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A 12-month prospective study on the time to hospitalization and clinical management of a cohort of bipolar type I and schizoaffective bipolar patients

Published online by Cambridge University Press:  01 January 2020

Andrea Murru ,
Norma Verdolini ,
Gerard Anmella ,
Isabella Pacchiarotti ,
Ludovic Samalin ,
Alberto Aedo ,
Juan Undurraga ,
José M. Goikolea ,
Benedikt L Amann  and
Andre F. Carvalho
...Show all authors
Andrea Murru
Affiliation:
aBipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
Norma Verdolini
Affiliation:
aBipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain bDivision of Psychiatry, Clinical Psychology and Rehabilitation, University of Perugia, Perugia, Italy cFIDMAG Germanes Hospitalàries Research Foundation, Sant Boi de Llobregat, Barcelona, Catalonia, Spain
Gerard Anmella
Affiliation:
aBipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
Isabella Pacchiarotti
Affiliation:
aBipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
Ludovic Samalin
Affiliation:
dEA 7280, Department of Psychiatry, CHU Clermont-Ferrand, University of Auvergne 58, rue Montalembert, Clermont-Ferrand, 63000, France ePôle de psychiatrie, Fondation FondaMental, Hôpital Albert-Chenevier 40, rue de Mesly, Créteil, 94000, France
Alberto Aedo
Affiliation:
aBipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain fUnidad de Trastorno Afectivo Bipolar, Departamento de Psiquiatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
Juan Undurraga
Affiliation:
gDepartment of Psychiatry, Faculty of Medicine, Clínica Alemana Universidad del Desarrollo, Santiago, Chile hEarly Intervention Program, J. Horwitz Psychiatric Institute, Santiago, Chile
José M. Goikolea
Affiliation:
aBipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
Benedikt L Amann
Affiliation:
iInstitut de Neuropsiquiatria i Addiccions, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Research Unit Centro Fórum, CIBERSAM, Department of Psychiatry, Autonomous University Barcelona, Spain
Andre F. Carvalho
Affiliation:
jDepartment of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada kCentre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
Eduard Vieta*
Affiliation:
aBipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
*
*Corresponding author at: Bipolar Disorders Unit, Institute of Neuroscience, IDIBAPS CIBERSAM Hospital Clínic de Barcelona, c/Villarroel, 170, 12-0, 08036, Barcelona, Spain.

Abstract

Background.

Schizoaffective disorder, bipolar type (SAD) and bipolar disorder I (BD) present a large clinical overlap. In a 1-year follow-up, we aimed to evaluate days to hospitalization (DTH) and predictors of relapse in a SAD-BD cohort of patients.

Methods.

A 1–year, prospective, naturalistic cohort study considering DTH as primary outcome and incidence of direct and indirect measures of psychopathological compensation as secondary outcomes. Kaplan-Meyer survival analysis with Log-rank Mantel-Cox test compared BD/SAD subgroups as to DTH. After bivariate analyses, Cox regression was performed to assess covariates possibly associated with DTH in diagnostic subgroups.

Results.

Of 836 screened patients, 437 were finally included (SAD = 105; BD = 332). Relapse rates in the SAD sample was n = 26 (24.8%) vs. n = 41 (12.3%) in the BD sample (p = 0.002). Mean ± SD DTH were 312.16 ± 10.6 (SAD) vs. 337.62 ± 4.4 (BD) days (p = 0.002). Patients with relapses showed more frequent suicide acts, violent behaviors, and changes in pharmacological treatments (all p < 0.0005) in comparison to patients without relapse. Patients without relapses had significantly higher mean number of treatments at T0 (p = 0.010). Cox regression model relating the association between diagnosis and DTH revealed that BD had higher rates of suicide attempts (HR = 13.0, 95%CI = 4.0–42.0, p < 0.0005), whereas SAD had higher rates of violent behavior during psychotic episodes (HR = 12.0, 95%CI =.3.3-43.5, p > 0.0005).

Conclusions.

SAD patients relapse earlier with higher hospitalization rates and violent behavior during psychotic episodes whereas bipolar patients have more suicide attempts. Psychiatric/psychological follow-up visits may delay hospitalizations by closely monitoring symptoms of self- and hetero-aggression.

Keywords

Bipolar disorderSchizoaffective disorderAggressivenessSuicideLongitudinal study
Type
Original article
Information
European Psychiatry , Volume 61 , September 2019 , pp. 1 - 8
Copyright
Copyright © 2019 European Psychiatric Association

1. Introduction

Bipolar affective (BD) and schizoaffective (SAD) disorders are complex, severe conditions characterized by a high degree of clinical overlap during acute and cross-sectional evaluation, and a chronic, relapsing longitudinal course [Reference American Psychiatric Association1]. Together with schizophrenia, these conditions share high heritability estimates [Reference Nöthen, Nieratschker, Cichon and Rietschel2], substantial overlap with a high genetic correlation [Reference Lee, Ripke, Neale, Faraone, Purcell and Perlis3], and high relative risks of developing one of these conditions among relatives of both purely affective and psychotic patients [Reference Lichtenstein, Yip, Björk, Pawitan, Cannon and Sullivan4].

Contrary to BD and schizophrenia, a controversial nosological discussion [Reference Kraepelin5, Reference Kasanin6], criticism over its poor diagnostic reliability [Reference Santelmann, Franklin, Bußhoff and Baethge7] and its clinical heterogeneity [Reference Pagel, Baldessarini, Franklin and Baethge8] have surrounded the SAD diagnosis since its appearance in psychiatric diagnostic classifications.

When studied in clinical settings, SAD has been generally considered with intermediate severity, between BD and schizophrenia [Reference Benabarre, Vieta, Colom, Martínez-Arán, Reinares and Gastó9], and its clinical management has suffered from an overall lack of population-specific research, being mostly grounded on extrapolations from BD or purely psychotic samples [Reference Murru, Hidalgo, Bernardo, Bobes and Saiz-Ruiz10, Reference Murru, Pacchiarotti, Nivoli, Grande, Colom and Vieta11].

Despite an increase in the overall treatment options and optimistic results from randomized controlled trials, more than half of all BD patients relapse within 2 years, with possibility to experience at least 1 additional acute episode during their life time [12–Reference Radua, Grunze and Amann14]. Similar data on SAD are scant, as fewer randomized controlled trials and naturalistic studies have been performed so far [Reference Suppes, Rush, Dennehy, Crismon, Kashner and Toprac15, Reference Kulkarni, Filia, Berk, Filia, Dodd and de Castella16]. An indirect note for high relapse rates anyway is that SAD accounted for up to one-quarter of admissions to acute units in the past [Reference Kent, Fogarty and Yellowlees17] and up to 31.3% in inpatients settings currently [Reference Canuso, Kosik-Gonzalez, Sheehan, Mao and Kalali18]. SAD and BD may seem indistinguishable in acute, cross-sectional clinical presentation. A longitudinal diagnostic evaluation especially aimed at the persistence and overall duration of affective and psychotic symptoms seems of paramount importance to better define the bipolar and schizoaffective populations [Reference Salvatore, Baldessarini, Tohen, Khalsa, Sanchez-Toledo and Zarate19], but, contrary to BD, clinical research on the course of illness of SAD is scant. Luckily, the latest international classification system introduced a more longitudinal evaluation of the time spent with purely psychotic or affective symptoms [Reference Malaspina, Owen, Heckers, Tandon, Bustillo and Schultz20], with an improved reliability in SAD’s diagnostic stability [Reference Freedman, Lewis, Michels, Pine, Schultz and Tamminga21], but with unclear clinical implications.

Consequently, prospective, observational naturalistic studies are warranted and could clarify practical implication in distinguishing SAD bipolar from pure BD populations, and they might help filling the gap between the scant clinical trials and clinical practice in SAD. Comparison with BD would be specially needed to understand to which extent SAD may be reduced to a severe form of BD. For this reason, we decided to follow-up a cohort of patients followed-up in our tertiary care setting.

We hypothesized that relapsing patients would be more frequent among the SAD population, and that SAD patients would show a more severe clinical course, and a decreased tendency to psychopathological compensation. For this reason, we compared the clinical course of a cohort of BD and SAD patients followed-up during one year, considering time to hospitalization as a main outcome. We also considered direct (i.e. following hospitalizations, violent behaviors and suicidal acts), and indirect (i.e. type and number of treatments, and changes in treatments during the follow-up) measures of psychopathological compensation. Finally, we also evaluated possible hazards ratio associated with predictor variables in the BD and SAD diagnostic subgroups.

2. Methods

2.1 Study design and participants

In this prospective, naturalistic cohort study we chose a priori one year (referred to as index year, IY) in the life and course of illness of patients enrolled, assessed and treated in the Bipolar Disorders Unit of Barcelona, with the approval of the local ethics committees and in accordance with the ethical principles of the Declaration of Helsinki. [Reference Vieta22].

2.2 Inclusion/Exclusion criteria

Patients were considered for inclusion only if their clinical history was electronically recorded. We considered an index year (IY) starting from the 1st of January 2015, to the 31th December 2015. Inclusion criteria were age older than 18 years, fulfilling diagnosis for BD type I or SAD according to DSM-IV-TR [Reference American Psychiatric Association23] and a follow-up during at least one year. Exclusion criteria were pregnancy or no availability of data during the IY (e.g. patients not resident in the catchment area that had a brief contact with our Unit).

2.3 Assessment

Basic demographic information (age, gender) were extracted from the electronic clinical history of each patient. Direct measures of psychopathological compensation were defined a priori as the presence of a new hospitalization, time to a new hospitalization, total number of hospitalizations, episode type of hospitalization (i.e. purely psychotic, nonpsychotic or psychotic manic, nonpsychotic or psychotic mixed, nonpsychotic or depressed episode), presence and number of suicidal attempts, presence and number of violent behaviors (physical, either towards objects or people), episode type of violent behaviors (psychotic, manic, depressive, mixed), and number of emergency attendances for acute symptoms not resulting in hospitalization, but not for other reasons such as prescription renewal.

Indirect, treatment-related measures of psychopathological compensation were defined a priori as number of “major treatment” (definition see below) at T0 (alone, with benzodiazepines, with other psychotropic medications), number of “major treatments” at T1 (alone, with benzodiazepines, with other psychotropic medications), total changes in “major treatments”, total number and change of antipsychotic medication taken in 365 days, total number and change of mood-stabilizers taken in 365 days, total number and change of antidepressants taken in 365 days, beginning or discontinuation, or both beginning and discontinuation of long-acting treatment, and treatment with electroconvulsive therapy (ECT). “Major treatments” were defined as first- or second-line treatments for at least 1 phase among acute mania, acute depression, long-term treatment for BD and for SAD [24–Reference Goodwin, Haddad, Ferrier, Aronson, Barnes and Cipriani26]. We decided to use the same definition of “major treatment” also for SAD patients due to the lack of clinical guidelines for SAD and the substantial overlap in the type of drugs used [Reference Murru, Pacchiarotti, Nivoli, Grande, Colom and Vieta11, Reference Murru, Hidalgo, Bernardo, Bobes and Saiz-Ruiz27].

2.4 Statistical analyses

Kaplan-Meyer survival analysis with Log-rank Mantel-Cox test was used to compare diagnostic subgroups as to time to hospitalization, using the overall mean time to hospitalization as a threshold for event/censorship. Bivariate analyses were performed with Chi-square tests, independent-samples t-test, or Mann-Whitney U test (according to type of distribution of the variable). Cox regression (proportional hazard analysis) was performed in order to assess covariates possibly associated with time to hospitalization, and including statistically significant variables differentiating the 2 diagnostic subgroups. Statistical analyses were performed using the Statistical Package for Social Sciences (Statistical Package for Social Science-SPSS, 23.0 version for Windows Inc., Chicago, IL, USA). All p values were two-tailed and statistical significance was set at p<0.05.

3. Results

A complete flowchart showing the patients’ selection process from computerized entries (visits) during IY to final sample included is presented in Fig. 1.

Fig. 1. Flowchart of included patients. All electronic visit entries scanned during Index Year were attributed to a pool of patients that underwent screening for inclusion or exclusion from the present study. BD = Bipolar disorder, type I; IY = Index Year; SAD = Schizoaffective disorder, bipolar subtype.

A total of 836 patients were screened for inclusion in the present study, of which 437 were finally included in the present study. Of those, 332 fulfilled a diagnosis for BD type I disorder, 105 for SAD, bipolar subtype. Baseline characteristics (sex and mean age) of the diagnostic subgroups were not statistically different (see Table 1).

Table 1 Baseline demographic characteristics in diagnostic subgroups.

Notes: BD = Bipolar Disorder; SAD = Schizoaffective Disorder; SD = Standard Deviation.

Type of statistical test:

1. = Chi square test;

2. = independent-samples t-test.

3.1 Relapses and time to hospitalization

SAD patients relapsed with hospitalization statistically more frequently than BD patients SAD (n = 26/105, 24.8%) vs. BD (n = 41/332, 12.3%), χ2 = 9.468, p = 0.002). Mean time (±SD) to hospitalization was 312.2 (±10.6) days for SAD and 337.6 (±4.4) days for BD. These differences were statistically significant (Mantel Cox χ2 = 9,421, p = 0.002) (Fig. 2).

Fig. 2. Kaplan–Meier curves for time to hospitalization. BD = Bipolar disorder, type I; SAD = Schizoaffective disorder, bipolar subtype. Relapses: SAD (n = 26/105, 24.8%) vs. BD (n = 41/332, 13.3%), χ2 = 9.468, p = 0.002. Mean time ± SD to hospitalization: SAD = 312.16 ± 10.62 days vs. BD = 337.62 ± 4.43 days, Mantel Cox χ2 = 9,421, p = 0.002.

Note: Hospitalization was decided when an acute exacerbation of manic, psychotic, suicidal symptoms, was present or whereas psychomotor agitation, aggressiveness and/or lack of insight and need for treatment could impair patients’ safety.

When relapsing patients were compared according to diagnostic subgroups, SAD patients showed significantly less (0, [0-0]) depressive episodes without psychotic symptoms than BD patients (0, [0–1], U = 390.000, p = 0.004), less changes in mood-stabilizers (SAD = 0, [0–1], BD = 0, [0–4], U = 281,500, p < 0.0001).

3.2 Direct measures of psychopathological compensation

3.2.1 All patients relapse versus non-relapse

All relapsing patients, both BD and SAD, had more emergency attendances and suffered from more frequent suicidal acts and violent behaviors than those without relapses (all <0.0005). A summary of the differences between patients with or without relapses in direct measures of psychopathological compensation is presented in Table 2.

Table 2 Differences among patients relapsing and not relapsing.

Notes: BD = Bipolar Disorder type I; SAD = Schizoaffective disorder, bipolar type.

Type of statistical test:

1. = Chi square;

2. = independent-samples t-test;

3. = Mann-Whitney.

* Mann-Whitney test was used for non-parametric variables. Means and standard errors are reported in the table for descriptive purpose.

3.2.2 Intra-group differences

3.2.2.1 Patients without relapse

No statistically significant differences in age or gender were found in the relapsing group between BD and SAD patients. Globally, no statistical differences were found between BD and SAD without relapse subgroups in emergency attendances, suicidal or violent acts.

3.2.2.2 Patients with relapse

No statistically significant differences in age or gender were found in the BD and SAD patients with relapse. SAD patients with relapse did not present higher hospitalizations compared to BD patients (1.2 ± 0.5 vs. 1.2 ± 0.4, ns). SAD patients predictably presented psychotic relapses, but BD patients in change presented with significantly more pure manic (0.3 ± 0.5 vs. 0.0 ± 0.2, Mann-Whitney 423.0, p = 0.028) and depressive episodes (0.3 ± 0.5 vs. 0.0 ± 0.0 Mann-Whitney = 390.0, p = 0.004). No significant differences in emergency attendances, suicidal acts and violent behaviors were recorded, but SAD patients committed more violent behaviors exclusively during acute pure psychotic episodes (n = 6, 23.1%), whilst BD patients during purely manic (n = 4, 9.8%) or mixed (n = 2, 4.9%) episodes.

3.3 Indirect measures of psychopathological compensation

Patients without relapse showed a significantly higher mean number of treatments at T0, “major” treatments (p = 0.01), combined with benzodiazepines (p = 0.012) or total (p = 0.028). Total changes, specific changes in antidepressants, antipsychotics and mood-stabilizers were significantly higher in the relapsing group (all p < 0.0005), as well as the total number of antipsychotics used during IY (p < 0.0005). Prevalent use and beginning of treatment with long-acting injectable drugs were significantly higher in relapsing patients (p = 0.005 and p < 0.0005 respectively), as well as treatment with electroconvulsive therapy (ECT, p = 0.012) (Table 3).

Table 3 Differences in indirect (treatment) measures of psychopathological compensation in diagnostic subgroups.

Notes: BD = Bipolar Disorder; BZD = Benzodiazepines; ECT = Electroconvulsive Treatment; IY = Index Year; N = Number; SAD = Schizoaffective Disorder; T0 = Beginning of IY; T1 = Conclusion of IY.

Tests: M–W = Mann-Whitney test; χ2= Chi square test.

* Mann-Whitney test was used for non-parametric variables. Means and standard errors are reported in the table for descriptive purpose.

3.3.1 Intra-group differences

3.3.1.1 Patients with relapse

BD patients with relapse showed significantly more frequent changes in mood-stabilizer medication compared to relapsing SAD patients (0.9 ± 1.2 vs. 0.2 ± 0.4, Mann-Whitney = 355.5, p = 0.008) and an overall significantly higher number of mood-stabilizers used during IY (1.4 ± 0.7 vs. 0.8 ± 0.7, Mann-Whitney = 2.81.5, p < 0.0005).

3.3.1.2 Patients without relapse

At T0, SAD patients without relapse showed significantly higher number of major treatments (2.8 ± 1.2 vs. 2.3 ± 1.0, Mann-Whitney = 13,665.6, p = 0.007), major treatments with benzodiazepines (3.2 ± 1.3 vs. 2.8 ± 1.2, Mann-Whitney = 13.473.0, p = 0.015) and total treatments (3.6 ± 1.6 vs. 2.9 ± 1.3, Mann-Whitney 14.009-5, p = 0.002). At the end of IY, SAD patients showed a significant total number of treatments (3.5 ± 1.4 vs. 3.1 ± 1.4, Mann-Whitney = 13.248.0, p = 0.033). No significant differences were found in total and specific changes in antidepressants, antipsychotics and mood-stabilizers, but SAD patients without relapse showed a significant higher number of antipsychotics tried during IY (1.7 ± 0.9 vs. 1.0 ± 0.8, Mann-Whitney 16609.5, p < 0.0005) and lower number of mood-stabilizers tried during IY (0.9 ± 0.7 vs. 1.2 vs. 0.6, Mann-Whitney = 8132.0, p < 0.0005). Also, SAD without relapse were more frequently on long-acting injectable treatment than BD patients without relapse (15, 19.0% vs. 12, 4.1%, X2 = 20.291, p < 0.0005)

3.4 Prediction of hospitalization by diagnostic subgroups

We performed two Cox-Regression analyses on diagnostic subgroups in order to detect possible factors contributing to risk of hospitalization.

3.4.1 Bipolar subgroup

Cox-Regression analysis for BD subgroup was overall statistical significant (χ2 = 494.819, df = 10, p < 0.0005). Variables with a single significant contribution were: suicide attempts (HR = 13.0, 95%CI = 4.0–42.0, p < 0.0005), purely manic first relapse in IY (HR = 12.5, 95%CI = 5.7–23.0, p < 0.0005), purely depressed first relapse in IY (HR = 9.8, 95%CI = 4.2–23.0, p < 0.0005), violent behavior during mixed phase (HR = 9.1, 95%CI = 1.8–45.4, p = 0.007), violent behavior during manic phase (HR = 6.8, 95%CI = 2.3–20.8, p = 0.001), total number of antipsychotics tried in IY (HR = 1.5, 95%CI = 1.1–2.2, p = 0.025), total number of emergency attendances (HR = 1.5, 95%CI = 1.2–1.8, p = 0.050), and changes in antipsychotics (HR = 1.3, 95%CI = 1.1–1.6, p = 0.003).

3.4.2 Schizoaffective subgroup

Cox-Regression analysis for SAD subgroup was overall statistical significant (χ2 = 357.845, df = 9, p < 0.0005). Variables with a single significant contribution were: violent behavior during purely psychotic phase (HR = 12.1, 95%CI = 3.3–43.5, p > 0.0005), purely psychotic first relapse in IY (HR = 9.9, 95%CI = 4.0–24.7, p < 0.0005), suicide attempts (HR = 9.1, 95%CI = 2.7–30.7, p < 0.0005), changes in antipsychotics (HR = 1.6, 95%CI = 1.3–1.9, p < 0.0005), total number of emergency attendances (HR = 1.5, 95%CI = 1.2–1.9, p < 0.0005), and total drugs at T0 (HR = 1.3, 95%CI = 1.1–1.5).

4. Discussion

Our prospective naturalistic 1-year follow-up study comparing BD with SAD patients revealed some clinical relevant results. First of all, the hospitalization rate during the one-year follow-up was significantly higher in the SAD sample than in the BD subgroup (24.8% vs. 12.3%). Secondly, when relapsing, the diagnostic subgroups did not present differences in overall number of hospitalizations, yet SAD almost invariantly relapsed into psychotic episodes, while BD patients more frequently into pure mania and depression. Overall, SAD and BD subgroups seem to confirm a differential severity in the course of illness measured as time to hospitalization and acute clinical exacerbation, with SAD being the more severe condition. Yet, these diagnostic labels may be not informative on the actual prognosis of the patients. Thirdly and as expected, all patients with a relapse presented statistically more frequently signs of psychopathological unbalance such as suicide attempts, emergency attendances, and violent behaviors. Subpopulations at risk for worst outcomes should be defined in order to improve the prognostic value of a diagnosis. For instance, a careful evaluation of symptom dimensions would allow for better defining, addressing and managing critical treatment targets [Reference Vieta28, Reference Vieta29].

Furthermore, hetero-aggressiveness with violent behaviors played a major role in predicting hospitalization in our sample, as SAD patients presenting violent behaviors during a purely psychotic episode had a 12-fold increased risk to hospitalization, while BD present a 9-fold increased risk when presenting violent behaviors during mixed phase and 6-fold increased risk when presenting violent behaviors during manic phase. According to national surveys, the prevalence of violence in the general population is about 2% while it ranges from 0.8 to 34.7% in samples including individuals with mental illness, depending on the psychiatric disorder considered [Reference Corrigan and Watson30]. The relevance of aggressiveness as a cross-diagnostic negative prognostic factor finds ground on its frequent association with BD, especially in acute mixed phases [Reference Verdolini, Perugi, Samalin, Murru, Angst and Azorin31], and it seems an even more important factor in SAD populations [Reference Huber, Smieskova, Schroeder, Studerus, Harrisberger and Aston32]. Common shared genetic liability could be hypothesized, as, for instance, neuronal splicing regulator RBFOX1 has been found associated to BD [Reference Noor, Lionel, Cohen-Woods, Moghimi, Rucker and Fennell33] as well as schizophrenia [Reference Li, Yoshikawa, Brennan, Ramsey and Meltzer34], and, more recently, to violent aggressive behavior [Reference Fernàndez-Castillo, Gan, van Donkelaar and Vaht35]. On the other hand, it is possible that biological bases underpinning aggressive behavior only partially relate with a clinical syndrome, e.g. psychosis. A recent study outlined that lower levels of morning cortisol and cortisol variability significantly related to both aggression and psychosis, but independently, and no correlation with age, gender or psychosis severity or duration [Reference Das, Sengupta, Pathak, Sah, Mehta and Avinash36]. In this sense, categorical diagnoses predictably show a limited predictive validity, and the clinical assessment of patients could benefit from a different type of stratification considering, for instance, high levels of impulsivity, hostility, positive symptoms and substance use, low level of insight and low social functioning [Reference Moulin, Palix, Golay, Dumais, Gholamrezaee and Azzola37].

In our study, self-aggressiveness also plays a major role in predicting hospitalization. SAD patients presented in our sample a 9-fold increased risk for hospitalization while BD patients presented a 13-fold increased risk when presenting suicidal acts. Conceptualization of suicide and aggressive/violent acts tends to a semantic similarity, framing these behaviors as self- and hetero- aggressiveness. A partial overlap in clinical presentation, with a possible predictive role of hetero-aggressiveness for suicidality, is possible [Reference Oquendo, Galfalvy, Russo, Ellis, Grunebaum and Burke38] and could recognize a shared liability for impulsivity [Reference Jiménez, Arias, Mitjans, Goikolea, Ruíz and Brat39, Reference Mann, Arango, Avenevoli, Brent, Champagne and Clayton40]. Yet, these behaviors could also derive from different symptoms dimensions, as well as genetic or biological mechanisms [Reference Fabbri and Serretti41].

Interestingly, violent behaviors occurred only during acute episodes in our study. This has to be emphasized, and seems reinforced when considering the struggle for symptom control. In fact, relapsing patients presented more frequent changes in overall major treatments. Interestingly, patients not relapsing during IY presented a higher number of treatments at T0. In our regression models, both diagnostic subgroups presented more frequent changes in antipsychotic medications (and total antipsychotics tried in IY in bipolar subsample). Notably, average drug combinations in our study fall far beyond clinical guidelines recommendations [Reference Yatham, Kennedy, Parikh, Schaffer, Bond and Frey42, Reference Verdolini, Hidalgo-Mazzei, Murru, Pacchiarotti and Samalin43]. The high rates of relapses in SAD populations might derive from the severity of the disease or from the lack of efficacy of current treatment options, undetected by pure populations recruited in randomized clinical trials. Also, it is possible that the frequent use of polypharmacy combinations stretching beyond evidence-based practices, produces complex interactions [Reference Procyshyn, Honer, Wu, Ko, McIsaac and Young44, Reference Golden, Goethe and Woolley45]. In the real-world, there is a clinical need for specifically tailored treatment plans, paradoxically and unanimously suggested by the very same guidelines.

On the other hand, past studies agree on the need for proper symptomatic and clinical management for better illness and overall health outcomes [Reference Angst, Sellaro and Angst46], but mortality rates in severe mental illness could derive from iatrogenic effects [Reference Vancampfort, Vansteelandt, Correll, Mitchell and De Herdt47] as well as from an under-prescription for other comorbid medical conditions [Reference Laursen, Mortensen, MacCabe, Cohen and Gasse48, Reference Ayerbe, Forgnone, Foguet-Boreu, González, Addo and Ayis49]. So, caution must be called for the risk of cumulative prescription and subsequent overtreatment [Reference Murru, Colom, Nivoli, Pacchiarotti, Valenti and Vieta24].

When considering the role of aggressiveness in our study, evidence supports a benefit of second-generation antipsychotic medication in its management in psychotic conditions, with no apparent influence of mood-stabilizers or antidepressants [Reference Stahl, Morrissette, Cummings, Azizian, Bader and Broderick50, Reference Fond, Boyer, Gaman, Laouamri, Attiba and Richard51], yet the benefit of beginning or suspending of the latter may clearly relate to acute mood prevention that in our sample invariably associated with such behavior [Reference Samalin, Murru and Vieta52].

Stabilized, SAD patients without relapse presented higher number of tried and actual treatments compared to BD patients without relapse. The use of long-acting injectable antipsychotics failed to ensure a good control of symptomatology in our study, which is in accordance with previous data that reported increased odds for relapse despite of an evidence of their efficacy [Reference Morken, Widen and Grawe53]. This apparent contradiction could result from a selection bias for candidates to these treatments, tolerability issues, or anyway an improvement compared to previous course of illness for these patients. Unluckily, the design of our study did not allow for a throughout analysis of this aspect.

Lastly, we found in our study that frequent emergency attendances constitute a clear signal of increased risk for acute relapse. It is possible that psychosocial interventions aimed at an improving insight and awareness in patients and caregivers alike contribute to this effect [Reference Reinares, Sánchez-Moreno and Fountoulakis54, Reference Popovic, Reinares, Scott, Nivoli, Murru and Pacchiarotti55]. Hereby, patients might benefit from further psychosocial/psychotherapeutic interventions aimed at encompassing cognitive deficits in a preventive way [Reference Madre, Canales-Rodríguez, Ortiz-Gil, Murru, Torrent and Bramon56], impaired functioning [Reference Torrent, del M Bonnin, Martínez-Arán and Valle57], or untreated adverse events [Reference Novo, Landin-Romero, Radua, Vicens, Fernandez and Garcia58].

Some limitations of our work have to be taken into consideration. In order to minimize selection bias, the choice of the Index Year was performed a priori. Yet, a selection bias may not be excluded. Another limitation is the choice of considering a change of treatment as a measure of psychopathological compensation, as to say of efficacy, whilst it may also represent a measure of tolerability of the treatments prescribed. However, this possible bias was true for both BD and SAD diagnostic subgroups. Average doses of drugs used would have been ideal, yet the overall sample size did not allow for a dose-specific analysis. Recollection of other variables would have been also informative (e.g., number and type of previous episodes), but data were not collected in the clinical corresponding histories.

Compared to BD, SAD patients present a more severe course of illness measured as time to hospitalization. Violent acts towards selves (BD) or others (SAD) strongly predict a worse course of illness and may represent strategic therapeutic targets. Interventions aimed at improving patients’ and caregivers’ awareness on the disorder should be systematically implemented, as increased emergency attendances signal at-risk situations and would possibly allow for recurrence prevention. Increased emergency attendances should call for optimized combination treatments, warranting an improved control over symptoms, thus delaying hospitalizations.

4.1 Sources of financial and material support

  1. - B.L. Amann receives a grant (PI/15/02242) from the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación, Plan Nacional 2008–2011 and 2013–2016, a NARSARD Independent Investigator Grant from the Brain & Behavior Research Foundation (24397) with and a grant within the “Pla estratègic de recerca i innovació en salut” (PERIS; G60072253) by the Catalan Government.

  2. - E. Vieta thanks the support of the Spanish Ministry of Economy and Competitiveness integrated into the Plan Nacional de I + D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental); the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014_SGR_398) and the CERCA Programme / Generalitat de Catalunya.

  3. - The other authors declare no role for funding sources.

Role of the sponsor

No source of financial and material support had any role in this study.

Declaration of Competing Interest

  1. - Andrea Murru, has received CME-related honoraria from Asofarma, Otsuka, Pfizer.

  2. - Ludovic Samalin has received grants, honoraria, or consulting fees from AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, Otsuka, Sanofi-Aventis, and Takeda.

  3. - Eduard Vieta grants from AB-Biotics, personal fees from Allergan, grants from Dainippon Sumitomo Pharma, grants and personal fees from Ferrer, personal fees from Geodon Richter, grants and personal fees from Janssen, grants and personal fees from Lundbeck, personal fees from Otsuka, personal fees from Sunovion, personal fees from Takeda, outside the submitted work.

  4. - Norma Verdolini, Gerard Anmella, Isabella Pacchiarotti, Juan Undurraga, José M. Goikolea, Benedikt L. Amann, Andre F. Carvalho declare no conflict of interest.

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Figure 0

Fig. 1. Flowchart of included patients. All electronic visit entries scanned during Index Year were attributed to a pool of patients that underwent screening for inclusion or exclusion from the present study. BD = Bipolar disorder, type I; IY = Index Year; SAD = Schizoaffective disorder, bipolar subtype.

Figure 1

Table 1 Baseline demographic characteristics in diagnostic subgroups.

Figure 2

Fig. 2. Kaplan–Meier curves for time to hospitalization. BD = Bipolar disorder, type I; SAD = Schizoaffective disorder, bipolar subtype. Relapses: SAD (n = 26/105, 24.8%) vs. BD (n = 41/332, 13.3%), χ2 = 9.468, p = 0.002. Mean time ± SD to hospitalization: SAD = 312.16 ± 10.62 days vs. BD = 337.62 ± 4.43 days, Mantel Cox χ2 = 9,421, p = 0.002.Note: Hospitalization was decided when an acute exacerbation of manic, psychotic, suicidal symptoms, was present or whereas psychomotor agitation, aggressiveness and/or lack of insight and need for treatment could impair patients’ safety.

Figure 3

Table 2 Differences among patients relapsing and not relapsing.

Figure 4

Table 3 Differences in indirect (treatment) measures of psychopathological compensation in diagnostic subgroups.

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