How effective are mood stabilizers in treating bipolar patients comorbid with cPTSD? Results from an observational study

Abstract

Background: Multiple traumatic experiences, particularly in childhood, may predict and be a risk factor for the development of complex post-traumatic stress disorder (cPTSD). Unfortunately, individuals with bipolar disorder (BP) are more likely to have suffered traumatic events than the general population. Consequently, cPTSD could be comorbid with BD, and this may negatively affect psychopathological manifestations. To date, no one has explored whether such comorbidity also affects the response to treatment with mood stabilizers in BD patients.
Results: Here, a cross-sectional study was carried out by comparing the response to treatment, measured by the Alda scale, in a cohort of 344 patients diagnosed with BD type I and II, screened for the presence (or absence) of cPTSD using the International Trauma Questionnaire. The main result that emerged from the present study is the poorer response to mood stabilizers in BD patients with comorbid cPTSD compared with BD patients without cPTSD.
Conclusions: The results collected suggest the need for an add-on therapy focused on trauma in BD patients. This could represent an area of future interest in clinical research, capable of leading to more precise and quicker diagnoses as well as suggesting better tailored and more effective treatments.

Full text

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How effective are mood stabilizers in treating bipolar patients
comorbid with cPTSD? Results from an observational study
Anna Maria Iazzolino
University of Catanzaro Magna Graecia
Marta Valenza
SAPIENZA University of Rome
Martina D’Angelo
University of Catanzaro Magna Graecia
Grazia Longobardi
University of Catanzaro Magna Graecia
Valeria Stefano
University of Catanzaro Magna Graecia
Steardo Luca
Università Giustino Fortunato
Caterina Scuderi
SAPIENZA University of Rome
Luca Steardo jr (  steardo@unicz.it )
University of Catanzaro Magna Graecia
Research Article
Keywords: Bipolar Disorder, Complex Posttraumatic Stress Disorder, Clinical correlates, Lithium, Treatment
Posted Date: December 21st, 2023
DOI: https://doi.org/10.21203/rs.3.rs-3776264/v1
License:   This work is licensed under a Creative Commons Attribution 4.0 International License.  Read Full License
Additional Declarations: No competing interests reported.

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Abstract
Background: Multiple traumatic experiences, particularly in childhood, may predict and be a risk factor for the development of complex post-
traumatic stress disorder (cPTSD). Unfortunately, individuals with bipolar disorder (BP) are more likely to have suffered traumatic events
than the general population. Consequently, cPTSD could be comorbid with BD, and this may negatively affect psychopathological
manifestations. To date, no one has explored whether such comorbidity also affects the response to treatment with mood stabilizers in BD
patients.
Results: Here, a cross-sectional study was carried out by comparing the response to treatment, measured by the Alda scale, in a cohort of
344 patients diagnosed with BD type I and II, screened for the presence (or absence) of cPTSD using the International Trauma
Questionnaire. The main result that emerged from the present study is the poorer response to mood stabilizers in BD patients with comorbid
cPTSD compared with BD patients without cPTSD.
Conclusions: The results collected suggest the need for an add-on therapy focused on trauma in BD patients. This could represent an area
of future interest in clinical research, capable of leading to more precise and quicker diagnoses as well as suggesting better tailored and
more effective treatments.
Introduction
In 2018, the 11th Revision of the International Classication of Diseases (ICD-11) formally acknowledged Complex Post-Traumatic Stress
Disorder (cPTSD) as an independent syndrome distinct from PTSD. Both are classied under the main category of "Disorders specically
related to stress" which comprises severe mental disorders that develop following exposure to an event or series of events of an extremely
threatening or horric nature, from which escape is dicult or impossible (e.g., torture, slavery, genocide campaigns, prolonged domestic
violence, repeated childhood sexual or physical abuse) (ICD-11 for Mortality and Morbidity Statistics). In addition to the three main
symptoms of PTSD (reexperience, avoidance, and hypervigilance), cPTSD symptoms includes severe and perduring impairments in three
domains of self-organization (DSO) which are emotional dysregulation, negative self-concept, and interpersonal diculties (Nestgaard &
Schmidt, 2021). The prevalence of the disorder in the general population varies between 1–8%, while in psychiatric institutions it reaches up
to 50% (Maercker et al., 2022), which increases the probability of developing other psychiatric disorders such as anxiety disorders and major
depression (Karatzias et al., 2019; Letica-Crepulja et al., 2020; Murphy et al., 2021), bipolar disorder (BD) and personality disorders (Lewis et
al., 2022) and increases the risk of suicidality (Karatzias et al., 2019). When different mental illnesses co-occur, it is likely that there are
common risk factors contributing to the onset of these conditions. In the case of comorbid cPTSD with BD, the common factor is trauma. It
is known that individuals with BD are more likely than the general population to have experienced traumatic events. Estimates suggest that
up to 82% of them have experienced childhood trauma, and childhood adversity may predict and be a risk factor for the development of
cPTSD (Tian et al., 2022). Cumulative trauma is common in bipolar disorder and has a negative impact on its course (Kira, 2010; Shevlin et
al., 2008), but little is known about its effect on treatment response. Studies in the literature have primarily focused on the impact of
childhood trauma and considered it a potentially important factor in the treatment of mood disorders (Agnew-Blais & Danese, 2016; Cotter
et al., 2015). Several studies have shown an association between childhood trauma and poorer response to pharmacotherapy in
adolescents and adults diagnosed with major depressive disorder (Klein et al.,2009; Shamseddeen et al., 2011; Douglas et al., 2012; Nanni
et al., 2012). However, there are only few studies that have examined a similar association in BD (Etain et al.,2017; Cakir et al., 2016;
Cascino et al., 2021; Benarous et al., 2017; Perugi et al., 2018) although some reports suggest that childhood trauma may attenuate
treatment outcomes in this population. In 2017 Etain and collaborators showed that higher levels of physical abuse were associated with
poorer response to lithium measured with the Alda Scale. Also, patients who had experienced multiple types of childhood trauma (i.e.,
physical, sexual, or emotional abuse) were more likely to have an inadequate response to mood stabilizers than patients who had not been
exposed to traumatic events in childhood (Etain et al., 2017).
Cascino and colleagues (2021) conrmed in a small sample of adult BD patients that a history of childhood abuse inuences clinical
response to lithium, but not to other mood stabilizers. In contrast, comorbid PTSD seems to affect response to treatment to both quetiapine
and lithium in patients with BD (Russell et al., 2023).
This suggests that comorbid PTSD has an impact on the therapeutic management of BD. However, to the best of our knowledge, no study
has yet examined the impact of cPTSD on response to mood stabilizer treatment in adult patients affected by BD. Therefore, the present
paper aims to contribute to ll this gap by studying the response to pharmacological treatment in BD patients with and without cPTSD. To
do so we used the Alda scale, an 11-point rating scale (Grof et al., 2002) adapted to measure the response to mood stabilizers (Garnham et
al., 2007; Steardo et al. 2019). Based on the aforementioned literature, we hypothesized that BD patients with comorbid cPTSD would
respond less well to treatment than patients who had never been exposed to trauma.

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Methods
Study design, recruitment of participant and eligibility criteria
The study here presented is observational and cross-sectional, and the methods used are here reported according to the STROBE checklist
(https://www.equator-network.org/reporting-guidelines/strobe/).
Patients were enrolled by the Unit of Psychiatry of the University of Catanzaro "Magna Graecia". Each participant was adequately informed
about the purpose of the research protocol, the protection of personal data, and the preservation of privacy and anonymity. Participation in
the study was voluntary and required the patient to sign a formal consent form. Three hundred and forty-four patients were included in the
study and followed up as outpatients from February 2021 to August 2023. The inclusion criteria were the following: i) having been
diagnosed BD according to criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), assessed by clinical interviews
and administration of psychometric scales (SCID-5-CV); ii) age between 18 and 75 years; iii) written informed consent to participate in the
study.
Exclusion criteria were the following: i) inability to provide written consent; ii) diagnosis of major neurological and psychiatric diseases
(such as epilepsy, cognitive disabilities, and genetic syndromes with psychiatric manifestations); iii) the presence of any condition that did
not allow to complete the overall assessment, such as language barriers and severe specic cognitive disabilities (e.g. dyslexia).
After recruitment, participants underwent a series of clinical and psychopathological assessments during outpatient clinical visits. Each
enrolled patient underwent a semi-structured clinical interview in order to gather clinical and medical history.
Patients clinical and sociodemographic characteristics, including gender, age at study entry, employment status, educational level, family
history of psychiatric illnesses, type of onset, lifetime number of affective episodes, the pattern of illness course, treatments, suicidal
ideation, and previous psychiatric hospitalizations, were recorded according to an ad-
hoc
schedule. Therefore, each participant underwent
two psychometric assessments, the International Trauma Questionnaire (ITQ) and the Alda Scale.
The ITQ was used to assess the trauma experienced and to diagnose cPTSD according to the ICD-11 guidelines. The questionnaire consists
of eighteen items measuring the main symptoms of PTSD and DSO (Cloitre et al., 2018; Cloitre et al., 2021; Rossi et al., 2022). The items
can be answered on a 5-point Likert scale from 0 (not at all) to 4 (very strongly). The maximum score for PTSD and/or DSO is therefore 24
(range 0–24), while the maximum score for cPTSD is 48 (range 0 to 48). All items can only be considered present if they have a value ≥ 2
on the Likert scale. Diagnosis of cPTSD requires the endorsement of one of two symptoms from each of the three PTSD symptom clusters
(re-experiencing, avoidance, and sense of current threat) and one of two symptoms from each of the three Disturbances in Self-Organization
(DSO) clusters: (1) affective dysregulation, (2) negative self-concept, and (3) disturbances in relationships. Functional impairment is present
when at least one cluster of functional impairment is associated with PTSD symptoms and one with DSO symptoms. In principle, a person
can only receive one of the two diagnoses, namely PTSD or cPTSD.
Response to mood stabilizer treatment was assessed using the mean score of the retrospective criteria for long-term treatment response in
BD (Alda Scale), which consists of two criteria: A) rating of the association between clinical improvement and treatment, and B) rating of
the degree of causal relationship between clinical improvement and prophylactic treatment. The total score was determined by subtracting
the B score from the A score. Subjects were scored on a 0 − 10 scale. A total score ≥ 7 indicates a good response, a score from 4 to 6 a
moderate response, and a score of ≤ 3 a poor response. The Alda scale is a valid measure with an interrater reliability of 0.54–0.75 in
assessing long-term response to treatment (Manchia et al., 2013; Steardo et al., 2019). The study was carried out in accordance with the
latest version of the Declaration of Helsinki and was approved by the Ethics Committee of the Calabria Region (N. 307/2020).
Statistical analysis
Statistical analysis was carried out using the Statistical Package for Social Sciences Version 26 (SPSS, Chicago, Illinois, USA). Descriptive
analyses were carried out to evaluate the distribution of the variables in the whole sample and the normality distribution was assessed
through Shapiro Wilk’s test. Subject were divided into two groups according to the presence/absence of cPTSD. Groups were compared
using the Chi-square or the Student’s
t
test depending on the type of variable. The logistic regression model was used to analyze the
association between the presence of cPTSD and the response to treatment with mood stabilizers. The level of statistical signicance was
set at a value of
p
≤ .05.
Results

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Sociodemographic and clinical description of the sample
Three hundred and forty-four patients met the inclusion criteria and were included in the study. The demographic information shown in
Table1 provides insights into the gender distribution, educational background, marital status, and employment status of the sample. The
prevalence of certain clinical characteristics including age of onset of BD, family history, aggressive behaviors, and psychiatric symptoms
further contributes to the overall prole of this patient cohort. A schematic description of all such features is reported in Table1. In detail,
the most frequent diagnosis was BD of type I (N = 253, 73.5%), compared with BD of type II (N = 91, 26.5%). The mean age was 47 years old
(± 14), and the age at onset of BD was about 26 years (± 9.4). The patients were rather evenly distributed by sex (Female N = 177, 51.5%;
Male N = 167, 48.5%) and marital status (N = 186, 54.1%). A signicant majority of them completed their education (71.5%), but only half of
the cohort were employed (N = 171, 49.7%).
The duration of untreated illness was for approximately 6 years (± 10.3), and the average number of affective episodes was 11.4 (± 9.87).
This included an average of 5.81 (± 5.92) depressive episodes, 4.04 (± 4.41) manic episodes, and 2.65 (± 2.69) hypomanic episodes. Nearly
half of the individuals (49.7%) reported seasonality features. More than half of the cohort of patients presented aggressive behaviors (N =
194, 56.4%) mixed features (N = 193, 56.1%). Approximately 42% reported psychotic symptoms, whereas 24.7% experienced mania triggered
by antidepressant use. Suicide attempts were reported by 40.1% of enrolled patients. ).
Table2 shows the types of treatments in the whole sample, with most patients being treated with polytherapy (N = 277, 80.5%), particularly
the combination of lithium with other mood stabilizers, and antipsychotic drugs (N = 141, 41%), or a combination of an antipsychotic with
either valproate (N = 84, 24.4%), or lithium (N = 33, 9.6%), or another mood stabilizer (N = 19, 5.5%). Approximately 20% of patients were
treated only with lithium (N = 67).

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Table 1
Description of the cohort of BD patients enrolled in the study (N = 344)
and results from sociodemographic and clinical assessment
Characteristic M or N ± SD or %
Age, M (± SD) 46.88 ± 13.94
Age at onset, M (± SD) 25.73 ± 9.40
duration of untreated illness, M (± SD) 5.84 ± 10.31
number of depressive episodes, M (SD±) 5.81 ± 5.92
number of manic episodes, M (± SD) 4.04 ± 4.41
number of hypomanic episodes, M (SD±) 2.65 ± 2.69
numbers of total affective episodes, M (± SD) 11.39 ± 9.87
Female, N (yes%) 177 51.5%
Graduation, N (yes%) 246 71.5%
Marital status, N (yes%) 186 54.1%
Employed, N (yes%) 171 49.7%
Diagnosis of bipolar disorder I, N (yes%) 253 73.5%
Diagnosis of bipolar disorder II, N (yes%) 91 26.5%
Family history of psychiatric disorder, N (yes%) 190 55.2%
Seasonality, N (yes%) 171 49.7%
Aggressive behaviors, N (yes%) 194 56.4%
Mixed features, N (yes%) 193 56.1%
Lifetime abuse, N (yes%) 124 36.0%
Psychotic symptoms, N (yes%) 144 41.9%
Antidepressant mania, N (yes%) 85 24.7%
Suicide attempts, N (yes%) 138 40.1%
Note. Mean (M), Numerosity (N), standard deviation (SD).
Table 2
Description of the therapeutic management of the BD patients enrolled in the
study (N = 344).
Li ms + ap Li + ap dvp + ap Li + ms + ap
N% N % N % N % N %
67 19.5 19 5.5 33 9,6 84 24.4 141 41.0
Note. lithium (Li); mood stabilizer (ms); antipsychotic (ap); valproic acid (dvp).
Identication of BD patients with comorbid cPTSD using the ITQ score
The ITQ questionnaire was administered to all BD patients recruited in the study (N = 344) and the analysis of the distribution of our sample
in both PTSD and DSO domains is displayed in Table3.
For each PTSD symptom cluster (Re-experiencing, Avoidance, and Hyperarousal), the mean scores are relatively low, indicating a generally
lower level of severity in these specic symptoms.
Within the DSO symptom cluster, both Affective Dysregulation and Disturbances in Relationships show slightly higher mean scores,
suggesting a comparatively higher level of impairment in these areas. Instead, the Negative Self-Concept cluster shows a lower mean but a
wider interquartile range (IQR), indicating greater variability in the severity of this symptom among individuals in the sample. Overall, these

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results provide insights into the distribution and severity of PTSD and DSO symptoms within the studied population, helping to understand
the impact of trauma on different aspects of their mental health.
Table 3
Results of the administration of the ITQ to the whole sample (N = 344), describing
the distribution of patients in each symptom cluster.
  Mean SD Median IQR
PTSD scores Re-experiencing 1.48 1.42 1 3
Avoidance 1.29 1.34 1 3
Hyperarousal 1.46 1.34 1 3
DSO scores Affective dysregulation 1.72 1.66 1 3
Negative self-concept 1.32 1.45 1 4
Disturbances in relationships 1.69 1.68 1 4
DSO,
Disturbances in Self-Organization
; PTSD,
Post-traumatic stress disorder
.
Considering the ITQ score, 44.8% of enrolled patients (N = 154) met the criteria for cPTSD diagnosis, and their characteristics are
summarized in Table4. By comparing the sociodemographic and clinical characteristics of patients between the two groups, we detected
statistical differences in gender distribution and educational background between subjects that met the criteria for cPTSD and who did not.
Marital status shows a signicant difference, with a higher percentage of individuals being married in the cPTSD group whereas
employment status does not show a signicant difference between the two groups.
The group with cPTSD tended to be relatively younger, even at the onset of BD, and were mostly diagnosed with BD-I. Interestingly, among
BD-I patients, 54.5% met the criteria for cPTSD, whereas among subjects affected by BD-II, only 16 out of 91 (17%) showed comorbid
cPTSD. The duration of untreated illness is signicantly shorter in the cPTSD group, suggesting that individuals with cPTSD sought
treatment earlier.
A family history of psychiatric disorder was prevalent in individuals with cPTSD who showed higher rate of various clinical features,
including a greater number of total psychiatric episodes, aggressive behaviors, psychotic symptoms, and mixed features than patients
without cPTSD. Also, cPTSD-positive patients showed more seasonality than cPTSD-negative patients, with a higher prevalence of lifetime
abuse, antidepressant-induced mania as well as suicide attempts, indicating a potentially more complex clinical prole in this subgroup of
BD patients.

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Table 4
Description of enrolled BD patients with and without comorbid cPTSD, classied based on ITQ
score, and results from the statistical comparisons between groups using t-test or chi-square as
appropriate.
Variables cPTSD 
 No
N = 190
Yes
N = 154
p
Age, M (± SD) 48.7 ± 13.48 44.65 ± 14.21 .008
Age at onset, M (± SD) 27.0 ± 10.29 24.15 ± 7.93 .004
duration of untreated illness, M (± SD) 7.03 ± 10.98 4.36 ± 9.25 .015
number of depressive episodes, M (± SD) 5.71 ± 6.84 5.94 ± 4.56 .71
number of manic episodes, M (± SD) 3.94 ± 5.60 4.12 ± 3.12 .71
number of hypomanic episodes, M (± SD) 2.50 ± 2.12 2.84 ± 3.27 .27
numbers of total affective episodes, M (± SD) 10.45 ± 10.85 12.56 ± 8.40 .043
Alda Scale, M (± SD) 5.07 ± 2.83 4.07 2.40 < .001
Female, N (yes%) 108 56.8% 69 44.8% .026
Graduation, N (yes%) 127 66.8% 119 77.3% .033
Marital status, N (yes%) 93 48.9% 93 60.4% .034
Employed, N (yes%) 96 50.5% 75 48.7% .74
Diagnosis of bipolar disorder I, N (yes%) 115 60.5% 138 89.6% < .001
Diagnosis of bipolar disorder II, N (yes%) 75 39.5% 16 19.4% < .001
Family history of psychiatric disorder, N (yes%) 91 47.9% 99 64.3% .002
Seasonality, N (yes%) 78 41.9% 93 60.8% < .001
Aggressive behaviors, N (yes%) 83 43.7% 111 72.1% < .001
Mixed features, N (yes%) 71 37.4% 122 79.2% < .001
Lifetime abuse, N (yes%) 45 23.7% 79 51.3% < .001
Psychotic symptoms, N (yes%) 14 7.5% 130 84.4% < .001
Antidepressant mania, N (yes%) 20 10.5% 65 42.2% < .001
Suicide attempts, N (yes%) 28 14.7% 110 71.4% < .001
BD patients with comorbid cPTSD show a worse response to pharmacological treatment.
As shown in Table5, we detected differences in the distribution of pharmacological therapy between groups. The p-value is < .001 and it
suggests a signicant difference in therapeutic approaches (polytherapy vs monotherapy). A higher percentage of patients with cPTSD
were on polytherapy, and a lower percentage were treated only with lithium compared to those without cPTSD.
To determine whether there was a different response to therapy between cPTSD-positive and cPTSD-negative BD patients we analyzed the
data obtained from the Alda scale, and we detected a signicant difference in the mean Alda score between groups (presence/absence of
cPTSD). Specically, BD patients with comorbid cPTSD show a lower level of mean Alda score compared to those without it.
Furthermore, as shown in Table6, the results of the logistic regression model indicate that higher Alda scores (thus better treatment
response) are associated with a decrease in the log odds of having cPTSD. Indeed, the intercept results show that for a one-unit increase in
the Alda score, the odds of having cPTSD are 1.554 times higher. Conversely, BD patients with lower Alda scores (indicating poorer
treatment response) are more likely to have comorbid cPTSD. The results of the estimate show that for a one-unit increase in the Alda score,
the odds of having cPTSD decrease by a factor of 0.867. Overall, these ndings suggest signicant associations between therapeutic
approaches, Alda score, and the presence of cPTSD in BP patients.

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Table 5
Results of the analysis of the distribution of enrolled BD patients into
different therapeutic approaches as well as of the Alda score between
BD-patients with and without cPTSD
cPTSD 
 No
N = 190
Yes
N = 154
p
Polytherapy, N (yes%) 146 76.8% 131 85.1% < .001
Lithium, N (yes%) 44 23.2% 23 14.9% < .001
Alda score, M (± SD) 5.07 ± 2.83 4,.07 ± 2.40 < .001
Table 6
Results of the logistic regression analysis
95% Condence Interval 95% Condence
Interval 
Predictor Estimate Lower Upper SE Z p Odds
ratio Lower Upper
Intercept  0.441  0.0109  0.8702  0.2192  2.01  0.044  1.554  1.011  2.387 
alda_tot  -0.142  -0.2240  -0.0603  0.0418  -3.40  < .001  0.867  0.799  0.941 
Note.
Estimates represent the log odds of "cPtsd = 1" vs. "cPtsd = 0" 
Discussion
The current study intended to assess the impact of cPTSD on the response to mood stabilizers (single drug or in combination) in an adult
outpatient population with BD. It was reported that patients with BD are more likely than the general population to have suffered traumatic
events, especially during childhood and adolescence, and that these experiences, when extended over time, may be predictive for the
development of cPTSD, representing a dened and serious risk factor (Tian et al., 2022). There is consensus in the literature that a history of
repeated trauma is common in individuals suffering from BD and can have a very negative impact on the course of the disease (Kira, 2010;
Shevlin et al., 2008). In line with this evidence, our cohort of BD patients with comorbid cPTSD exhibited more severe symptomatology, such
as an earlier age at onset of BD, a higher frequency of affective episodes, aggressive behavior, mixed features, psychotic symptoms, and a
greater number of suicide attempts.
All the above suggest that a history of multiple trauma precipitating cPTSD could play a relevant role in the psychopathology of BD,
although the cellular and molecular mechanisms by which this comorbidity may inuence the response to treatment remains to be
elucidated.
Indeed, the present results revealed a signicant difference in treatment outcomes between the two samples (presence/absence of cPTSD)
and a signicant correlation between the presence of cPTSD and poor response to treatment with mood stabilizers. Actually, the whole
sample showed a moderate response to treatment on average (5.07 for the sample without cPTSD; 4.07 for the sample with cPTSD).
However, when the sample was further divided into two subgroups according to the presence/absence of cPTSD, the presence of
cumulative trauma was found to to affect the response to treatment. These ndings are consistent with previous results showing that
showed childhood trauma per se may blunt treatment (Etain et al.,2017; Cakir et al., 2016; Cascino et al., 2021; Benarous et al., 2017; Perugi
et al., 2018) and this may result in a greater likelihood of inadequate response to pharmacotherapy (Etain et al.,2017). Moreover, cPTSD as
a comorbidity may also inuence the outcome of the combined treatment with quetiapine and lithium in BD patients (Russell et al., 2023).
This study demonstrated that the concomitant use of multiple mood stabilizers is common in this population, especially in patients with
previous poor responses to treatment (Baek et al., 2014), and how this was not able to change at all a greater probability of a weaker
ecacy of therapy (Lee et al., 2020). Consistent with this, our patients with comorbid cPTSD tended to have a limited response to treatment
with a single rst-line agent (lithium), thus necessitating a combination, which still failed to modify the likelihood of a poor outcome to
treatment.

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The evidence that combined treatments with multiple medications were equally ineffective in bipolar patients comorbid with cPTSD is not
without relevance considering the greater incidence of affective episodes as well as the more rapid cyclicity and higher frequency of mixed
states. Above all,, the signicantly higher risk of suicide in these patients than cPTSD-negative patients must be considered, which we
would counteract with less effective tools.
The ndings of the present study should be read considering the following limitations. First, the cross-sectional design and the relatively
small sample size may have limited the generalizability of the results. Furthermore, patients were studied in different phases of illness and
in different settings. Despite this, the study mainly relied on the analysis of lifetime variables that were not affected by clinical severity at
the time of assessment. Future prospective studies are required to clarify the association between BD and cPTSD and possibly identify
specic risk factors and clinical phenotypes according to BD subtype. Nonetheless, the major strengths of this study are that the focus of
the study was very specic, as we analyzed the comorbidity of BD with cPTSD in a real-world setting, using broad inclusion criteria which
contributed to the representativeness of the sample of the whole BD population. Furthermore, the present study conrmed specic clinical
correlates of a history of trauma in BD, providing results about treatment response assessed with an instrument with high validity and
interrater reliability.
Conclusion
The results of the present study suggest that the comorbidity of cPTSD with BD worsens the course of both and reduces the therapeutic
ecacy of mood stabilizers, administered alone or in combination, and stimulates further research studies to explore the neurobiological
mechanisms responsible for the reduced response to pharmacological treatment. This could expand our knowledge and enable us to
develop more tailored and effective treatments that are suited to the characteristics of patients.
The possible occurrence of cPTSD in subjects suffering from BD should be carefully researched starting from the onset of the disease,
since this simultaneous association leads to greater clinical severity and should prompt to a close monitoring of response to treatments,
because they prove to be less satisfactory in this condition. Moreover, an add-on treatment specically targeted to trauma could result in a
better outcome and response in this population of BD. The implementation of personalized interventions is required to optimize the clinical
management of BD patients with c-PTSD.
Abbreviations
AP Antipsychotic
BD Bipolar Disorder
cPTSD Complex Posttraumatic Stress Disorder
DSO Disturbances in Self-Organization
DVP Valproic Acid
ITQ International Trauma Questionnaire
LI Lithium
MS Mood Stabilizer
PTSD Posttraumatic Stress Disorder
Declarations
Author Contributions: Conceptualization, L.S.J. methodology, L.S.J.; formal analysis, L.S.J.; investigation, A.M.I., M.D., G.L., V.D.S. and L.S.;
data curation, L.S.J.; writing—original draft preparation,
A.M.I., M.V., C.S., and L.S.J.; writing—review and editing, A.M.I., M.V., M.D., G.L., V.D.S., L.S., C.S., and L.S.J. All authors have read and agreed
to the published version of the manuscript.
Funding: This research received no external funding.

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Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki and approved by Ethics
Committee of University of Catanzaro (protocol code 307/2020).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Written informed consent has been
obtained from the patient(s) to publish this paper.
Data Availability Statement: The data that support the ndings of this study are available from the corresponding author, upon reasonable
request.
Conicts of Interest: The authors declare no conict of interest.
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