Received: 12 November 2021 | Accepted: 13 February 2022 DOI: 10.1111/acps.13415 ORIGINAL ARTICLE Prodromal phase: Differences in prodromal symptoms, risk factors and markers of vulnerability in first episode mania versus first episode psychosis with onset in late adolescence or adulthood Norma Verdolini1,2 | Roger Borràs1,2 | Giulio Sparacino1,3 | Marina Garriga1,2 | Maria Sagué-­Vilavella1 | Santiago Madero4 | Roberto Palacios-­Garrán1,5 | Maria Serra1 | Maria Florencia Forte4 | Estela Salagre1,2 | Alberto Aedo1,6 | Pilar Salgado-­Pineda2,7 | Irene Montoro Salvatierra2,8 | Vanessa Sánchez Gistau2,8 | Edith Pomarol-­Clotet2,7 | Josep Antoni Ramos-­Quiroga2,9,10,11 | Andre F. Carvalho12 | Clemente Garcia-­Rizo2,4 | Juan Undurraga13,14 | María Reinares1 | Anabel Martinez Aran1,2 | Miguel Bernardo2,4 | Eduard Vieta1,2 | Isabella Pacchiarotti1,2 | Silvia Amoretti2,9,10,11 1 Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain 2 Biomedical Research Networking Center for Mental Health Network (CIBERSAM), Barcelona, Spain 3 Department of Health Sciences, Università degli Studi di Milano, Milan, Italy 4 Barcelona Clinic Schizophrenia Unit, Institute of Neurosciences, University of Barcelona, IDIBAPS, Barcelona, Spain 5 University Hospital Santa Maria, University of Lleida, Lleida, Spain 6 Bipolar Disorders Unit, Department of Psychiatry, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile 7 FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain 8 Hospital Universitari Institut Pere Mata, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain 9 Group of Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain 10 Psychiatric Genetics Unit, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain 11 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain 12 The IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia 13 Department of Neurology and Psychiatry, Faculty of Medicine, Clinica Alemana Universidad del Desarrollo, Santiago, Chile 14 Early Intervention Program, Instituto Psiquiátrico Dr. J. Horwitz Barak, Santiago, Chile Correspondence Eduard Vieta, Bipolar and Depressive Abstract Disorders Unit, Hospital Clinic, Objective: This study was aimed at identifying differences in the prodromal University of Barcelona, Institute of symptoms and their duration, risk factors and markers of vulnerability in patients Neuroscience, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-­0, 08036, Barcelona, presenting a first episode mania (FEM) or psychosis (FEP) with onset in late ado- Catalonia, Spain. lescence or adulthood in order to guide tailored treatment strategies. Email: EVIETA@clinic.cat Isabella Pacchiarotti and Silvia Amoretti equally contributed to this work. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd. 36 |  wileyonlinelibrary.com/journal/acps Acta Psychiatr Scand. 2022;146:36–50. VERDOLINI et al.    | 37 Funding information The funding sources had no role in Methods: Patients with a FEM or FEP underwent a clinical assessment. the design and conduct of the study; Prodromes were evaluated with the Bipolar Prodrome Symptom Scale-­ collection, management, analysis, and Retrospective (BPSS-­R). Chi-­squared tests were conducted to assess specific interpretation of the data; preparation, review or approval of the manuscript prodromal symptoms, risk factors or markers of vulnerability between groups. and decision to submit the manuscript Significant prodromal symptoms were entered in a stepwise forward logistic re- for publication. gression model. The probabilities of a gradual versus rapid onset pattern of the prodromes were computed with logistic regression models. Results: The total sample included 108 patients (FEM = 72, FEP = 36). Social isolation was associated with the prodromal stage of a FEP whilst Increased energy or goal-­directed activity with the prodrome to a FEM. Physically slowed down pre- sented the most gradual onset whilst Increased energy presented the most rapid. The presence of obstetric complications and difficulties in writing and reading during childhood were risk factors for FEP. As for markers of vulnerability, im- pairment in premorbid adjustment was characteristic of FEP patients. No specific risk factor or marker of vulnerability was identified for FEM. Conclusion: Early characteristics differentiating FEP from FEM were identified. These findings might help shape early identification and preventive intervention programmes. KEYWORDS first episode mania, first episode psychosis, markers of vulnerability, prodromes, risk factors 1 | I N T RO DU CT ION Significant outcomes • Increased energy or goal-­directed activity was as- In recent years, there has been an increased focus on the sociated with the prodromal stage of a first epi- early identification of different disorders and on their sode of mania (FEM) whilst Social isolation was prompt intervention, with attempts to predict the clinical associated with the prodrome of a first episode characteristics of those individuals who will progress to of psychosis (FEP). full-­threshold disorder.1,2 Particularly, researchers have • Even though the duration of the FEP prodrome concentrated on the prodromal phase given its potential was longer than the FEM prodrome, the pro- clinical relevance in early intervention. dromal phase of FEM patients was long enough The prodromal phase of first episode psychosis (FEP) to enable an early intervention. has been more frequently studied than the prodrome of first • A higher prevalence of obstetric complications and episode mania (FEM). A major limitation of previous liter- difficulties in writing and reading during child- ature is that a majority of studies have failed to distinguish hood were risk factors for FEP patients while im- between affective and non-­affective FEP, considering them pairment in premorbid adjustment was a marker of as a single factor.3 Due to the overlap in psychotic symp- vulnerability more characteristic of FEP patients. toms between FEPs and FEMs, there is a real possibility to incorrectly classify these patients at their first episode.4 Limitations For example, about 10% of affective psychoses progress to schizophrenia (SCZ) in the long-­term.4 The identification • The FEM and the FEP groups had different during the prodromal phase of specific symptoms that sample sizes, which might have influenced the allow differentiating patients developing SCZ or bipolar assessment of differences between groups. disorder (BD) might help tailor early interventions.5 • The retrospective assessment of prodromes Previous studies assessing and directly comparing the might have caused a possible recall bias. manifestations and duration of the prodromal phase in • The lack of a control group should be acknowl- both patients presenting a FEP or a FEM are scant in the edged since it might have helped in assessing the literature, with studies investigating FEM6,7 and FEP8-­10 specificity of prodromal symptoms and risk factors. patients separately. In addition, these previous studies 38 |    VERDOLINI et al. generally assessed prodromes to early onset BD or SCZ, in Interview for DSM Disorders (SCID-­I-­II),19,20 and diagno- children and adolescents.11,12 ses were confirmed according to DSM-­5 criteria.21 If the In terms of risk factors or markers of vulnerability, BD patient met the DSM-­5 A-­D criteria for a manic episode, was more frequently associated with a family history for they were subsequently categorized as a FEM. If the pa- mood disorders and ADHD7,13 whilst obstetric/perinatal tient presented at least two of the five symptoms of the complications,14 worse premorbid adjustment,15,16 and criterion A for a DSM-­5 psychotic disorder but had not high rates of cannabis abuse before the first episode of experienced the DSM-­5 A-­D criteria for a manic episode, disease17 were more frequently reported in SCZ. they were categorized as a FEP. Only outpatients with either a FEM or a FEP in late adolescence (≥15 years old) or adulthood (≤45 years old) 1.1 | Aims of the study were enrolled. Patients were included if they (i) were aged between 18 and 45 years at the time of evaluation; (ii) had Given the research suggesting the clinical significance of experienced their FEM/FEP in the previous 4 years and the challenges in early treatment strategies in FEM and (iii) provided signed informed consent. Exclusion crite- FEP, the main aims of this study were to identify sympto- ria were the presence of (i) a mental intellectual disabil- matic and temporal differences between the proximal pro- ity (defined as intelligence quotient (IQ) <70); (ii) any dromal phases of a first episode of mania compared with severe medical condition (i.e. cancer, HIV); (iii) alcohol/ first episode of psychosis with onset in late adolescence substance dependence or (iv) electroconvulsive therapy or adulthood. In addition, the study was aimed at explor- (ECT) in the previous 12 months. ing differences in risk factors and markers of vulnerability The study was carried out following the latest version between these groups. of the Declaration of Helsinki, and was reviewed by the ethical committee of the recruiting institutions. 2 | M AT E R IAL AN D M ET H OD S 2.3 | Socio-­demographic information 2.1 | Participants Socio-­demographic data (i.e. age, educational level and This is a cross-­sectional study with a retrospective assess- working status) were collected and stored in an electronic ment of information on early manifestations. Subjects data repository. Parental socioeconomic status (SES) was were drawn from the ‘Prodromes and Predictors in First determined using Hollingshead's Two-­Factor Index of Episode Mania and Psychosis’—­ProPreF project, a 2-­year Social Position.22 longitudinal, multicentric study investigating prodromes and predictors of clinical and longitudinal outcomes in patients presenting a FEM/FEP. Its ultimate goal was to 2.4 | Clinical assessment comprehensively and exhaustively assess the clinical pres- entation of the patients together with their biomarkers in Clinical information on onset features (i.e. age at onset, order to guide early identification and tailored early in- age at first hospitalization) was collected. The dura- tervention strategies. The study included the Bipolar and tion of untreated psychosis (DUP) was calculated as the Depressive Disorders Unit of IDIBAPS-­Hospital Clinic number of days between the first manifestations of psy- in Barcelona, the FIDMAG research foundation and the chotic symptoms and the initiation of psychiatric treat- Institut Pere Mata, under the umbrella of the Spanish ment (for those patients presenting psychotic symptoms Research Network on Mental Health (CIBERSAM).18 at onset). Clinical symptoms at the time of evaluation were as- sessed with the Positive and Negative Syndrome Scale 2.2 | Procedures (PANSS),23 the Young Mania Rating Scale (YMRS)24 and the Montgomery–­Asberg Depression Rating Scale To determine the presence of a full FEP or FEM, the sum- (MADRS).25 Psychosocial functioning was assessed maries of the patients’ clinical history and the assessment through the Functional Assessment Short Test (FAST).26 of the clinical presentation at onset of FEM or FEP were Information was also collected for physical or psychi- reviewed by at least two investigators, and an agree- atric comorbidities as well as for current pharmacological ment was reached on the diagnosis. Then, patients were treatment. Current antipsychotic mean doses were mea- clinically assessed by a trained investigator using a semi-­ sured as risperidone equivalents,27,28 current antidepres- structured interview based on the Structured Clinical sant mean doses were measured as fluoxetine equivalents29 VERDOLINI et al.    | 39 and current benzodiazepine mean doses were measured as symptoms’ severity and frequency were rated on an ordi- diazepam equivalents,30 based on international consensus. nal scale from 0 (absent) to 4 (static lifetime or character Patients also underwent an assessment of adherence to trait).6,11 Any prodromal symptom independent of sever- treatment, which was categorized as good, irregular and ity, frequency and any episode occurring before the FEM/ bad; well-­being was assessed through the World Health FEP in the lifetime of the patient was assessed in the inter- Organization Well Being Index (WHO-­5); and insight was view. Only those symptoms occurring within 3 years and evaluated with the Insight Scale.31 1 month before12 the first full episode was considered as part of the proximal prodrome. Only symptoms of at least moderate severity were considered in the analyses.6,11 In 2.5 | Information on early addition, symptoms with a frequency score of 4 = static manifestations lifetime or character trait, were not included as they are not considered part of the proximal prodrome.6,11 The In line with the procedures adopted in a previous study32 onset pattern of the prodromal stage was defined as ‘grad- and through a process of adaptation of these procedures ual’ if ≥4 months or ‘rapid’ if <4 months. The deteriora- to the clinical environment of the recruiting centres, in- tion pattern was defined as ‘slow’ if ≥4 weeks and ‘rapid’ formation was collected on three domains: 1. Prodromal if <4 weeks. Three different patterns of presentation were phenomenological manifestations; 2. Risk factors and 3. then derived, namely 1 = gradual onset with slow dete- Markers of vulnerability. rioration; 2 = gradual onset with rapid deterioration and 3 = rapid onset with rapid deterioration. 2.5.1 | Prodromal symptoms type and duration 2.5.2 | Risk factors Patients (and their caregivers when available) were asked Specific risk factors have been identified as increasing to retrospectively report prodromal symptoms’ type and the a risk of developing schizophrenia or bipolar disor- duration. First, we explained psychosis in clear language. der.1,32 Such risk factors are not early manifestations of We then provided the patient with the date of their first the disorder per se. The patients and their parents (when hospitalization or contact with the mental health service in available) were interviewed on the presence of the fol- order to set a time point for diagnosis. Following this, pa- lowing risk factors: (i) history of illness in first-­degree tients were asked when they first experienced changes in relatives for psychiatric disorders. At baseline, the par- behaviour or prodromal symptoms. During the interview, ticipants were asked to report family history of psychi- we used a timeline and asked for important dates in the atric disorders. Specifically, information was gathered life of the patients in order to help the recalling process. A on the presence of first-­degree family history, namely trained evaluator conducted a semi-­structured interview parents’ history of psychotic, depressive, bipolar, per- with the Bipolar Prodrome Symptom Scale-­Retrospective sonality and substances related disorders. When possi- (BPSS-­R),11 which systematically assesses the onset pattern, ble, the information was double-­checked with relatives duration, severity and frequency of 39 symptoms and signs or medical records; (ii) obstetric complications, assessed newly emerging of the proximal prodrome and includes sub- through the Lewis–­Murray33 scale, as a dichotomous threshold manic, depressive, general psychopathology and variable (yes/no); (iii) life stressors occurring during psychotic symptoms (see Table S1). The prodromal symp- the 12 months preceding the first episode of mania or toms were categorized into four subgroups, according to the psychosis. Life-­time traumatic events were considered psychopathological index of each symptom: 1. Mania Index when patients reported at least one traumatic event or Symptoms; 2. Depressive Index; 3. General Psychopathology situation of the list of the Post-­Traumatic Stress Disorder Index Symptoms and 4. Psychosis Index. Specific symp- (PTSD) Symptom Scale34 (PSS); (iv) childhood traumas, toms, such as the Lack of concentration can be considered assessed through the Childhood Trauma Questionnaire as both manic and depressive. The total score of each Index (CTQ-­30)35; (v) delayed language acquisition, when the considers all symptoms within a specific subgroup. On the individual produced sentences with two words only contrary, the BPSS-­R total score is calculated by adding the after the 24th month; (vi) delayed psychomotor devel- main subscores, considering the duplicated items only once. opment, when the individual was able to walk only after Trained evaluators conducted a semi-­structured in- the 18th month; (vii) nocturnal enuresis, after the age terview with the Bipolar Prodrome Symptom Scale-­ of five36 and (viii) difficulties in writing and reading, ei- Retrospective (BPSS-­R),11 focusing mainly on prodromic ther self-­reported or when the patient was referred to a symptoms’ type, frequency and duration. Prodromal speech therapist as a child). 40 |    VERDOLINI et al. 2.5.3 | Markers of vulnerability symptoms were entered in a stepwise forward selection algorithm to select variables included in the final mul- Some early developmental, behavioural or personality tivariate logistic regression model (FEM versus FEP as patterns and some biological characteristics are more fre- the dependent variable). Odds ratio and 95% confidence quently reported in the life history of patients that later interval (CI) were calculated. Receiver operating charac- develop bipolar disorder or schizophrenia.1,32 These may teristic (ROC) analysis was used to evaluate the model be early manifestations of the disorder itself and are con- performance. sidered as ‘markers of vulnerability’. Specific lifetime di- Differences between FEP and FEM patients in the du- agnoses, such as attention deficit hyperactivity disorder ration of the prodromal symptoms in months were as- (ADHD) or Conduct Disorder and the presence of previ- sessed through Student t-­test. We wanted to assess if each ous depressive episodes or hypomania can be reported specific prodromal symptom (considering only prodro- by patients that later develop a first episode of mania or mal symptoms that significantly differed in prevalence psychosis as well as specific personality features. In the between FEP or FEM patients) appeared more gradually present study, clinical information on prior contact with or rapidly during the proximal prodrome. In order to do mental health services during childhood/adolescence so, we computed the predicted probabilities of a gradual as well as on previous diagnoses and pharmacological versus rapid onset pattern of each prodromal symptom treatment was collected. The presence of features asso- with a logistic regression model, defining prodromal ciated with ADHD was evaluated through The Wender symptoms as the predictive variables. We evaluated the Utah Rating Scale.37 Life-­time impulsivity was assessed distribution of prodromal symptoms in the whole sam- through the Barratt Impulsiveness Scale (BIS-­11).38 In ad- ple to assess which of them appeared more gradually or dition, the assessment of lifetime history of alcohol-­ and rapidly. drug-­related problems was of interest. We specifically Statistical analysis was performed using R for Windows assessed information on the presence of suicidal ideas (version 4.0.3, R Project for Statistical Computing, Vienna, or attempts and on the use of cannabis and alcohol dur- Austria). Statistical significance was set at p < 0.05. ing the prodromal phase. Conus et al.32 also assessed the Premorbid Adjustment Scale (PAS)39 to examine attain- ment of developmental goals at each of several periods of 3 | RESULTS a participant's life before the onset of the illness. In the present study, only childhood and adolescence life peri- The total sample included 108 participants, 72 (66.7%) ods were assessed. patients with a FEM and 36 (33.3%) patients with a FEP (flow chart in Figure S1). No differences were identified in socio-­demographic variables (Table 1 and Table S2). 2.6 | Statistical analysis Descriptive statistics were used to define sample charac- 3.1 | Clinical variables teristics, the prevalence of prodromes and the duration among the subgroups of the prodromal stage. Continuous variables were given as mean value ± standard deviation and were compared No differences for mean age at onset and age at first hospi- using Student t-­test. Categorical variables were expressed talization were found (Table 1). The DUP of FEM was sig- as total number and percentages and differences among nificantly shorter than for FEP patients (Mean Difference groups were assessed through Chi-­square of Fisher's exact (MD) = 79.086, CI = 5.16–­153.01). test. At the time of evaluation, FEP patients showed The prodromal symptoms were categorized into sub- higher scores in the PANSS subdomains (positive symp- groups according to their psychopathological index6,12,40 toms: MD = 1.94, CI = 0.64–­3.23; negative symptoms: (Appendix S1 and Table S1). The BPSS-­R total score was MD = 5.20, CI = 2.53–­7.87; general psychopathol- calculated by adding the main subscores, considering the ogy: MD = 5.84, CI = 2.94–­8.73), PANSS total score duplicated items only once. (MD = 12.97, CI = 7.03–­18.92) and depressive (MADRS Univariate logistic regression models (FEM versus FEP total score: MD = 3.68, CI = 1.39–­5.97) but not manic as the dependent variable) were computed for each of the symptoms. potential predictors, considering only those prodromal The two groups differed in the total FAST score, symptoms with at least a minimum number of events, in with worse psychosocial functioning for FEP patients order to fit the predictive model. Significant prodromal (MD = 12.97, CI = 7.03–­18.92). VERDOLINI et al.    | 41 TABLE 1 Socio-­demographic data, clinical characteristics, risk factors and markers of vulnerability Groups Statistics FEM (n = 72) FEP (n = 36) t or χ2, p-­value Socio-­demographic Variables Age (years, mean ± SD) 26.58 ± 7.03 27.78 ± 6.90 −0.838, 0.404 Female sex (n, %) 37, 51.4 18, 50.0 0.000, 1.000 Education Level (n, %) 4.625, 0.100 Primary School 1, 1.4 4, 11.1 Secondary School 44, 61.1 20, 55.6 University 27, 37.5 12, 33.3 Marital status, Married, yes (n, %) 13, 18.1 5, 13.9 0.075, 0.784 Employment (n, %) 0.000,1.000 Working 22, 30.6 11, 30.6 Not Working 50, 69.4 25, 69.4 Socio-­economic status (n, %) 4.857, 0.301 I 7, 9.7 5, 14.3 II 13, 18.1 2, 5.7 III 10, 13.9 7, 20.0 IV 16, 22.2 11, 31.4 V 26, 36.1 10, 28.6 Clinical Variables Age at first episode, any type (years, mean ± SD) 22.90 ± 7.79 22.17 ± 7.96 0.459, 0.647 Age at FEM or FEP (years, mean ± SD) 25.78 ± 6.91 27.14 ± 7.06 0.958, 0.340 Age at first hospitalization (years, mean ± SD) 25.49 ± 6.97 26.48 ± 7.41 −0.627, 0.532 Duration of Untreated Psychosis (days, mean ± SD) 29.58 ± 56.01 108.67 ± 204.62 −2.172, 0.037 MADRS Total Score (mean±SD) 5.47 ± 4.80 9.15 ± 5.69 −3.419, 0.001 PANSS Positive Symptoms Score (mean ± SD) 7.58 ± 1.67 9.52 ± 3.50 −3.023, 0.004 PANSS Negative Symptoms Score (mean ± SD) 10.20 ± 4.87 15.39 ± 6.87 −3.916, <0.001 PANSS General Psychopatology Score (mean ± SD) 22.44 ± 6.34 28.27 ± 7.09 −4.209, <0.001 PANSS Total Score (mean ± SD) 40.21 ± 11.49 53.18 ± 15.09 −4.836, <0.001 YMRS Total Score (mean ± SD) 1.64 ± 2.70 1.33 ± 1.81 0.592, 0.555 FAST Total Score (mean ± SD) 17.20 ± 13.18 25.31 ± 12.69 −3.019, 0.003 Psychopharmacological Treatment, Current (n, %) 68, 94.40 35, 97.20 0.419, 0.663 Length of time between the diagnosis and the study 296.76 ± 340.19 307.64 ± 333.97 −0.158, 0.875 assessment (days, mean ± SD) Risk factors Family History of Psychosis, yes (n, %) 11, 15.5 8, 22.9 0.436, 0.509 Family History of Bipolar Disorder, yes (n, %) 17, 23.9 6, 17.1 0.301, 0.583 Family History of Major Depressive Episode, yes (n, %) 28, 39.4 15, 42.9 0.016, 0.899 Obstetric complications, yes (n, %) 16, 23.6 16, 44.4 3.976, 0.046 Abnormal Psychomotor Development, yes (n, %) Acquisition of walking ability 4, 10.3 2, 7.4 0.157,1.000 Acquisition of language 3, 7.9 4, 18.5 1.651, 0.260 Nocturnal enuresis 5, 13.5 7, 25.9 0.869, 0.331 Acquisition of reading/writing ability 1, 2.7 6, 25.9 7.697, 0.008 Stressors during prodromal phase, yes (n, %) 49, 70.0 26, 72.2 0.000, 0.990 Childhood Trauma, yes (n, %) 16, 43.2 8, 61.5 0.661, 0.416 (Continues) 42 |    VERDOLINI et al. TABLE 1 (Continued) Groups Statistics FEM (n = 72) FEP (n = 36) t or χ2, p-­value Markers of vulnerability Previous contact with MHS, yes, (n, %) 42, 60.0 22, 64.7 0.061, 0.804 Age at first contact with MHS (mean ± SD) 20.4 ± 8.97 20.04 ± 7.83 0.178, 0.859 Psychopharmacological Treatment in childhood/adolescence, 30, 42.30 24, 66.70 4.761, 0.029 (n, %) Psychiatric Diagnoses in childhood/adolescence (n, %) 30, 41.70 22, 61.1 2.897, 0.089 PAS childhood score (mean ± SD) 4.56 ± 3.39 6.74 ± 4.38 −2.840, 0.005 PAS adolescence score (mean ± SD) 6.78 ± 4.31 9.94 ± 5.61 −3.222, 0.002 PAS total score (mean ± SD) 11.33 ± 6.93 16.69 ± 9.01 −3.388, 0.001 Cannabis use during prodromal phase, yes (n, %) 41, 59.4 17. 48.6 0.712, 0.399 Alcohol use during prodromal phase, yes (n, %) 42, 60.9 20, 55.6 0.100, 0.752 Suicidal Ideation during prodromal phase, yes (n, %) 6, 8.3 5, 13.9 0.810, 0.574 Treatment during prodromal phase, yes (n, %) 25, 35.2 10, 27.8 0.310, 0.578 Antidepressants during prodromal phase, yes (n, %) 16, 22.5 3, 8.3 2.398. 0.121 Abbreviations: FAST, Functional Assessment Staging; FEM, First Episode Mania; FEP, First Episode Psychosis; MADRS, Montgomery-­Asberg Depression Rating Scale; MHS, Mental Health Services; PANSS; PAS, Premorbid Adjustment Scale; Positive and Negative Syndrome Scale; SD, Standard Deviation; WHO, World Health Organization; YMRS, Young Mania Rating Scale. Bold for statistically significant p values. 3.2 | Prevalence of prodromal symptoms with an area under the curve (AUC) = 0.78 (CI = 0.70–­ 0.86) (SF 3). The differences in prevalence of prodromal symptoms are displayed in Table 2 and Figure S2. The mean num- ber of total prodromal symptoms was not different be- 3.3 | Duration of prodromal symptoms tween groups, but FEM patients presented more Mania prodromal symptoms than FEP (MD = 2.18, CI = 1.21–­ More FEP patients reported a pattern of presentation with 3.15) whilst FEP patients reported more psychosis gradual onset and slow deterioration than FEM patients prodromal symptoms than FEM (MD = 0.43, CI = 0.03–­ (52.8% versus 25%, OR = 3.35, CI = 1.44–­7.78). 0.83). No difference was observed in the mean number The duration of prodromal symptoms prior to a FEP of total prodromal symptoms between psychotic and or a FEM is shown in Table 2. The mean duration of the non-­psychotic FEM (6.57 ± 4.59 vs 8 ± 4.76, t = 0.781, BPSS-­R prodromal stage was longer for FEP patients than p = 0.437). for FEM patients (MD = 5.66, CI = 2.69–­8.63). Moreover, Five out of 72 FEM patients (6.9%) and eight out of 36 the mean duration of the Manic, Depression, General FEP patients (22.2%) reported no prodromal symptoms Psychopathology and Psychotic prodromes was statisti- (OR = 0.26, CI = 0.08–­0.87, p = 0.030). cally longer in FEP than FEM patients. The mean duration Univariate and multivariate logistic regression find- of the prodromal stage did not significantly differ between ings are reported in Table 3. In the multivariate logistic psychotic FEM (3.35 ± 3.31 months) and non-­psychotic regression (Chi-­square = 30.532, df = 2, p < 0.001), the FEM (1.13 ± 0.24 months) (t = −1.629, p = 0.108). prodromal General Psychopathology symptom Social iso- As for the predicted probabilities of a gradual versus lation was associated with the prodromal stage of a FEP rapid onset pattern (Figure 1), the Depression symptom (OR = 4.95, CI = 1.47–­16.66, p = 0.010), whilst the mania Physically slowed down was the symptom that most prob- symptom Increased energy or goal-­directed activity with ably presented a gradual onset pattern, followed by two the prodromal stage of a FEM (OR = 0.08, CI = 0.02–­0.29, General Psychopathology Symptoms, Social isolation and p < 0.001). The ROC analysis supported the utility of the Ambivalence/difficulty making decisions. The Manic Symptom model and its variables because it performed significantly Increased energy or goal−directed activity was the symptom better than chance in predicting the association between that most probably presented a rapid onset pattern, followed prodromal symptoms and presenting a FEP versus a FEM, by the mania or depression symptom Physical agitation. VERDOLINI et al.    | 43 T A B L E 2 Reported prevalence and duration of prodromal symptoms prior to First Episode Mania (FEM) or Prior to First Episode Psychosis (FEP) Prevalence (Yes/No) Duration (Months) FEM FEP (n = 72, (n = 36, FEM (n = 72, FEP (n = 36, 66.7%) 33.3%) 2 66.7%) 33.3%) Prodromal symptom X or F, p characteristics N % N % value Mean SD Mean SD t, p value Mania Index Symptoms Increased energy or goal-­ 38 52.8 3 8.3 18.827, <0.001 2.42 2.11 3.33 0.58 −0.737, 0.465 directed activity Overly cheerful, happy, on top 27 37.5 4 11.1 6.928, 0.008 2.13 1.46 3.50 1.91 −1.685, 0.103 of the world Racing thoughts 24 33.3 5 13.9 3.683, 0.055 2.39 2.38 3.20 1.92 −0.705, 0.487 Overly talkative 27 37.5 1 2.8 13.313, <0.001 2.09 1.26 2.00 -­ 0.072, 0.943 Decreased need for sleep 25 34.7 2 5.6 9.389, 0.002 2.88 6.95 1.50 0.71 0.276, 0.785 Irritability or anger 29 40.3 11 30.6 0.601, 0.438 2.93 2.67 11.36 10.54 −2.622, 0.025 Overly self-­confidence 22 30.6 2 5.6 7.292, 0.007 2.20 1.31 2.50 0.70 −0.309, 0.760 Increased sexual interest 12 16.7 2 5.6 2.626, 0.135 2.20 1.23 4.00 1.41 −1.878, 0.085 Reckless or dangerous 4 5.6 2 5.6 0.000, 1.000 1.25 0.50 2.00 0.00 −2.000, 0.116 behaviours Risky sexual behaviour 4 5.6 1 2.8 0.419, 0.663 1.50 1.00 2.00 -­ −0.447, 0.685 Mania or Depression Index Symptoms Lack of concentration 21 29.2 10 27.8 0.000, 1.000 2.81 2.05 9.70 8.18 −2.625, 0.026 Physical agitation 26 36.1 4 11.1 6.283, 0.012 1.96 1.39 6.50 7.68 −1.179, 0.323 Depression Index Symptoms Depressed mood 1 1.4 5 13.9 7.147, 0.015 4.00 -­ 12.80 8.41 −0.955, 0.393 Tiredness or lack of energy 2 2.8 7 19.4 8.573, 0.006 9.00 7.07 13.57 12.49 −0.480, 0.646 Anhedonia 6 8.3 6 16.7 1.688, 0.209 6.00 3.74 10.17 8.95 −1.052, 0.329 Insomnia 28 38.9 14 38.9 0.000, 1.000 3.28 6.57 9.54 7.73 −2.680, 0.011 Feeling of worthlessness or guilt 2 2.8 2 5.6 0.519, 0.599 3.50 0.71 9.50 12.02 −0.705, 0.554 Weight loss or decrease in 9 12.5 6 16.7 0.087, 0.768 4.05 3.50 9.17 7.91 −1.725, 0.108 appetite Physically slowed down 3 4.2 6 16.7 4.909, 0.057 6.33 6.80 19.00 11.30 −1.753. 0.123 Thinking about suicide 2 2.8 2 5.6 0.519, 0.599 13.50 14.85 9.50 12.02 0.296, 0.795 Hypersomnia 0 -­ 2 5.6 4.075, 0.109 -­ -­ 10.50 9.19 -­ Attempting suicide 0 -­ 1 2.8 2.019, 0.333 -­ -­ 14.00 -­ -­ Weight gain or increasing in 3 4.2 2 5.6 0.105, 1.000 3.67 2.31 9.50 2.12 −2.842, 0.066 appetite General Index Symptoms Educational and occupational 17 23.6 13 36.1 1.298, 0.255 5.22 6.18 11.54 11.16 −1.827, 0.085 dysfunction Anxiety or nervousness 28 38.9 18 50.0 0.800, 0.371 3.96 3.91 7.71 8.19 −1.758, 0.093 Social Isolation 7 9.7 12 33.3 7.672, 0.006 2.93 1.88 11.33 10.07 −2.809, 0.015 Mood lability 33 45.8 7 19.4 6.080, 0.014 3.26 6.10 8.14 9.06 −1.362, 0.214 Ambivalence/difficulty 3 4.2 8 22.2 8.553, 0.006 3.17 1.44 5.50 4.28 −0.899, 0.392 making decisions Obsessions and compulsions 10 13.9 6 16.7 0.009, 0.924 3.35 1.83 5.17 2.86 −1.564, 0.140 (Continues) 44 |    VERDOLINI et al. TABLE 2 (Continued) Prevalence (Yes/No) Duration (Months) FEM FEP (n = 72, (n = 36, FEM (n = 72, FEP (n = 36, 66.7%) 33.3%) 2 66.7%) 33.3%) Prodromal symptom X or F, p characteristics N % N % value Mean SD Mean SD t, p value Losing temper frequently or 11 78.6 3 8.3 1.077, 0.375 1.64 1.21 9.33 12.74 −1.045, 0.405 trouble controlling anger Day/Night Sleep Reversal 2 2.8 0 -­ 1.019, 0.551 14.00 16.97 -­ -­ -­ Self-­harming behaviour (no 0 -­ 0 -­ -­ -­ -­ -­ -­ -­ intent to kill self) Oppositionality 2 2.8 1 2.8 0.000, 1.000 2.50 0.71 2.00 -­ 0.577, 0.667 Increased creativity 23 31.9 1 2.8 10.185, 0.001 2.65 2.66 3.00 -­ −0.128, 0.899 Giddy, clownish 2 2.8 1 2.8 0.000, 1.000 1.50 0.71 3.00 -­ −1.732, 0.333 Psychosis, Mania and Depression Index Symptoms Difficulty thinking or 4 5.6 6 16.7 3.527, 0.081 2.37 1.38 15.83 13.06 −2.503, 0.053 communicating clearly Psychosis Index Symptoms Suspiciousness/persecutory 11 15.3 13 36.1 4.882, 0.027 2.91 3.33 5.15 3.21 −1.678, 0.108 ideas Strange or unusual ideas 17 23.6 12 33.3 0.713, 0.398 2.82 3.02 4.12 2.31 0.026, 0.222 Hallucinations 1 1.4 1 2.8 0.255, 1.000 2.00 -­ 3.00 -­ -­ FEM (n = 92) FEP (n = 28) FEM (n = 92) FEP (n = 28) Mean SD Mean SD t, p value Mean SD Mean SD t, p value Mania Index 3.65 2.74 1.47 2.18 4.482, 2.84 3.84 11.48 10.94 3.377, 0.003 <0.001 Depression Index 1.46 1.52 2.03 1.92 −1.533, 3.63 5.58 10.52 8.93 3.489, 0.001 0.131 General 1.90 1.56 1.94 1.76 −0.129, 3.56 3.61 9.18 7.78 3.379, 0.002 Psychopathology 0.897 Index Psychosis Index 0.46 0.75 0.89 1.06 −2.175, 2.63 2.70 7.97 8.51 2.500, 0.022 0.034 BPSS-­R Total Score 6.70 4.62 5.61 4.73 1.146, 3.15 3.22 8.8 7.42 3.884, <0.001 0.254 Abbreviations: BPSS-­R, Bipolar Prodrome Symptom Scale-­Retrospective. Bold for statistically significant p values; FEM, First Episode Mania; FEP, First Episode Psychosis; SD, Standard Deviation. 3.4 | Risk factors 3.5 | Markers of vulnerability No difference was reported in family history of psychiatric A similarly high percentage of FEM and FEP patients disorders (Table 1). reported previous contact with mental health services FEP patients reported higher rates of OC (OR = 2.59, (60% versus 64.7%) with a similar mean age at first con- CI = 1.10–­6.08) and difficulties in writing and reading tact (around 20 years old) (Table 1). Patients in the FEP (OR = 12.6, CI = 1.45–­109.85). group more frequently received psychopharmacologi- Both FEM and FEP patients frequently experienced cal treatment in the past than FEM patients (OR = 2.73, stressors in the prodromal phase. Similarly, they reported CI = 1.18–­6.32). high rates of lifetime traumatic experiences and child- As for premorbid adjustment, FEP patients reported hood abuse, with no difference between groups. worse performance than FEM (PAS childhood: 6.74 ± 4.38 VERDOLINI et al.    | 45 TABLE 3 Associations of prodromal symptoms to a First Episode Mania (FEM) or Prior to First Episode Psychosis (FEP) Univariate analyses Multivariate forward stepwise analysis Beta Type of symptoms OR (95% CI) p-­value OR (95% CI) p-­value coefficient Mania Index Symptoms Racing thoughts 0.32 (0.11–­0.94) 0.037 Overly cheerful or happy 0.21 (0.07–­0.65) 0.007 Increased energy or goal-­directed activity 0.08 (0.02–­0.29) <0.001 0.08 (0.02–­0.29) <0.001 −2.544 Mania or Depression Index Symptoms Physically agitated 0.22 (0.07–­0.70) 0.010 Depression Index Symptoms Physically slowed down 4.60 (1.08–­19.62) 0.039 General Index Symptoms Social isolation 4.64 (1.63–­13.18) 0.004 4.95 (1.47–­16.66) 0.010 1.599 Ambivalence/difficulty making decisions 6.57 (1.62–­ 25.59) 0.008 Mood lability 0.29 (0.11–­0.74) 0.009 Psychosis Index Symptoms Suspiciousness 3.13 (1.23–­7.99) 0.017 Constant −0.336 Abbreviations: FEM, First Episode Mania; FEP, First Episode Psychosis; IC, Intervals of confidence; OR, Odds ratio. Bold for statistically significant p values. versus 4.56 ± 3.39, MD = 2.187, CI = 0.66–­3.71; PAS ad- In terms of psychopathology, Mania prodromal olescence: 9.94 ± 5.61 versus 6.78 ± 4.31, MD = 3.17, symptoms, namely Increased energy or goal-­directed ac- CI = 1.01–­5.32; PAS total score: MD = 5.35, CI = 2.22–­ tivity, Physical agitation, Racing thoughts, Overly cheer- 8.4). The PAS scale revealed a progressive decline in both ful, happy, and on top of the world, were more frequently FEP (Mean = 3.2, CI = 1.66–­4.74, t = −4.234, p < 0.001) reported in FEM patients whilst Psychosis prodromal and FEM (Mean = 2.22, CI = 1.41–­3.04, t = −5.442, symptoms, such as Suspiciousness/persecutory ideas, p < 0.001) patients. or the depression symptoms Physically slowed down, No differences were observed in cannabis and alcohol were more frequently included in the FEP prodrome. use in the prodromal phase. Notably, both FEM and FEP The manic prodrome was characterized by at least patients reported high rates of cannabis (59.4% versus three subthreshold manic symptoms in more than half 48.6%) and alcohol (60.9% versus 55.6%) consumption. of the youth assessed by Correll and colleagues.6 In a systematic review, subthreshold manic symptoms such as Overly talkative, Racing thoughts and Physical agita- 4 | DI S C USSION tion were among the most frequently reported symp- toms in the initial prodrome to mania in BD type I.41 The following key findings emerged from the present On the contrary, Reduced drive and motivation, Anergia, study. First, Social isolation was associated with the pro- Depressed mood and subsyndromal Delusional ideas or dromal stage of a FEP whilst Increased energy or goal-­ Suspiciousness were among the prodromal features most directed activity was associated with the prodrome to a commonly described in FEP studies.3,42 In the compar- FEM. Second, the duration of the FEP prodrome was ison between the psychotic and the manic prodromes, longer than the FEM prodrome, although in FEM pa- attenuated psychotic symptoms12 and unusual subsyn- tients, the prodrome was long enough to enable an early dromal ideas11 were the symptoms more frequently intervention. Third, the risk factors that clearly differenti- associated with the prodromal phase to a FEP, whilst ate FEM from FEP patients were the higher prevalence of subsyndromal manic symptoms were more frequently OC and difficulties in writing and reading during child- associated with the manic prodrome.11,12 hood in FEP patients. Finally, FEM and FEP patients Even though prodromal symptoms were differenti- shared a number of vulnerability factors, but a clear im- ated in the two groups depending on their nature, it was pairment in premorbid adjustment was more character- not rare to find that a small percentage of FEP patients istic of FEP patients. reported subsyndromal manic symptoms. This could due 46 |    VERDOLINI et al. F I G U R E 1 Probabilities of a gradual versus rapid onset pattern of prodromal symptoms to the heterogeneity that characterizes FEMs and FEPs at As for Increased energy, it was one of the most frequently their onset and to the dimensional nature of their clini- described prodromal symptoms in FEM.7,11 Specifically, cal presentation that sometimes does not match perfectly half of the patients reported having experienced Increased with dichotomous diagnostic entities. Furthermore, the energy in a study evaluating the manic prodrome,6 sug- most frequent symptoms reported by FEP patients that gesting that this symptom, and other subthreshold manic felt within the Mania Index were generally symptoms that symptoms, might serve as specific markers of emerging were shared by other Indexes, such as lack of concentra- bipolarity.6 Furthermore, it was significantly more com- tion (Mania or Depression Index) or difficulty thinking or mon in patients with later psychotic mania than in pa- communicating clearly (Psychosis, Mania and Depressive tients not presenting psychotic symptoms during their Index Symptoms). Nonetheless, only a minority of FEP FEM, thus representing an early predictor of severity.6 patients reported symptoms included in the Mania Index. Finally, Increased energy, and other prodromal subthresh- When we assessed the prodromal symptoms in a pre- old manic symptoms, showed a more rapid onset than dictive model, Social isolation was the symptom most other prodromal symptoms although their duration was associated with the prodromal stage of a FEP, whilst long enough to allow preventive strategies, such as clini- Increased energy or goal-­directed activity was more associ- cal high-­risk programs for individuals with a first-­degree ated with the FEM prodrome. Social isolation is one of the relative suffering from BD.11 most prevalent prodromal symptoms of a FEP found in OC and difficulties in writing and reading during literature.8,43,44 It was considered an essential component childhood were the only risk factors that differentiated of the initial prodrome in SCZ and preceded the onset FEP from FEM patients. OC have been identified as a risk of psychosis by 2–­4 years.45 However, Jackson and col- factor for psychosis, representing a marker of increased leagues argued that it could be a sensitive but poorly spe- severity of the clinical presentation16,46 and further out- cific prodrome for SCZ.8 Nevertheless, Social Isolation was comes.47 Similarly, low performance in spelling, reading considered, together with cognitive deficits, affective dis- skills and comprehension in childhood was associated turbances and school failure, one of the four domains of with psychotic experiences in early adolescence.16,48 As the vulnerability core for SCZ, regardless of the severity of a result, our findings support the neurodevelopmental emerging positive symptoms.43 Moreover, Social isolation hypothesis of SCZ, in which pre/perinatal brain damage in adolescence was reported in one out of three patients underlies the later emergence of psychosis.49,50 Similarly, that later developed a FEP and was found to differentiate a clear marker of vulnerability was the impairment in pre- patients hospitalized for psychosis from those hospitalized morbid adjustment. FEM patients showed better premor- for other reasons.44 Furthermore, it presented a predictive bid adjustment than patients developing a FEP in previous role in the following social development, since the level of studies,51,52 with important implications in longitudinal social abilities reached during the prodromal phase set the outcomes.53,54 Consistently, while FEM patients presented upper limit on the social development reached along the an average minimal functional impairment, FEP patients course of illness.43,45 Consequently, Social isolation might reported worse psychosocial functioning as well as higher be addressed in early intervention.43 clinical severity at the moment of evaluation.55 VERDOLINI et al.    | 47 Of note, no differences emerged in terms of both life- without a genetic liability.13,42 Finally, the presence of a time traumatic experiences and childhood abuse as well control group might have allowed an evaluation of the as cannabis and alcohol consumption since high rates specificity of the prodromal symptoms and other risk fac- were reported in both groups. Trauma and drug abuse tors. However, in comparing FEM and FEP patients, we have been previously reported as intertwined risk factors identified which prodromal symptoms were more spe- and early markers of the vulnerability of affective and cific for each group. Despite these limitations, the pres- non-­affective psychoses.56,57 In consideration of the high ent study contains a quite large sample size. Moreover, rates reported in the present study, they represent univer- it is the first study of its kind to assess the prodromes of sal or transdiagnostic targets of primary preventive strat- late adolescence and adult-­onset FEP or FEM patients. A egies. In addition, specific prodromal symptoms such as core strength of the project is the use of a comprehensive Social isolation or Increased energy or goal-­directed activity and exhaustive assessment that goes beyond the standard should be firstly recognized by psychiatrists but also by clinical practice, allowing a complete phenotypic char- general practitioners, families and teachers as warning acterization of the patients recruited in the study. As the signs that signal a need to provide primary preventive ProPreF project is longitudinal by nature, assessing the strategies. In terms of secondary prevention health, the predictive role of prodromes on the mid-­term clinical out- findings of the present study suggest clinical potential to comes is possible once the programmed follow-­up study shape early interventions addressing specific differential is complete. characteristics of FEP and FEM patients. Since FEP pa- In conclusion, both the psychotic and manic prodrome tients presented worse premorbid adjustment and current may contribute in the identification of patients with a psychosocial functioning, functional remediation could higher risk of developing their first episode of disease. be a recommended treatment approach. Conversely, FEM The specific prodromal symptoms together with risk fac- patients, who reported a slighter clinical and functional tors and markers of vulnerability identified in the present impairment than FEP, might benefit from potentiation study might help develop targeted early treatment strat- strategies. Both groups of patients should receive at least egies on the basis of the individual characteristics of the psychoeducation. Finally, family intervention aimed at patients and of the prodromes they experienced. providing psychoeducational advice and information on prodromic symptoms, risk factors and markers of vulner- CONFLICT OF INTEREST abilities in families with a higher genetic load should be NV has received financial support for CME activities and guaranteed. travel funds from the following entities (unrelated to the The present study has limitations. First, the group of present work): Angelini, Janssen, Lundbeck, Otsuka. MG FEP patients was smaller, which might have influenced has received grants and served as consultant or advisor for the assessment of differences between groups. As a result, Ferrer, Lundbeck, and Janssen-­Cilag. MSV has received the present study should be considered as exploratory and financial support for CME activities and travel funds from needs replication in further studies with bigger sample Janssen-­Cilag and Lundbeck, and reports no financial sizes. Second, to assess prodromal symptoms, we used or other relationship relevant to the subject of this arti- the BPSS-­R scale, which was developed to assess prodro- cle. JARQ was on the speakers’ bureau and/or acted as mal symptoms in BD and major depressive disorder.11 consultant for Eli-­Lilly, Janssen-­Cilag, Novartis, Shire, Nonetheless, the development of the BPSS-­R was guided Takeda, Bial, Shionogui, Lundbeck, Almirall, Braingaze, by a review of existing literature on BD, but also on the Sincrolab, Medice and Rubió, Raffo in the last 5 years. He basis of interviews for the assessment of the psychotic also received travel awards (air tickets + hotel) for taking prodrome and inputs from experts in the areas of the SCZ part in psychiatric meetings from Janssen-­Cilag, Rubió, prodrome. Moreover, Correll and colleagues11 stated that Shire, Takeda, Shionogui, Bial, Medice and Eli-­Lilly. The a wide variation in symptomatology was present in their Department of Psychiatry chaired by him received unre- study due to the different methodologies used to ascertain stricted educational and research support from the fol- pre-­illness symptoms. Consequently, we used the BPSS-­R lowing companies in the last 5 years: Eli-­Lilly, Lundbeck, to assess both FEM and FEP patients to limit this bias. In Janssen-­ Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, addition, the retrospective assessment of prodromes with Psious and Rubió. AMA has received funding for research possible recall bias should be acknowledged. Even though projects and/or honoraria as a consultant or speaker for the previous studies assessed individuals at risk for develop- following companies and institutions (work unrelated to ing a FEP or a FEM to evaluate their prodromes prospec- the topic of this manuscript): Otsuka, Pfizer, AstraZeneca, tively, only individuals with higher genetic risk, that is Bristol-­Myers Squibb, Lundbeck, the Spanish Ministry those with family history for BD and SCZ were included, of Economy and Competitiveness and Instituto de thus not assessing prodromal symptoms of those patients Salud Carlos III. MB has been a consultant for, received 48 |    VERDOLINI et al. grant/ research support and honoraria from, and been Maria Florencia Forte https://orcid. on the speakers/advisory board of ABBiotics, Adamed, org/0000-0001-5930-5501 Angelini, Casen Recordati, Janssen-­Cilag, Menarini, Rovi Estela Salagre https://orcid.org/0000-0001-6352-5179 and Takeda. EV has received grants and served as con- Alberto Aedo https://orcid.org/0000-0003-0986-8773 sultant, advisor or CME speaker for the following enti- Pilar Salgado-­Pineda https://orcid. ties (unrelated to the present work): AB-­Biotics, Abbott, org/0000-0001-7720-0885 Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Vanessa Sánchez Gistau https://orcid. Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi-­ org/0000-0002-8635-7144 Aventis and Takeda. IP has received CME-­related hono- Edith Pomarol-­Clotet https://orcid. raria or consulting fees from ADAMED, Janssen-­Cilag org/0000-0002-8159-8563 and Lundbeck. The rest of authors report no biomedical Josep Antoni Ramos-­Quiroga https://orcid. financial interests or potential conflicts of interest related org/0000-0003-1622-0350 to the present article. Clemente Garcia-­Rizo https://orcid. org/0000-0002-4855-1608 ACKNOWLEDGEMENTS Juan Undurraga https://orcid.org/0000-0001-6958-2369 This work was supported by The Secretaria d’Universitats i María Reinares https://orcid.org/0000-0001-8859-4453 Recerca del Departament d’Economia i Coneixement (2017 Anabel Martinez Aran https://orcid. SGR 1365; 2017-­SGR-­1271); the Centro de Investigación org/0000-0002-0623-6263 Biomédica en Red de Salud Mental-­CIBERSAM; the Eduard Vieta https://orcid.org/0000-0002-0548-0053 Centres de Recerca de Catalunya-­CERCA Programme; Isabella Pacchiarotti https://orcid. the Spanish Ministry of Science, Innovation and org/0000-0002-7822-0367 Universities (CPII16/00018 to EPC, CM17/00102 to MG, Silvia Amoretti https://orcid.org/0000-0001-6017-2734 CM19/00123 to ES, CD20/00177 to SA, PI12/0091 to EV and JU, PI15/00283 to EV, PI18/00805 to EV, PI18/01001 REFERENCES to IP); the ‘Pla estrategic de Recerca i Innovacio en Salut 1. Arango C, Díaz-­Caneja CM, McGorry PD, et al. Preventive 2016–­2020’ (SLT006/17/00357 to EV, SLT006/17/00345 strategies for mental health. Lancet Psychiatry. to MB); the Biomedicine international training research 2018;5:591-­604. 2. Vieta E, Salagre E, Grande I, et al. Early intervention in bipolar programme for excellent clinician-­scientists-­BITRECS disorder. Am J Psychiatry. 2018;175:411-­426. project (Marie-­Curie grant No 754550 and ‘La Caixa’ 3. Barajas A, Pelaez T, González O, et al. Predictive capacity of Foundation LCF/PR/GN18/50310006 to NV); the ANID-­ prodromal symptoms in first-­episode psychosis of recent onset. PIA-­ACT192064, ANID-­FONDECYT 1180358, 120060 to Early Interv Psychiatry. 2019;13(3):414-­424. 10.1111/eip.12498 JU and the Agency for Management of University and 4. Fusar-­Poli P, Cappucciati M, Rutigliano G, et al. Diagnostic Research Grants-­AGAUR (Beatriu de Pinós grant to MR). stability of ICD/DSM first episode psychosis diagnoses: meta-­ We thank Dr. Derek Clougher for the English revision. analysis. Schizophr Bull. 2016;42:1395-­1406. 5. Joa I, Gisselgård J, Brønnick K, McGlashan T, Johannessen JO. Primary prevention of psychosis through interventions in the PEER REVIEW symptomatic prodromal phase, a pragmatic Norwegian ultra The peer review history for this article is available at high risk study. BMC Psychiatry. 2015;15(1):1-­9. doi:10.1186/ https://publo​ns.com/publo​n/10.1111/acps.13415. s1288​8-­015-­0470-­5 6. Correll CU, Hauser M, Penzner JB, et al. Type and duration of DATA AVAILABILITY STATEMENT subsyndromal symptoms in youth with bipolar I disorder prior The data that support the findings of this study are avail- to their first manic episode. Bipolar Disord. 2014;16:478-­492. able on request from the corresponding authors. 7. Conus P, Ward J, Lucas N, et al. Characterisation of the pro- drome to a first episode of psychotic mania: Results of a retro- spective study. J Affect Disord. 2010;124:341-­345. ORCID 8. Jackson HJ, McGorry PD, Dudgeon P. Prodromal symptoms of Norma Verdolini https://orcid. schizophrenia in first-­episode psychosis: Prevalence and speci- org/0000-0001-9488-2881 ficity. Compr Psychiatry. 1995;36:241-­250. Marina Garriga https://orcid.org/0000-0001-7312-4969 9. Addington J, Liu LU, Buchy L, et al. North American Prodrome Maria Sagué-­Vilavella https://orcid. Longitudinal Study (NAPLS 2): the prodromal symptoms. J org/0000-0002-8037-7937 Nerv Ment Dis. 2015;203:328-­335. Santiago Madero https://orcid.org/0000-0002-1123-4211 10. Zhang TH, Xu LH, Tang YY, et al. Prediction of psychosis in prodrome: development and validation of a simple, personal- Roberto Palacios-­Garrán https://orcid. ized risk calculator. Psychol Med. 2019;49:1990-­1998. org/0000-0002-9047-3738 VERDOLINI et al.    | 49 11. Correll CU, Penzner JB, Frederickson AM, et al. Differentiation 29. Hayasaka YU, Purgato M, Magni LR, et al. Dose equivalents of in the preonset phases of schizophrenia and mood disorders: antidepressants: evidence-­based recommendations from ran- evidence in support of a bipolar mania prodrome. Schizophr domized controlled trials. J Affect Disord. 2015;180:179-­184. Bull. 2007;33:703-­714. 30. https://clinc​alc.com/Benzo​diaze​pine/ 12. Kafali HY, Bildik T, Bora E, Yuncu Z, Erermis HS. Distinguishing 31. Birchwood M, Smith J, Drury V, Healy J, Macmillan F, prodromal stage of bipolar disorder and early onset schizophre- Slade M. A self-­report Insight Scale for psychosis: reliabil- nia spectrum disorders during adolescence. Psychiatry Res. ity, validity and sensitivity to change. Acta Psychiatr Scand. 2019;275:315-­325. 1994;89:62-­67. 13. Faedda GL, Baldessarini RJ, Marangoni C, et al. An International 32. Conus P, Ward J, Hallam KT, et al. The proximal prodrome to Society of Bipolar Disorders task force report: precursors and first episode mania a new target for early intervention. Bipolar prodromes of bipolar disorder. Bipolar Disord. 2019;21:720-­740. Disord. 2008;10:555-­565. 14. Cannon TD, Mednick SA, Parnas J. Genetic and perinatal deter- 33. Lewis SW, Owen MJMR. Obstetric complications and schizo- minants of structural brain deficits in schizophrenia. Arch Gen phrenia: methodology and mechanisms. In: Schultz SCTC, ed. Psychiatry. 1989;46:883-­889. Schizophrenia. Oxford University Press; 1989:56-­68. 15. Cuesta MJ, Sánchez-­Torres AM, Cabrera B, et al. Premorbid 34. Foa EB, McLean CP, Zang Y, et al. Psychometric properties of adjustment and clinical correlates of cognitive impairment the posttraumatic stress disorder symptom scale interview for in first-­episode psychosis: the PEPsCog Study. Schizophr Res. DSM-­5 (PSSI-­5). Psychol Assess. 2016;28:1159-­1165. 2015;164:65-­73. 35. Hernandez A, Gallardo-­Pujol D, Pereda N, et al. Initial vali- 16. Arango C, Fraguas D, Parellada M. Differential neurodevel- dation of the spanish childhood trauma questionnaire-­short opmental trajectories in patients with early-­onset bipolar form: factor structure, reliability and association with parent- and schizophrenia disorders. Schizophr Bull. 2014;40(Suppl ing. J Interpers Violence. 2013;28:1498-­1518. 2):S138-­S146. doi:10.1093/schbu​l/sbt198 36. Salehi B, Chiegan PY, Rafeei M, Mostajeran M. The relationship 17. Bioque M, Mas S, Costanzo MC, et al. Gene-­environment in- between child anxiety related disorders and primary nocturnal teraction between an endocannabinoid system genetic poly- enuresis. Iran J Psychiatry Behav Sci. 2016;10:1-­4. doi:10.17795/​ morphism and cannabis use in first episode of psychosis. Eur ijpbs​-­4462 Neuropsychopharmacol. 2019;29:786-­794. 37. Ward MF, Wender PH, Reimherr FW. The Wender Utah rat- 18. Salagre E, Arango C, Artigas F, et al. CIBERSAM: ten years of ing scale: an aid in the retrospective diagnosis of childhood collaborative translational research in mental disorders. Rev attention deficit hyperactivity disorder. Am J Psychiatry. Psiquiatr Salud Ment. 2019;12:1-­8. 1993;150:885-­890. 19. First MB, Gibbon M, Spitzer RL, Williams JB, Benjamin 38. Patton JH, Stanford MS, Barratt ES. Factor structure of the bar- EJ. Structured Clinical Interview for DSM-­IV Axis II ratt impulsiveness scale. J Clin Psychol. 1995;51:768-­774. personality disorders (SCID-­II). American Psychiatric 39. Cannon-­Spoor HE, Potkin SG, Jed WR. Measurement of pre- Association; 1997. morbid adjustment in chronic schizophrenia. Schizophr Bull. 20. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured 1982;8:470-­480. Clinical Interview for DSM-­IV Axis I Disorders, Clinician 40. Zeschel E, Bingmann T, Bechdolf A, et al. Temperament and Version (SCID-­CV). American Psychiatric Press Inc; 1996. prodromal symptoms prior to first manic/hypomanic episodes: 21. American Psychiatric Association. Diagnostic and statistical results from a pilot study. J Affect Disord. 2015;173:39-­44. manual of mental disorders, 5th edn. American Psychiatric 41. Andrade-­González N, Álvarez-­Cadenas L, Saiz-­Ruiz J, Lahera Association (2013) Diagnostic and statistical manual of mental G. Initial and relapse prodromes in adult patients with epi- disorders. 5th ed. American Psychiatric Association; 2013. sodes of bipolar disorder: a systematic review. Eur Psychiatry. 22. Hollingshead AB, Redlich FC. Social class and mental illness: a 2020;63(1). doi:10.1192/j.eurpsy.2019.18 community study. Am J Public Health. 2007;97:1756-­1757. 42. Yung AR, McGorry PO. The prodromal phase of first-­episode 23. Kay SR, Fiszbein A, Opler LA. The positive and negative psychosis: past and current conceptualizations. Schizophr Bull. syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1996;22:353-­370. 1987;13:261-­276. 43. Cornblatt BA, Lencz T, Smith CW, Correll CU, Auther AM, 24. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale Nakayama E. The schizophrenia prodrome revisited: a neuro- for mania: reliability, validity and sensitivity. Br J Psychiatry. developmental perspective. In: Schizophrenia Bulletin. DHHS 1978;133:429-­435. Public Health Service. 2003;633-­651. 25. Montgomery SA, Asberg M. A new depression scale designed to 44. Mäki P, Koskela S, Murray GK, et al. Difficulty in making con- be sensitive to change. Br J Psychiatry. 1979;134:382-­389. tact with others and social withdrawal as early signs of psycho- 26. Rosa AR, Sánchez-­Moreno J, Martínez-­Aran A, et al. Validity sis in adolescents-­the Northern Finland Birth Cohort 1986. Eur and reliability of the Functioning Assessment Short Test (FAST) Psychiatry. 2014;29:345-­351. in bipolar disorder. Clin Pract Epidemiol Ment Health. 2007;3:5. 45. Häfner H, Löffler W, Maurer K, Hambrecht M, An Der Heiden 27. Leucht S, Crippa A, Siafis S, Patel MX, Orsini N, Davis JM. W. Depression, negative symptoms, social stagnation and so- Dose-­response meta-­analysis of antipsychotic drugs for acute cial decline in the early course of schizophrenia. Acta Psychiatr schizophrenia. Am J Psychiatry. 2020;177:342-­353. Scand. 1999;100:105-­118. 28. Leucht S, Samara M, Heres S, Davis JM. Dose equivalents 46. Mezquida G, Fernandez-­Egea E, Treen D, et al. Obstetric phe- for antipsychotic drugs: the DDD method. Schizophr Bull. notypes in the heterogeneity of schizophrenia. J Nerv Ment Dis. 2016;42:S90-­S94. 2018;206:882-­886. 50 |    VERDOLINI et al. 47. Garcia-­Rizo C, Bitanihirwe BKY. Implications of early life stress 55. Amoretti S, Mezquida G, Rosa AR, et al. The functioning as- on fetal metabolic programming of schizophrenia: A focus on sessment short test (FAST) applied to first-­episode psycho- epiphenomena underlying morbidity and early mortality. Prog sis: psychometric properties and severity thresholds. Eur Neuro-­psychopharmacology Biol Psychiatry. 2020;101:109910. Neuropsychopharmacol. 2021;47:98-­111. doi:10.1016/j.euron​ doi:10.1016/j.pnpbp.2020.109910 euro.2021.02.007 48. Hameed MA, Lewis AJ, Sullivan S, Zammit S. Child literacy 56. Langlois S, Zern A, Kelley ME, Compton MT. Adversity in and psychotic experiences in early adolescence: findings from childhood/adolescence and premorbid tobacco, alcohol, and the ALSPAC study. Schizophr Res. 2013;145:88-­94. cannabis use among first-­episode psychosis patients. Early 49. Davies C, Segre G, Estradé A, et al. Prenatal and perinatal risk Interv Psychiatry. 2020;15(5):1335-­1342. doi:10.1111/eip.13086 and protective factors for psychosis: a systematic review and 57. Tomassi S, Tosato S, Mondelli V, et al. Influence of childhood meta-­analysis. Lancet Psychiatry. 2020;7:399-­410. trauma on diagnosis and substance use in first-­episode psycho- 50. Murray RM, Lewis SW, Lecturer L. Is schizophrenia a neurode- sis. Br J Psychiatry. 2017;211:151-­156. velopmental disorder? Br Med J. 1987;295:681-­682. 51. Salagre E, Grande I, Vieta E, et al. Predictors of bipolar disorder versus schizophrenia diagnosis in a multicenter first psychotic SUPPORTING INFORMATION episode cohort: baseline characterization and a 12-­month Additional supporting information may be found in the follow-­up analysis. J Clin Psychiatry. 2020;81. doi:10.4088/ online version of the article at the publisher’s website. JCP.19m12996 52. McClellan J, Breiger D, McCurry C, Hlastala SA. Premorbid functioning in early-­onset psychotic disorders. J Am Acad How to cite this article: Verdolini N, Borràs R, Child Adolesc Psychiatry. 2003;42:666-­672. 53. Amoretti S, Verdolini N, Mezquida G, et al. Identifying clini- Sparacino G, et al. Prodromal phase: Differences in cal clusters with distinct trajectories in first-­episode psychosis prodromal symptoms, risk factors and markers of through an unsupervised machine learning technique. Eur vulnerability in first episode mania versus first Neuropsychopharmacol. 2021;47:112-­129. doi:10.1016/j.euron​ episode psychosis with onset in late adolescence or euro.2021.01.095 adulthood. Acta Psychiatr Scand. 2022;146:36–­50. 54. Salagre E, Grande I, Solé B, et al. Exploring risk and resilient doi:10.1111/acps.13415 profiles for functional impairment and baseline predictors in a 2-­year follow-­up first-­episode psychosis cohort using latent class growth analysis. J Clin Med. 2020;10:73.