Remission Of Positive Symptoms Research Articles

Changing vistas of psychosis and antipsychotic drug dosing toward personalized management of antipsychotics in clinical practice.

To discuss current evidence on tapering antipsychotic drugs in view of changing vistas of psychosis, suggesting a provisional framework for safely tapering antipsychotic drugs to an optimal low dose, in collaboration with patients and their relatives, to promote functional recovery while preventing relapse. Paradigm shifts during recent years regarding the nature of psychotic disorders and the role of the dopamine system are discussed, including the positive effects of dopamine blockade in acute psychosis and the limitations and drawbacks of dopamine blockade regarding negative and cognitive symptoms after remission of positive symptoms. Recent advances in tapering strategies and upcoming ways to solve the dilemma between the need to prevent relapses with antipsychotics on the one hand and the need to minimize side effects by tapering these drugs on the other are presented. Modern tapering strategies appear to reduce relapse risk to acceptable levels and offer a feasible personalized option to find the least effective dose to treat and prevent positive symptoms without redundant side effects and functional incapacity. These findings need replication, and several trials that might provide more certainty are on their way. Preliminary evidence and clinical experience indicate that personalized dose reduction of antipsychotics is feasible and safe if carried out in close collaboration with patients and their relatives, according to a provisionally suggested framework presented here. These preliminary directions still must be confirmed, revised, and adjusted according to upcoming trial results. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Interpersonal trauma and discharge symptom severity among individuals with psychotic disorders: A population-based cohort study in Ontario

Interpersonal trauma is associated with poorer prognoses for individuals with psychotic disorders; however, its association with symptom severity at hospital discharge is unknown. Among 57,106 individuals hospitalized for a psychotic disorder in Ontario, Canada (2009–2019), 12,805 (22.4 %) with and 44,301 (77.6 %) without a history of interpersonal trauma were compared on the positive symptom scale (PSS) score at discharge. In a subcohort of individuals with an elevated PSS score of at least 6 on admission, we calculated the relative risk of positive symptom remission (PSS<6) at discharge comparing those with and without interpersonal trauma. Interpersonal trauma was associated with a higher PSS discharge score. Effect sizes were greater for those with who experienced interpersonal trauma in the past year. Results were similar by type of trauma (physical, sexual, emotional) and specific diagnosis (schizophrenia, schizoaffective disorder, other psychotic disorder). In the subcohort, fewer inpatients with vs. without a history of interpersonal trauma had PSS<6 at discharge. Thus, individuals with psychotic disorders who have a history of interpersonal trauma are at risk for elevated symptom burden at hospital discharge. Integration of trauma-informed frameworks and trauma-focused therapies in the inpatient psychiatric setting may optimize outcomes at discharge.

Patient‐reported outcome measures in early psychosis: Evaluating the psychometric properties of the single‐item self‐reported health and self‐reported mental health measures in Chennai, India and Montreal, Canada

AbstractAimPatient‐reported outcome measures (PROMs) provide valuable information and promote shared decision‐making but are infrequently used in psychosis. Self‐rated Health (SRH) and Self‐rated Mental Health (SRMH) are single‐item PROMs in which respondents rate their health and mental health from ‘poor’ to ‘excellent’. We examined the psychometric properties of the SRH and SRMH in early psychosis services in Chennai, India and Montreal, Canada.MethodsAssessments were completed in Tamil/English in Chennai and French/English in Montreal. Test–retest reliability included data from 59 patients in Chennai and Montreal. Criterion validity was examined against clinician‐rated measures of depression, anxiety, positive and negative symptoms, and a quality‐of‐life PROM for 261 patients in Chennai and Montreal.ResultsSRH and SRMH had good to excellent test–retest reliability (ICC &gt;0.63) at both sites and in English and Tamil (but not French). Results for criterion validity were mixed. In Montreal, low SRH was associated with not being in positive symptom remission, and poorer functioning and quality of life. SRH was associated only with functioning in Chennai. No associations were found for SRMH in Montreal. In Chennai, low SRMH was associated with not being in positive symptom remission and poorer functioning.ConclusionsPatient‐reported outcome measures may perform differently across contexts as a potential function of variations in sociodemographics, illness characteristics/course, understandings of health/mental health, and so forth. More work is needed to understand if discrepancies between PROMs and CROMs indicate poor validity of PROMs or ‘valid’ differences between patient and clinician perceptions. Our work suggests that single‐item PROMs can be feasibly integrated into clinical settings.

Influence of time to clozapine prescription on the clinical outcome.

This study investigates whether early clozapine use is associated with improved responses in different clinical domains, including positive and negative symptoms, functioning, and well-being. Data from 254 clozapine-treated patients at Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) were analysed. Among them, 231 (90.9%) had a diagnosis of schizophrenia, 21 (8.3%) schizoaffective disorder, and 2 (0.8%) had other diagnoses. The International Classification of Diseases-Mortality and Morbidity Statistics criteria (ICD-10) were employed (World Health Organization, 1992). The cohort was assessed using the positive and negative syndrome scale (PANSS), the Brief Negative Symptom Scale (BNSS), Global Assessment of Functioning Scale (GAF), and the short version of Warwick-Edinburgh Mental Well-being Scale (SWEMWBS). Logistic regression models (for positive and negative symptom remission) and linear regression (for functioning and well-being) were utilized to assess the influence of time to clozapine initiation (TCI), age at the first episode of psychosis (AFE), duration of clozapine treatment (DCT), and gender. Early clozapine treatment (within the first three years after the first episode of psychosis) was associated with increased negative symptom remission (exp (B)=0.38; p=0.02) and higher functioning scores (β=-0.12, p=0.046). However, no effect of time to clozapine initiation was found on positive symptom remission rates or well-being scores. Initiating clozapine treatment within the first 3years of the first episode of psychosis may lead to reduced severity of negative symptoms and improved functioning in clozapine-treated patients. The time to clozapine initiation did not influence its effect on positive symptom remission rates.

20-year trajectories of positive and negative symptoms after the first psychotic episode in patients with schizophrenia spectrum disorder: results from the OPUS study.

This study aimed to identify the 20-year trajectories of positive and negative symptoms after the first psychotic episode in a sample of patients with an ICD-10 diagnosis of schizophrenia spectrum disorder, and to investigate the baseline characteristics and long-term outcomes associated with these trajectories. A total of 373 participants in the OPUS trial were included in the study. Symptoms were assessed at baseline and after 1, 2, 5, 10 and 20 years using the Scales for the Assessment of Positive and Negative Symptoms. We used latent class growth mixture modelling to identify trajectories, and multinominal regression analyses to investigate predictors of membership to identified trajectories. Five trajectories of positive symptoms were identified: early continuous remission (50.9% of the sample), stable improvement (18.0%), intermittent symptoms (10.2%), relapse with moderate symptoms (11.9%), and continuous severe symptoms (9.1%). Substance use disorder (odds ratio, OR: 2.83, 95% CI: 1.09-7.38, p=0.033), longer duration of untreated psychosis (OR: 1.02, 95% CI: 1.00-1.03, p=0.007) and higher level of negative symptoms (OR: 1.60, 95% CI: 1.07-2.39, p=0.021) were predictors of the relapse with moderate symptoms trajectory, while only longer duration of untreated psychosis (OR: 1.01, 95% CI: 1.00-1.02, p=0.030) predicted membership to the continuous severe symptoms trajectory. Two trajectories of negative symptoms were identified: symptom remission (51.0%) and continuous symptoms (49.0%). Predictors of the continuous symptoms trajectory were male sex (OR: 3.03, 95% CI: 1.48-6.02, p=0.002) and longer duration of untreated psychosis (OR: 1.01, 95% CI: 1.00-1.02, p=0.034). Trajectories displaying continuous positive and negative symptoms were linked to lower neurocognition, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS) (z-score: -0.78, CI: -1.39 to -0.17, for continuous positive symptoms; z-score: -0.33, CI: -0.53 to -0.13, for continuous negative symptoms). The same trajectories were also linked to higher use of antipsychotic medication at 20-year follow-up (continuous positive symptoms: 78%; continuous negative symptoms: 67%). These findings suggest that the majority of patients with first-episode schizophrenia spectrum disorder have a trajectory with early stable remission of positive symptoms. Long duration of untreated psychosis and comorbid substance abuse are modifiable predictors of poor trajectories for positive symptoms in these patients. In about half of patients, negative symptoms do not improve over time. These symptoms, in addition to being associated with poor social and neurocognitive functioning, may prevent patients from seeking help.

Subjective quality of life among first-episode psychosis patients in Chennai, India and Montreal, Canada.

Differences in subjective quality of life among persons receiving early intervention for psychosis in varying geo-sociocultural contexts have rarely been examined. Our prospective longitudinal study compared the quality of life of persons with first-episode psychosis receiving two years of similar early intervention in Chennai, India and Montreal, Canada. We hypothesized that general life satisfaction would be higher in Chennai compared to Montreal, and that social relations (a specific quality of life component) would also be higher in Chennai and positively contribute to general life satisfaction. Participants completed the general satisfaction and social relations domains of the Wisconsin Quality of Life Index at baseline, months 12 and 24. Baseline weighted mean general satisfaction and social relations scores were in the low to moderate range. Generalized estimating equation analyses showed that general satisfaction scores increased with time [Wald χ2 (1)=125.28, p<0.001] and were higher in Chennai than in Montreal [Wald χ2 (1)=7.50, p=0.006]. Social relations scores showed the highest association with general satisfaction scores (B=0.52), followed by positive symptom remission (B=0.24) and gender (B=0.18) with Chennai males having the highest general satisfaction scores. Social relations weighted mean scores increased with time [Wald χ2 (1)=87.30, p<0.001] and were positively associated with years of education [Wald χ2 (1)=4.76, p=0.029] and early negative symptom remission [Wald χ2 (1)=7.38, p=0.007]. Our results suggest that subjective quality of life may improve following early intervention for psychosis across contexts. Our findings advance knowledge about the role of sociocultural (e.g., gender) and clinical factors in influencing subjective outcomes in psychosis, and point to social support networks and symptom remission as avenues to boost quality of life.

An observational study of antipsychotic medication discontinuation in first-episode psychosis: clinical and functional outcomes.

To study the impact of supervised antipsychotic medication discontinuation on clinical and functional outcomes in first-episode psychosis (FEP) in two different cultural environments. FEP patients(N = 253), treated in two early intervention services (Montreal, Canada and Chennai, India) for 2 years, were assessed for medication use, positive and negative symptom remission and social-occupational functioning at regular intervals. Between months 4 and 24 of treatment, 107 patients discontinued medication ('Off'group) as compared to 146 who stayed on medication ('On'group). Medication discontinuation was higher in Chennai as compared to Montreal (n = 80, 49.07% vs n = 27, 16.87%; χ2 37.80, p < 0.001), with no difference in time to discontinuation [Means(SDs) = 10.64(6.82) and 10.04(5.43), respectively, p = 0.71). At month 24 (N = 235), there were no differences in the rate of positive symptom remission between the on and Off groups (81.5 vs 88.0%, respectively) at both sites. The rate of negative symptom remission was lower among patients in the On compared to the Off group (63.2 vs 87.9%, respectively, χ2 = 17.91, p < 0.001), but only in Montreal (55.4% vs 80.0%, respectively, χ2 = 4.12, p < 0.05). Social and Occupational Functioning Assessment Scale scores were equally high in both Off and On medication groups in Chennai [Means (SDs) = 79.43(12.95) and 73.59(17.63), respectively] but higher in the Off compared to the On group in Montreal Means (SDs) = 77.47(14.97) and 64.94(19.02), respectively; Time × site interaction F = 3.96(1,217), p < 0.05]. Medication status (On-Off) had no impact on the outcomes, independent of other variables known to influence outcomes. Certain cultural environments and patient characteristics may facilitate supervised discontinuation of antipsychotic medication following treatment of an FEP without negative consequences.

Pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia: Japanese Society of Clinical Neuropsychopharmacology treatment algorithms.

ObjectiveThere are only a few treatment algorithms for first‐episode schizophrenia. Moreover, all the algorithms apply to acute treatment, but not maintenance treatment. Therefore, we aimed to develop acute and maintenance treatment algorithms for first‐episode schizophrenia.MethodsThe algorithm committee of the Japanese Society of Clinical Neuropsychopharmacology developed pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first‐episode schizophrenia.ResultsThe acute treatment algorithm focuses on drug‐naïve patients with first‐episode schizophrenia who are not old or very agitated and recommends first‐line treatment with aripiprazole, second‐ or third‐line treatment with risperidone/paliperidone or olanzapine, and fourth‐line treatment with clozapine. Long‐acting injection of the current antipsychotic agent can be used for poor medication adherence or based on patient preference. The agitation treatment algorithm recommends first‐line treatment with lorazepam and second‐ or third‐line treatment with quetiapine or levomepromazine and clearly instructs that the medication used for agitation should be reduced and then discontinued after remission of agitation. The maintenance treatment algorithm recommends the gradual reduction of antipsychotics to the minimum effective dose after remission of positive symptoms.ConclusionsWe hope that our unique algorithms will be used broadly and will contribute to minimizing patients' burden related to antipsychotic treatment.

Exploring unusual bodily experiences, basic self disturbances and multimodal hallucinations in the non-clinical population: a cross-sectional study

AimsPsychosis research has largely focused on symptoms which are easier to define. Symptoms which are challenging to detect and articulate, including disturbances in the basic- and bodily-self, may not be volunteered by patients, despite causing significant distress. Increased understanding of such symptoms, which may present in the prodromal phase of psychosis and persist following the remission of positive symptoms, may allow patients who experience these to be better supported.This study aims to explore how disturbances in the basic- and bodily-self relate to multimodal hallucinations. Through sampling a non-clinical population, this study takes the continuum approach to psychosis, where individuals experience sub-clinical psychotic symptoms which do not cause distress or functional impairment.It is hypothesised that individuals with greater hallucination proneness will exhibit greater severity of ambiguous and imprecise mapping of bodily experiences, and will report greater levels of basic and bodily-self disturbance. This project also aims to evaluate Audiograph as a newly developed tool for creating representations of visual hallucinations.MethodThis is a two-stage cross-sectional study. In stage one, participants completed the Multi-Modality Unusual Sensory Experiences Questionnaire to assess hallucination-proneness. In stage two, all participants were invited to complete seven further validated questionnaires which assessed basic- and bodily self-disturbances alongside co-variates including anxiety and depression symptoms, delusion-proneness and loneliness. Participants also completed emBODY, a computer-based task which allows participants to map the bodily sensations they experience during 13 different emotional states. Participants with high-hallucination proneness also completed the Audiograph task. Hierarchical linear regression, conducted using Stata, will be used to model the influence of hallucination proneness on measures of basic- and bodily-self disturbance. MATLAB will be used to generate topographical maps of the data from emBODY; maps will be compared between different emotional states using linear discriminant analysis, and between high and low hallucination proneness groups using Spearman's test.ResultCurrently, 50 of the 104 stage one participants have completed stage two.Since this project comprises a compulsory component of the presenting author's intercalated degree, data collection will cease on the 29th of March in advance of their poster and write-up submission deadlines in May.ConclusionAlthough basic- and bodily-self disturbances have been assessed in previous studies using various techniques, no single study has assessed these alongside multimodal hallucinations to link these concepts together as a whole, especially not in a general population sample. The added value of this project is to precisely address this gap in knowledge.

Suicidality Over the First 5 Years of Psychosis: Does Extending Early Intervention Have Benefits?

We aimed to investigate whether individuals with first-episode psychosis (FEP) receiving extended early intervention (EI) were less likely to experience suicidal ideation and behaviors than those transferred to regular care after 2 years of EI. Another objective was to examine the 5-year course of suicidality in FEP. We conducted a secondary analysis of a randomized controlled trial where 220 patients were randomized after 2 years of EI to receive extended EI or regular care for the subsequent 3 years. Suicidality was rated using the Brief Psychiatric Rating Scale. Linear mixed model analysis was used to study time and group effects on suicidality. Extended EI and regular care groups did not differ on suicidality. There was a small decrease in suicidality over time, F(7, 1038) = 1.84, P = 0.077, with an immediate sharp decline within a month of treatment, followed by stability over the remaining 5 years. Patients who endorsed suicidality at entry (46.6%) had higher baseline positive, negative, and depressive symptoms. The 5-year course fell in 3 groups: never endorsed suicidality (33.9%), endorsed suicidality at low-risk levels (43.1%), and endorsed high-risk levels (23.0%). The high-risk group had a higher proportion of affective versus nonaffective psychosis diagnosis; higher baseline positive and depressive symptoms; higher 5-year mean depression scores, and fewer weeks of positive symptom remission over the 5-year course. The first month of treatment is a critical period for suicide risk in FEP. Although early reductions in suicidality are often maintained, our findings make the case for sustained monitoring for suicide risk management.

O3.5. EARLY TRAJECTORIES OF POSITIVE SYMPTOMS REMISSION IN FIRST EPISODE-PSYCHOSIS: A 2-YEAR FOLLOW-UP STUDY

BackgroundThe Prevention and Early intervention Program for Psychosis (PEPP) provides young people with first episode psychosis (FEP) rapid access to appropriate mental health services designed on the principles of early intervention (EI). We have previously demonstrated high rates of positive symptom (PS) remission. However, the relationship between PS, negative symptoms (NS) and functional outcomes remains unclear. Adherence to medication and early treatment response have been shown to be important independent determinants of the level of, and time to, symptom and functional remission, respectively. While trajectories of symptom severity have been shown to be heterogeneous, no previous study has investigated the prognosis of PS remission among individuals with FEP treated in an EI service. Identification of different trajectories of PS remission is a useful strategy to provide insight into clinically meaningful subgroups of patients while providing valuable information on NS and functioning for improving treatment outcomes.MethodsThe 2-year treatment at PEPP comprises different psychosocial (i.e., cognitive behavioral therapy, group intervention, family intervention, individual placement and support program) and psychopharmacological interventions (i.e., minimum effective dosage of second-generation antipsychotics). Monthly assessments were conducted from baseline to month 24. A total of 387 FEP patients, aged 14–35 years, with DSM IV affective or non-affective psychosis and little or no prior antipsychotic treatment (i.e., < 30 days) were included. PS remission was defined as absence of overt psychotic symptoms (i.e., all global SAPS items ≤ 2). A Latent Class Growth Analysis (LCGA) was used to investigate the distinct trajectories based on cumulative length of PS remission assessed at 3, 6, 9, 12, 15, 18, 21, and 24 months of treatment. Predictors of trajectories were investigated among sociodemographic, pre-treatment, as well as baseline and course clinical characteristics. Chi-square tests, one-way and mixed ANOVAs identified which baseline and longitudinal variables differed between and within trajectories. Candidate predictors that were statistically significant were then entered into a multinomial regression model to determine which factors independently predict trajectory membership.ResultsThree distinct trajectories of PS remission were identified. Excellent (68%), unstable (15%) and poor (17%) trajectory. Trajectories differed at baseline in DUP, diagnosis of affective psychosis and PS severity. Over the 24 months of treatment, negative, depressive, anxiety and mania symptoms, as well as functioning, best improved in the excellent trajectory among which patients were prescribed less antipsychotics in term of chlorpromazine equivalent than patients in other trajectories. Multinomial regression of baseline characteristics revealed that absence of early treatment response at 3 months (adjusted OR=2.53; 95%CI=1.24–5.16) independently predicted poorer trajectory.DiscussionThese results highlight the heterogeneous prognosis of PS remission suggesting that the diversity in FEP response and phenotypes may be determined by different pathophysiological underpinnings. The fact that early response was found to be a strong predictor of PS remission supports early and adequate symptom control for which medication is a critical issue. Further research applying data-driven trajectory analysis in FEP is warranted to facilitate better characterization of longer-term patterns of remission and development of targeted intervention to promote early recovery.

M200. CLOZAPINE-INDUCED HEPATOTOXICITY: TWO CASE REPORTS

BackgroundLiver function tests (LFT) abnormalities secondary to antipsychotics (AP) are common, early, and often mild and transient. Up to 60% of patients on clozapine experience an increase in LFT, at medium-range doses (200–400mg), and usually dose-dependent, with spontaneous resolution in half the cases, no dose reduction needed. Fatal outcomes are extremally rare, with an incidence around 0.001%. The hepatotoxic effects of clozapine have received considerable less attention than its cardiometabolic and hematologic counterparts. Consequently, there are few independents guidelines on how to handle such cases. Our objective is to report 2 cases of mild clozapine-induced liver injury and discuss possible protocols of early detection and management.MethodsWe described 2 cases of clozapine induced hepatitotoxicity in patients with schizophrenia.ResultsCASE 1: 33 y/o, male, caucasian, 5y of illness. Had previously used risperidone and paliperidone, and was currently taking olanzapine, without good response. Clozapine 25mg/d was introduced – in addition to olanzapine 15mg/d – with a 25mg increase every 2d. On D12 of clozapine (150mg/day), he reported nausea, diarrhea and dizziness, worsening the next few days, with confusion and choluria. Blood tests detected increases of ALT (242U/L), serum bilirubin (total 1.59mg/dL; direct 1.29g/dL; indirect 0.3mg/dL) and ESR (60mm/1sth). He was admitted and AP were interrupted. After 48h, presented full clinical recovery. Leukocyte blood count and ESR were still high in the first week, but LFT and bilirubins progressively decreased. All exams normalized in 1m. After 2w, olanzapine was reintroduced, with no LFT changes.CASE 248 y/o, female, caucasian, 15y of illness. Partial response to risperidone and olanzapine. 20d after clozapine was introduced (75mg/d), she reported nausea, vomiting, choluria, abdominal pain and headache. Presented elevated AST (88U/L), ALT (77U/L), CK (732U/L), GGT (141U/L) and ALP (161U/L), decreased Hb (9.6g/dL), mild leukocytosis (10,800/mm3), mild leukocyturia and hematuria, though bilirubin and platelet levels were normal. Clozapine was immediately suspended and olanzapine 10mg/d reintroduced progressively, maintaining partial remission of positive symptoms. Blood counts and LFT were normalized within 1m and no hospitalization was required.DiscussionBoth cases illustrate different presentations of hepatotoxicity by clozapine. Case 1 had no LFT dosage before the introduction and no indicative hepatic risk. With a regular dose evaluation, developed a severe hepatic injury. Case 2 had a history of side effects to previous antipsychotics. She started with normal LFT levels and evolved with mild hepatic injury due to the slow dose increase.In both cases LFT weren’t requested periodically until clinical symptoms emerged. At this point, it was fundamental to instruct the patient to report any warning clinical signs.A serialized LFT protocol wouldn’t show benefits to prevent hepatotoxicity in the outcome of our cases. However, some authors recommend monitoring them 4–6m after starting AP, specially the first 4–5w, since it could predict a bad outcome of severe hepatitis. Previous studies point ALT>3ULN or ALP>2ULN or any rise of transaminases with CK or bilirrubin altered as sensitive markers for liver damage. In such cases, the AP should be suspended.There is no consistent data regarding the indication of clozapine rechallenge after hepatotoxicity. Yet, the early onset of drug injury (1–6w) and the rapid rise in ALT on rechallenge may be a contraindication of a new try or continuous use of the drug.Considering guidelines on clozapine induced hepatotoxicity are not clear, we suggest the topic to be revisited and better established.

S145. CORTICO-THALAMIC DYSCONNECTIVITY LINKS WITH ABERRANT STRIATAL DOPAMINE IN SCHIZOPHRENIA A SIMULTANEOUS 18F-DOPA-PET/RESTING-STATE FMRI STUDY

BackgroundIn schizophrenia, among the most consistent brain changes are both aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei; however, it is unknown whether these changes are pathophysiologically related. Such a relationship is expected because cortico-thalamic-connectivity is modulated by striatal dopamine within topographically distinct, parallel but interacting cortico-basal-ganglia-thalamic circuits. We hypothesized: (1) Within-circuits, aberrant striatal dopamine contributes to aberrant cortico-thalamic-iFC, specifically, associative-striatum dopamine contributes to salience-network-thalamic-iFC, and sensorimotor-striatum dopamine to auditory-sensorimotor-network-thalamic-iFC. (2) Due to between-circuits interactions following an anterior-to-posterior gradient, salience-network-centered-system changes contribute to auditory-sensorimotor-network-centered-system changes.MethodsTo test these hypotheses, 19 patients with schizophrenia during symptomatic remission of positive symptoms and 19 age- and sex-comparable controls underwent simultaneous fluorodihydroxyphenyl-L-alanine positron emission tomography (18F-DOPA-PET) and resting-state functional magnetic resonance imaging (rs-fMRI). The influx constant kicer based on 18F-DOPA-PET was used to measure dopamine synthesis capacity (DSC), indicating striatal dopamine function; correlation coefficients between rs-fMRI time-series of cortical networks and thalamic regions-of-interest were used to measure iFC.ResultsIn the salience-network(SAL)-centered-system, patients had reduced associative-striatum-DSC, which correlated positively with SAL-mediodorsal-thalamus-iFC and mediated the reduction of SAL-thalamic-iFC in patients. In the auditory-sensorimotor-network(ASM)-centered-system, patients had reduced sensorimotor-striatum-DSC, which correlated positively with ASM-ventrolateral-thalamus-iFC, but did not mediate increased ASM-thalamic-iFC in patients. Finally, aberrant DSC and iFC of the SAL-centered-system mediated corresponding changes in the ASM-centered-system.DiscussionResults demonstrate that cortico-thalamic-dysconnectivity links with aberrant striatal dopamine in schizophrenia - in a topographically distinct way, with an anterior-to-posterior gradient, and primary changes in the SAL-centered system.

The downside of downregulation.

This scientific commentary refers to ‘Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms’, by Avram et al. (doi:10.1093/brain/awz093).

T197. Reduced Striatal Dopamine Synthesis Capacity Mediates Altered Within-Basal Ganglia Intrinsic Functional Connectivity in Patients With Schizophrenia During Symptomatic Remission of Positive Symptoms

Basal ganglia circuitry, organized in largely parallel dorsal and ventral/limbic pathways, is modulated by dopamine. We recently reported cortico-basal ganglia intrinsic functional connectivity (iFC) alterations in schizophrenia and identified decreased striatal dopamine synthesis capacity (DSC) in patients with schizophrenia during symptomatic remission of positive symptoms. However, the functional relationship between altered within-basal ganglia iFC and striatal-DSC is unknown in schizophrenia.

Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms.

While there is consistent evidence for increased presynaptic dopamine synthesis capacity in the striatum of patients with schizophrenia during psychosis, it is unclear whether this also holds for patients during psychotic remission. This study investigates whether striatal dopamine synthesis capacity is altered in patients with schizophrenia during symptomatic remission of positive symptoms, and whether potential alterations relate to symptoms other than positive, such as cognitive difficulties. Twenty-three patients with schizophrenia in symptomatic remission of positive symptoms according to Andreasen, and 24 healthy controls underwent 18F-DOPA-PET and behavioural-cognitive assessment. Imaging data were analysed with voxel-wise Patlak modelling with cerebellum as reference region, resulting in the influx constant kicer reflecting dopamine synthesis capacity. For the whole striatum and its subdivisions (i.e. limbic, associative, and sensorimotor), averaged regional kicer values were calculated, compared across groups, and correlated with behavioural-cognitive scores, including a mediation analysis. Patients had negative symptoms (Positive and Negative Syndrome Scale-negative 14.13 ± 5.91) and cognitive difficulties, i.e. they performed worse than controls in Trail-Making-Test-B (TMT-B; P = 0.01). Furthermore, kicer was reduced in patients for whole striatum (P = 0.004) and associative (P = 0.002) and sensorimotor subdivisions (P = 0.007). In patients, whole striatum kicer was negatively correlated with TMT-B (rho = -0.42, P = 0.04; i.e. the lower striatal kicer, the worse the cognitive performance). Mediation analysis showed that striatal kicer mediated the group difference in TMT-B. Results demonstrate that patients with schizophrenia in symptomatic remission of positive symptoms have decreased striatal dopamine synthesis capacity, which mediates the disorder's impact on cognitive difficulties. Data suggest that striatal dopamine dysfunction contributes to cognitive difficulties in schizophrenia.

Does relapse contribute to treatment resistance? Antipsychotic response in first- vs. second-episode schizophrenia.

Although some studies have suggested that relapse may be associated with antipsychotic treatment resistance in schizophrenia, the number and quality of studies is limited. The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse (i.e., second episode) in association with non-adherence; and (5) reintroduction of antipsychotic treatment with the same agent used to achieve response in the first episode. The following outcomes were used as an index of antipsychotic treatment response: changes in the brief psychiatric rating scale (BPRS) total and positive symptom scores and number of patients who achieved positive symptom remission and 20 and 50% response. A total of 130 patients were included in the analyses. Although all patients took the same antipsychotic in both episodes, there were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year in favor of the first episode compared to the second episode (50% response rate: 48.7 vs. 10.4% at week 7; 88.2 vs. 27.8% at week 27, respectively). Although antipsychotic doses in the second episode were significantly higher than those in the first episode, results remained unchanged after adjusting for antipsychotic dose. The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.

F121. DOES RELAPSE CONTRIBUTE TO TREATMENT RESISTANCE? ANTIPSYCHOTIC RESPONSE IN FIRST- VS. SECOND-EPISODE SCHIZOPHRENIA

BackgroundThe objective of this study was to compare trajectories of antipsychotic response before and after relapse following response from a first episode of schizophrenia or schizoaffective disorder.MethodsThe current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse (i.e., second episode) in association with non-adherence; and (4) reintroduction of antipsychotic treatment. The following outcomes were used as an index of antipsychotic treatment response: change in the Brief Psychiatric Rating Scale (BPRS) total score and number of patients who achieved positive symptom remission, including 20% and 50% response improvement.ResultsA total of 130 patients were included in the analyses. All patients took the same antipsychotic in both episodes. Antipsychotic doses in the second episode were significantly higher than those in the first episode (P=0.03). There were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year (all Ps<0.001) in favor of the first episode compared to the second episode. Results remained unchanged after adjusting for antipsychotic dose.DiscussionThe present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.

Pathways to functional outcomes following a first episode of psychosis: The roles of premorbid adjustment, verbal memory and symptom remission.

Most studies have investigated either the singular or relative contributions of premorbid adjustment, verbal memory and symptom remission to functional outcomes in first-episode psychosis. Fewer studies have examined the pathways of these factors in impacting functioning. Our study addresses this gap. The objective was to determine whether the relationship between premorbid adjustment and functional outcomes was mediated by verbal memory and symptom remission. A total of 334 first-episode psychosis participants (aged 14-35 years) were assessed on premorbid adjustment, verbal memory upon entry, and positive and negative symptom remission and functioning at multiple time points over a 2-year follow-up. Mediation analyses showed that over the first year, the relationship between premorbid adjustment and functioning was mediated by verbal memory and positive symptom remission (β = -0.18; 95% confidence interval = [-0.51, -0.04]), as well as by verbal memory and negative symptom remission (β = -0.41; 95% confidence interval = [-1.11, -1.03]). Over 2 years, the relationship between premorbid adjustment and functioning was mediated by verbal memory and only negative symptom remission (β = -0.38; 95% confidence interval = [-1.46, -0.02]). Comparatively less malleable factors (premorbid adjustment and verbal memory) may contribute to functional outcomes through more malleable factors (symptoms). Promoting remission may be an important parsimonious means to achieving better functional outcomes.

Recuperación funcional en la esquizofrenia

Recovery in schizophrenia is a topic that generates not only major clinical attention but also a significant economic and social impact. Until seventy years ago, these patients remained held in psychiatric institutions or asylums, usually with no hope of reintegrating into the community. A narrative review of relevant literature was conducted in order to answer key questions regarding recovery in schizophrenia. Treatment objectives in schizophrenia have changed substantially: from expecting a modest control of psychotic symptoms to considering functional recovery as a possibility. Available evidence indicates that one in seven patients with schizophrenia will achieve functional recovery, which implies that remission of positive symptoms is not the ultimate goal of treatment but only a basis for better social and cognitive functioning that translates into better quality of life. This view until recently was not believed to be possible for this major mental disorder.