease include delusions and hallucinations, associated with extremely disordered behavior and thinking, which may affect the daily lives of the patients. Advancements in technology have led to understanding the dynamics of the disease and the identification of the underlying causes. Multiple investigations prove that it is regulated genetically, and epigenetically, and is affected by environmental factors. The molecular and neural pathways linked to the regulation of schizophrenia have been extensively studied. Over 180 Schizophrenic risk loci have now been recognized due to several genome-wide association studies (GWAS). It has been observed that multiple transcription factors (TF) binding-disrupting single nucleotide polymorphisms (SNPs) have been related to gene expression responsible for the disease in cerebral complexes. Copy number variation, SNP defects, and epigenetic changes in chromosomes may cause overexpression or underexpression of certain genes responsible for the disease. Nowadays, gene therapy is being implemented for its treatment as several of these genetic defects have been identified. Scientists are trying to use viral vectors, miRNA, siRNA, and CRISPR technology. In addition, nanotechnology is also being applied to target such genes. The primary aim of such targeting was to either delete or silence such hyperactive genes or induce certain genes that inhibit the expression of these genes. There are challenges in delivering the gene/DNA to the site of action in the brain, and scientists are working to resolve the same. The present article describes the basics regarding the disease, its causes and factors responsible, and the gene therapy solutions available to treat this disease.

In recent years, there has been increasing global concern about the rising prevalence and rapid progression of psychosomatic disorders (PD). This surge can be attributed to irregular biological conditions and the increasingly stressful lifestyles that individuals lead, ultimately resulting in functional impairments of vital organs. PD arises from intricate interactions involving the central nervous, endocrine, and immune systems. Notably, the hypothalamic-pituitaryadrenal (HPA) axis plays an essential role, as its dysregulation is influenced by prolonged stress and psychological distress. Consequently, stress hormones, including cortisol, exert detrimental effects on immunological function, inflammation, and homeostatic equilibrium. It emerges as physical symptoms influenced by psychological factors, such as persistent pain, gastrointestinal disturbances, or respiratory complications, and is pertinent to highlight that excessive and chronic stress, anxiety, or emotional distress may engender the onset or exacerbation of cardiovascular disorders, namely hypertension and heart disease. Although several therapeutic strategies have been proposed so far, the precise etiology of PD remains elusive due to the intricate nature of disease progression and the underlying modalities of action. This comprehensive review seeks to elucidate the diverse classifications of psychosomatic disorders, explicate their intricate mechanisms, and shed light on their impact on the human body, which may act as catalysts for the development of various other diseases. Additionally, it explores the inherent medico-clinical challenges posed by PD and also explores the cutting-edge technologies, tools, and data analytics pipelines that are being applied in the contemporary era to effectively analyze psychosomatic data.

Elevated dopamine synthesis capacity is part of the pathophysiology of schizophrenia thought to underlie psychosis. Drugs that reduce this phenomenon could thus be potential treatments for these disorders. In this study, we evaluated the ability of the trace amine-associated receptor 1 (TAAR1) partial agonist ralmitaront to reduce presynaptic dopamine synthesis capacity.

Ralmitaront (3 mg/kg, i.p.), a TAAR1 partial agonist, was evaluated using [18F]DOPA PET for its ability to modulate presynaptic dopamine synthesis capacity in naïve mice as well as mice in an induced hyperdopaminergic state following acute cocaine administration (20 mg/kg, i.p.).

Cocaine treatment on its own did not induce elevated dopamine synthesis capacity when compared to the control group. Pretreatment with ralmitaront significantly reduced dopamine synthesis capacity when given either alone (44%) or in combination with the psychostimulant cocaine (50%) when compared to the control group.

The TAAR1 agonist ralmitaront reduces striatal dopamine synthesis capacity, indexed as KiMod, both in naïve animals and when given prior to acute cocaine. This indicates the potential of TAAR1 agonism to address disorders characterized by striatal hyperdopaminergia.

Several studies have shown that spontaneous brain activity, including the total and fractional amplitude of low-frequency fluctuations (LFF) and regional homogeneity (ReHo), is altered in psychosis. Nonetheless, neuroimaging results show a high heterogeneity. For this reason, we gathered the extant literature on spontaneous brain activity in first-episode psychosis (FEP), where the effects of long-term treatment and chronic disease are minimal.

A systematic research was conducted on PubMed, Scopus, and Web of Science to identify studies exploring spontaneous brain activity and local connectivity in FEP estimated using functional magnetic resonance imaging. 20 LFF and 15 ReHo studies were included. Coordinate-Based Activation Likelihood Estimation Meta-Analyses stratified by brain measures, age (adolescent vs adult), and drug-naïve status were performed to identify spatially-convergent alterations in spontaneous brain activity in FEP.

We found a significant increase in LFF in FEP compared to healthy controls (HC) in the right striatum and in ReHo in the left striatum. When pooling together all studies on LFF and ReHo, spontaneous brain activity was increased in the bilateral striatum and superior and middle frontal gyri and decreased in the right precentral gyrus and the right inferior frontal gyrus compared to HC. These results were also replicated in the adult and drug-naïve samples.

Abnormalities in the frontostriatal circuit are present in early psychosis independently of treatment status. Our findings support the view that altered frontostriatal can represent a core neural alteration of the disorder and could be a target of treatment.

Human cells and bacteria secrete extracellular vesicles (EV) which play a role in intercellular communication. EV from the host intestinal epithelium are involved in the regulation of bacterial gene expression and growth. Bacterial EV (bactEV) produced in the intestine can pass to various tissues where they deliver biomolecules to many kinds of cells, including neurons. Emerging data indicate that gut microbiota is altered in patients with psychotic disorders. We hypothesized that the amount and content of blood-borne EV from intestinal cells and bactEV in psychotic patients would differ from healthy controls.

We analyzed for human intestinal proteins by proteomics, for bactEV by metaproteomic analysis, and by measuring the level of lipopolysaccharide (LPS) in blood-borne EV from patients with psychotic disorders (n = 25), tested twice, in the acute phase of psychosis and after improvement, with age- and sex-matched healthy controls (n = 25).

Patients with psychotic disorders had lower LPS levels in their EV compared to healthy controls (p = .027). Metaproteome analyses confirmed LPS finding and identified Firmicutes and Bacteroidetes as dominating phyla. Total amounts of human intestine proteins in EV isolated from blood was lower in patients compared to controls (p = .02).

Our results suggest that bactEV and host intestinal EV are decreased in patients with psychosis and that this topic is worthy of further investigation given potential pathophysiological implications. Possible mechanisms involve dysregulation of the gut microbiota by host EV, altered translocation of bactEV to systemic circulation where bactEV can interact with both the brain and the immune system.

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.

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size.

Psychotic disorders are complex disorders with multiple etiologies. While increased dopamine synthesis capacity has been proposed to underlie psychotic episodes, dopamine-independent processes are also involved (less responsive to dopamine receptor-blocking medications). The underlying mechanism(s) of the reduction in antipsychotic responsiveness over time, especially after repeated relapses, remain unclear. Despite the consistent evidence of dopamine overactivity and hippocampal volume loss in schizophrenia, few accounts have been provided based on the interactive effect of dopamine on hippocampal synapse plasticity mediating autobiographical memory processes. The present hypothesis builds upon previous works showing the potential effects of dopamine overactivity on hippocampal-mediated neuroplasticity underlying autobiographical memory, alongside known patterns of autobiographical memory dysfunction in psychosis. We propose that spurious autobiographical memory of psychosis (SAMP) produced during active psychosis may be a key mechanism mediating relapses and treatment non-responsiveness. In a hyperdopaminergic state, SAMP is expected to be generated at an increased rate during active psychosis. Similar to other memories, it will undergo assimilation, accommodation, and extinction processes. However, if SAMP fails to integrate with existing memory, a discontinuity in autobiographical memory may result. Inadequate exposure to normalizing experiences and hyposalience due to overmedication or negative symptoms may also impede the resolution of SAMP. Residual SAMP is hypothesized to increase the propensity for relapse and treatment non-responsiveness. Based on recent findings on the role of dopamine in facilitating hippocampal synapse plasticity and autobiographical memory formation, the SAMP hypothesis is consistent with clinical observations of DUP effects, including the repetition of contents in psychotic relapses as well as the emergence of treatment non-responsiveness after repeated relapses. Clinical implications of the hypothesis highlight the importance of minimizing active psychosis, integrating psychosis memory, avoiding over-medication, and fostering normalizing experiences.

Disturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve patients with first-episode psychosis from healthy control subjects.

We included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from 18F-fluorodopa (18F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion.

Individual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p = .003) and included dopamine synthesis capacity (Ki4p) in the nucleus accumbens (p = .664), GABA levels in the ACC (p = .019), glutamate plus glutamine levels in the thalamus (p = .678), and the interaction term Ki4p × GABA (p = .016).

Our multimodal approach proved superior classification accuracy, implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between Ki4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information.

For many decades, delusional disorder (DD) has been considered a treatment-resistant disorder, with antipsychotics acknowledged as the best, though imperfect, treatment. It is possible that the discovery of the right drug could turn treatment resistance into treatment response. The goal of this narrative review is to provide a historical perspective of the treatment of DD since the introduction of antipsychotics 70 years ago. The following search terms were used to scan the literature: antipsychotics AND "delusional disorder". Findings were that therapy for DD symptoms has changed over time. Initial reports suggested that the drug of choice was the antipsychotic pimozide, and that this drug was especially effective for the somatic subtype of DD. Subsequent studies demonstrated that other antipsychotics, for instance, risperidone and olanzapine, were also highly effective. Treatment response may vary according to the presence or absence of specific symptoms, such as cognitive defect and depression. Clozapine, partial D2 agonists, and long-acting injectable drugs may be more effective than other drugs, but the evidence is not yet in. Because of the absence of robust evidence, treatment guidelines for the optimal management of DD are not yet available.

While associations between duration of untreated psychosis (DUP) and outcome have been widely reported, how long these relationships endure following initiation of treatment and how such associations are distributed across the range of DUP values encountered remain unclear. This study investigates prospectively (i) whether prediction of outcome by DUP and by duration of untreated illness (DUI) diminishes, remains stable or increases in the long term after initiating treatment, and (ii) whether these relationships for differing indices of outcome vary across gradations of DUP-DUI values. Sixty-two subjects were evaluated prospectively for DUP, DUI, premorbid features, psychopathology and quality of life at both first episode psychosis (FEP) and at 7-year follow-up; functionality and service engagement were assessed at follow-up. Data were analysed using mixed-effects models for DUP and DUI quantiles. Prediction by longer DUP and DUI of greater psychopathology, particularly negative symptoms, and lower quality of life remained stable between FEP and follow-up; longer DUP and DUI also predicted lower functionality and service engagement at follow-up. While most associations were confined to the longest DUP-DUI quartile, those between DUP-DUI and negative symptoms and quality of life were distributed in a graded manner across DUP-DUI quartiles. Material confounding with premorbid features, including lead-time bias, was not supported. These findings suggest that benefits of reducing DUP-DUI may endure for at least a decade beyond FEP and that even modest reductions in DUP-DUI may confer particular advantage in the more debilitating and intransigent domain of impairment.

The links between cerebral small vessel disease (CSVD) burden and neuropsychiatric symptoms (NPS) have not been fully studied.

We aimed to explore the associations of the CSVD burden with Neuropsychiatric Inventory (NPI) total scores and its subsyndromes in the elderly without dementia.

We investigated 630 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative. All of them had NPI assessments and 3 Tesla MRI scans at baseline and 616 had longitudinal NPI assessments during the follow-up. Linear mixed-effects models were used to investigate the cross-sectional and longitudinal associations of CSVD burden with NPI total scores and its subsyndromes.

Higher CSVD burden longitudinally predicted more serious neuropsychiatric symptoms, including NPS (p = 0.0001), hyperactivity (p = 0.0007), affective symptoms (p = 0.0096), and apathy (p <  0.0001) in the total participants. Lacunar infarcts (LIs), white matter hyperactivities (WMHs), and cerebral microbleeds (CMBs) might play important roles in the occurrence of NPS, since they were longitudinally associated with specific neuropsychiatric subsyndromes. LIs contributed to hyperactivity (p = 0.0094), psychosis (p = 0.0392), affective symptoms (p = 0.0156), and apathy (p <  0.0001). WMHs were associated with hyperactivity (p = 0.0408) and apathy (p = 0.0343). However, CMBs were only related to apathy (p = 0.0148).

CSVD burden was associated with multiple neuropsychiatric symptoms, suggesting the importance of monitoring and controlling vascular risk factors. Different markers of CSVD were associated with specific subsyndromes of NPS, suggesting that different markers tended to occur in different encephalic regions.

How striatal dopamine synthesis capacity (DSC) contributes to the pathogenesis of negative symptoms in first-episode schizophrenia (SZ) and delusional disorder (DD) has seldom been explored. As negative symptoms during active psychotic episodes can be complicated by secondary influences, such as positive symptoms, longitudinal investigations may help to clarify the relationship between striatal DSC and negative symptoms and differentiate between primary and secondary negative symptoms.

A longitudinal study was conducted to examine whether baseline striatal DSC would be related to negative symptoms at 3 months in first-episode SZ and DD patients.

Twenty-three first-episode age- and gender-matched patients (11 DD and 12 SZ) were consecutively recruited through an early intervention service for psychosis in Hong Kong. Among them, 19 (82.6%) patients (9 DD and 10 SZ) were followed up at 3 months. All patients received an ¹⁸F-DOPA PET/MR scan at baseline.

Baseline striatal DSC (K^occ;30-60) was inversely associated with negative symptoms at 3 months in first-episode SZ patients (r_s =  - 0.80, p = 0.010). This association remained in SZ patients even when controlling for baseline negative, positive, and depressive symptoms, as well as cumulative antipsychotic dosage (β =  - 0.69, p = 0.012). Such associations were not observed in first-episode DD patients. Meanwhile, the severity of negative symptoms at 3 months was associated with more positive symptoms in DD patients (r_s = 0.74, p = 0.010) and not in SZ patients.

These findings highlight the role of striatal DSC in negative symptoms upon resolution of active psychotic episodes among first-episode SZ patients. Baseline striatal dopamine activity may inform future symptom expression with important treatment implications.

Psychotic syndromes are divided into affective and non-affective forms. Even among the non-affective forms, substantial differences exist. The aim of this relatively brief review is to synthesize what is known about the differences between two non-affective psychoses, schizophrenia and delusional disorder (DD), with respect to clinical, epidemiological, sociodemographic, and treatment response characteristics. A PubMed literature search revealed the following: in schizophrenia, hallucinations, negative symptoms and cognitive symptoms are prominent. They are rare in DD. Compared to schizophrenia patients, individuals with DD maintain relatively good function, and their delusions are believable; many are beliefs that are widely held in the general population. Treatments are generally similar in these two forms of psychosis, with the exception that antidepressants are used more frequently in DD and, for acute treatment, effective antipsychotic doses are lower in DD than in schizophrenia. It is with the hope that the contrasts between these two conditions will aid in the provision of safe and effective treatment for both that this review has been conducted.

Dopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal decarboxylation rate of ¹⁸F-DOPA to ¹⁸F-dopamine (k₃) and the effect of treatment on psychotic symptoms in antipsychotic-naïve patients with first-episode psychosis. We further explored the effect of treatment with a partial dopamine D₂ receptor agonist (aripiprazole) on k₃ and dopamine synthesis capacity (DSC) determined by the four-parameter model and by the conventional tissue reference method.

Sixty-two individuals (31 patients and 31 control subjects) underwent ¹⁸F-DOPA positron emission tomography at baseline, and 15 patients were re-examined after 6 weeks. Clinical re-examinations were completed after 6 weeks (n = 28) and 6 months (n = 15). Symptoms were evaluated with the Positive and Negative Syndrome Scale.

High baseline decarboxylation rates (k₃) were associated with more positive symptoms at baseline (p < .001) and with symptom improvement after 6 weeks (p = .006). Subregion analyses showed that baseline k₃ for the putamen (p = .003) and nucleus accumbens (p = .013) and DSC values for the nucleus accumbens (p = .003) were associated with psychotic symptoms. The tissue reference method yielded no associations between DSC and symptoms or symptom improvement. Neither method revealed any effects of group or treatment on average magnitudes of k₃ or DSC, whereas changes in dopamine synthesis were correlated with higher baseline values, implying a potential effect of treatment.

Striatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k₃ and treatment effect potentially implicate on new treatment strategies.

[¹⁸F]FDOPA PET imaging has shown dopaminergic function indexed as K_i^cer differs between antipsychotic treatment responders and non-responders. However, the theragnostic potential of this biomarker to identify non-responders has yet to be evaluated. In view of this, we aimed to evaluate this as a theragnostic test using linear and non-linear machine-learning (i.e., Bernoulli, support vector, random forest and Gaussian processes) analyses and to develop and evaluate a simplified approach, standardised uptake value ratio (SUVRc). Both [¹⁸F]FDOPA PET approaches had good test-rest reproducibility across striatal regions (K_i^cer ICC: 0.68-0.94, SUVRc ICC: 0.76-0.91). Both our linear and non-linear classification models showed good predictive power to distinguish responders from non-responders (receiver operating curve area under the curve for region-of-interest approach: K_i^cer = 0.80, SUVRc = 0.79; for voxel-wise approach using a linear support vector machine: 0.88) and similar sensitivity for identifying treatment non-responders with 100% specificity (K_i^cer: ~50%, SUVRc: 40-60%). Although the findings were replicated in two independent datasets, given the total sample size (n = 84) and single setting, they warrant testing in other samples and settings. Preliminary economic analysis of [¹⁸F]FDOPA PET to fast-track treatment-resistant patients with schizophrenia to clozapine indicated a potential healthcare cost saving of ~£3400 (equivalent to $4232 USD) per patient. These findings indicate [¹⁸F]FDOPA PET dopamine imaging has potential as biomarker to guide treatment choice.