Syndrome or Symptoms? Assessing Cothymia, Neuroticism and Lifetime Comorbidity in a Sample of Psychiatric Patients

Abstract

Background. Cross-sectional and longitudinal psychiatric comorbidity rates could represent a syndromic process rather than the co-occurrence of different disorders. ‘Cothymia’, the concomitant presence of depression and anxiety symptoms, and the ‘neuroticism’ dimension have been proposed as candidate vulnerability factors for psychiatric disorders trajectories. Based on this background, the present research was aimed at assessing the role of cothymia and neuroticism as syndromic processes in lifetime psychiatric disorders, and examining homotypic or heterotypic trends in the diagnostic continuum of comorbid mental disorders. Materials and methods. Data collection was carried out retrospectively through the consultation of medical records at the Psychiatry Unit of the University Hospital of Messina. Cothymia was determined by the lifetime presence of depression and other anxiety disorders, and neuroticism was determined by the presence of borderline personality disorders and other personality disorders. Results. Cothymia and neuroticism were found in 580 patients with higher rates of hospitalization, drug prescription, polypharmacotherapy, and longer duration of illness. Furthermore, diagnostic trajectories in patients with cothymia and neuroticism followed both homotypic and heterotypic progressions. Limitations: This study presented several limitations. The small sample size from a restricted recruitment area, and the retrospective design may have influenced a realistic and accurate estimation of the lifetime prevalence of the disorders. Conclusions. Despite the limitations, the findings of this study confirm the presence of consistent and meaningful homotypic and heterotypic trajectories in psychiatric patients, suggesting that the evolution of lifetime diagnoses should become a focus in theoretical and practical approaches to psychiatric disorders.

Introduction

Traditional psychiatric nosography is marked by the difficulty in explaining the epidemiological findings that consistently report high rates of comorbid disorders; such clinical complexity is better outlined by the results from longitudinal studies suggesting the presence of common psychopathological trajectories at the roots of different mental disorders [1]. Some diseases appear to be closely related even though they belong to different nosographic classifications, and both homotypic and heterotypic comorbidities have been documented [2].

Psychopathological trajectories in psychiatry have been highlighted in the Dunedin Birth Cohort Study [3] and explained through the existence of a common factor underlying the vulnerability to mental illness. This general factor of psychopathology, named the "p factor", would indicate that an individual with one psychiatric condition might develop a second or third condition lifetime [4,5]. Caspi et al. [6] stated that the "p-factor" is quantitatively distributed in the general population, hypothesizing a developmental progression of "p" starting from internalizing (i.e., anxiety, depression) or externalizing (i.e., impulse dyscontrol, substance abuse) disorders and eventually resulting in psychotic episodes. Thus, p-factor may explain a lifetime continuity that is usually viewed as comorbidity, encouraging the development of a dynamic model aimed at explaining heterotypic comorbidity as a longitudinal progression of distinct disorders, although subtended by common pathways.

One of the most well-known transversal and longitudinal comorbidities in psychiatry is the frequent co-occurrence of depression and anxiety symptoms, a condition defined as cothymia [7,8], initially derived from the epidemiological studies on the prevalence of mixed anxiety and depression, and from treatment and outcome research that has shown worse long-term outcomes and poor recovery of cothymia when compared with single mood diagnoses [9].

Co-occurrence of depression and anxiety has been described both at a full and at a subthreshold level; this latter clinical condition in which neither depression nor anxiety meet the diagnostic criteria needed for reaching the diagnostic threshold, has also been defined as Mixed Anxiety and Depression Disorder – MADD [8], a diagnosis listed within the International Classification of Diseases – 10 (ICD-10) by the World Health Organization (WHO). Although subsyndromal, the concurrent morbidity of anxiety and depression symptoms can significantly impair functioning, well-being and quality of life, thus requiring clinical treatment. Anxiety and depression disorders may also partly share genetic risk factors and neurobiological dysfunctions in brain regions and circuits involved fear, anxiety and depressed mood, along with similar alterations in cognitive features and personality traits [10]. Strong genetic overlaps were found among anxiety disorders, depression, and neuroticism or negative affectivity, a personality trait characterized by a pervasive sense of uncontrollability with life events, higher stress reactivity, negative emotionality, inability to control urges, and ineffective ways of coping with stress [11]. The incorporation of personality dimensions and disorders within the framework of psychiatric comorbidity increases the complexity of this research field; nevertheless, it may be helpful in further clarifying convergent and/or divergent psychopathological trajectories and reminds us that the intrinsic nature of psychopathology is heterogeneous and composite, since it consists of a blend of clinical entities and maladaptive response and adjustment patterns [12].

Based on this background, the present research starts from the hypothesis that the high rates of longitudinal co-occurrence of anxiety and depression observed in psychiatric disorders might be related to personality disorders characterized by neuroticism, negative affectivity and emotional instability.

The first aim of the present study was to assess the lifetime continuum of cothymia and neuroticism/negative affectivity, as derived from the presence of personality disorders, and their potential role in influencing clinical courses and outcomes of different psychiatric disorders. The second aim was to examine homotypic and heterotypic trajectories in lifetime comorbidity of mental disorders.

Materials and Methods

Data collection was carried out retrospectively on medical records of patients admitted from 1 January 2014 and 30 July 2021 at the Psychiatry Unit of the University Hospital of Messina.

Psychiatric diagnoses found in the patients’ history were classified according to 16 categories: 1) Schizophrenia; 2) Other Psychoses; 3) Bipolar Disorder; 4) Depression; 5) Panic Disorder; 6) Obsessive-Compulsive Disorder; 7) Other Anxiety Disorders; 8) Borderline Personality Disorder; 9) Other Personality Disorders; 10) Eating Disorders; 11) Substance Abuse; 12) Impulse Disorder; 13) Neurocognitive Disorder; 14) Sleep Disorders; 15) Dissociative Disorder; 16) Pathological Gambling.

Cothymia was assessed by the lifetime occurrence of depression and other anxiety disorders; neuroticism was derived by the presence of borderline personality disorder and other personality disorders have been considered for their main features of negative affectivity, emotional dysregulation, and ineffective coping mechanisms.

Statistical Analysis

A descriptive analysis of the sample characteristics was carried out. Categorical variables (sex, current and past diagnoses, and types of psychotropic medications) were described through absolute frequencies and percentages. Continuous variables (age, number of admissions in the year of observation, total number of admissions, age at onset, years of illness, total number of past diagnoses, years since the insurgence of previous diagnoses, number of medications of each specific type) were expressed as mean values and standard deviations (SDs). The comparison between patients with or without cothymia and neuroticism was analyzed through the χ² test for categorical variables and the two-sample Wilcoxon rank-sum (Mann-Whitney) test for those continuous as the data were not normally distributed (Shapiro-Wilk test). Variables statistically different were introduced in a univariate regression model of Cox proportional hazard ratio (HR) to determine the risk that patients could develop cothymia and neuroticism during lifetime psychiatric illness. The diagnosis of cothymia and neuroticism was chosen as the dependent variable (absence/presence) and years of psychiatric illness as the time variable. For present and past diagnoses, the reference category was the absence of each specific diagnosis. The resulting HRs with 95% confidence intervals (95% CI) estimates are interpretable as the ratio of the hazard of suffering from cothymia and neuroticism versus no suffering from cothymia and neuroticism. We assessed each covariate deemed valuable to our analysis based on association with the outcome through univariable Cox regressions at p < 0.50 for consideration in the multivariable model. Backward stepwise selection based on Akaike’s Information Criterion (AIC) was used to select the best multivariate model. All the data were recorded electronically, and statistical analyses were carried out using the Stata Statistical Software: Release 15 (Stata Corp LP, College Station, TX, USA).

Results

The demographic characteristics of the sample (N=1221) are shown in

Table 1. Demographic characteristics of the sample.

. The mean age of the patients was 46.39±14.81 years and the majority of the subjects were females (52.34% vs 47.66%). When stratified for absence/presence of cothymia and neuroticism (n=580 and n=188, respectively), the two groups compared were homogeneous for age (p=0.247) and sex (p=0.464).

As shown in

Table 2. Hospital admissions and illness duration.

, patients with cothymia and neuroticism were characterized by a higher number of hospital admissions during the study period (1.27 0.60 vs 1.16 0.42, p=0.005), total admissions (3.09 2.67 vs 2.34 2.06, p<0.001) and longer illness duration (19.54 12.72 vs 17.16 13.38, p=0.033).

Table 3. Current and previous diagnoses.

shows the comparisons between current and previous diagnoses and illness duration. Statistically significant differences emerged for current diagnoses of psychosis not otherwise specified (17% vs 11%, p=0.031), depression (15% vs 9%, p=0.048), and other personality disorders (22% vs 14%, p=0.035) with higher frequencies in patients with cothymia and neuroticism. Conversely, the diagnosis of bipolar disorder was less associated with cothymia and neuroticism (35% vs 21%, p<0.001). Regarding previous diagnoses, the two groups widely differed, except for the diagnosis of schizophrenia, bipolar disorder, and pathological gambling, and with higher frequencies in cothymia and neuroticism group, as shown by the average of the nearly double total number of previous diagnoses (5 vs 3, p<0.001).

Considering psychopharmacological treatments, (

Table 4. Psychopharmacological treatments.

), statistically significant differences in drug use emerged in both classes, with higher prescription rates in the cothymia and neuroticism group.

The univariate Cox regression (

Table 5. Risk factors associated with cothymia and neuroticism during lifetime psychiatric illness.

) indicated the factors that potentially increase or decrease the risk of developing cothymia and neuroticism over the years of the disease. In the presence of statistical significance, variables were introduced in the multivariate model to identify independent factors that increase or decrease the possibility of developing cothymia and neuroticism over the years of disease: the risk of cothymia and neuroticism increased with previous diagnoses of depression (HR 2.84, 95% CI 1.64 - 4.93, p<0.001), other anxiety disorders (HR 4.60, 95% CI 2.87 - 7.38, p<0.001), other personality disorders (HR 3.77, 95% CI 2.46 - 5.77, p<0.001), impulse control disorder (HR 1.55, 95% CI 1.03 - 2.33, p=0.034) and higher number of benzodiazepines (HR 1.21, 95% CI 1.01 - 1.44, p=0.039); it decreased with increasing years since the onset of the third clinical disorder (as documented by the formal diagnosis) (HR 0.93, 95% CI 0.92 - 0.95, p<0.001) and the number of antipsychotics (HR 0.90, 95% CI 0.82 - 0.98, p=0.012) (Table 5).

Limitations

This study presented several limitations that should be considered and that do not allow the generalization of the obtained results. First, the small sample size from a restricted recruitment area may have limited the full understanding of lifetime comorbidity and diagnostic evolution of disorders, also because of the low rates of several, less represented, diagnostic entities in our sample (i.e. obsessive-compulsive disorder and eating disorders). Then, within the retrospective design, the almost arbitrary assumption that the diagnoses of borderline and other personality disorders without further specification stood as indexes of neuroticism, the trait disposition aligned with the negative affective domain. Furthermore, the same retrospective study design based on past clinical records may have influenced a realistic and accurate estimation of the lifetime prevalence of the disorders.

Discussions

Comorbidity is the rule rather than the exception among psychiatric patients [13]; a better understanding of the complex nature and trajectories of mental disorders may help develop more effective prevention and treatment strategies.

The frequent overlap of the psychopathological dimensions of internalizing disorders (i.e., anxiety and depressive symptoms), externalizing disorders (i.e., aggressive, delinquent hyperactive-impulsive traits) and psychosis (i.e., schizophrenia, bipolar disorder) has suggested the existence of psychopathological continuums among different psychiatric disorders, that could be interpreted as syndromic processes [6].

Given the frequent co-occurrence of anxiety and depression, both at threshold and subthreshold levels, the model chosen for our study was the “cothymia”, along with the personality trait of neuroticism or negative affectivity. We retrospectively assessed this clinical condition by detecting the co-presence of mood, anxiety, and personality disorders (borderline and other personality disorders) in the patients’ medical history. The percentage of 24.48 patients with cothymia and neuroticism found in our sample is almost congruent with similar rates of mixed anxiety, depression, and personality disorders found in other studies [14]. The presence of cothymia and neuroticism was associated with a higher number of hospitalizations and with a longer duration of illness. These results are consistent with previous data showing that comorbidity was associated with poor outcome, prolonged hospitalizations, repeated admissions, and worse remission and recovery rates [15]. Moreover, the risk of developing the association between cothymia and neuroticism proportionally increased with previous diagnoses of depression, other anxiety disorders, and other personality disorders.

The cothymia and neuroticism association was also related with higher prescription rates and higher number of drugs taken, thus confirming previous reports highlighting the significant increase in number of medications both prescribed and taken in case of comorbid disorders [16].

The second aim of our study was to evaluate homotypic or heterotypic trajectories of the disorders, according to previous and current diagnoses; cothymia and neuroticism patients were characterized by higher rates of psychosis, depression, and other personality disorders for current diagnoses. Consistently, high rates of depression and personality disorders were found in previous studies aimed at assessing the presence of lifetime personality disorders in patients who were exiting with the diagnosis of depression [17]. However, in our sample, the high rates of psychosis also suggest a heterotypic progression. Regarding previous diagnoses, higher frequencies of bipolar disorder, schizophrenia, and pathological gambling were found in cothymia and neuroticism patients. The bipolar and schizophrenia diagnoses in the same continuum of patients suffering from depression and personality disorders also underline a heterotypic trajectory; nevertheless, psychotic-like experiences are common in individuals with anxiety and depressive disorders, and an affective dimension, also characterized by mood instability, has been thoroughly described in patients with schizophrenia [18]. On these bases, lifetime comorbidity could be rethought as a psychiatric syndrome characterized by the sequential or simultaneous onset of multiple illnesses, thus supporting the model of network approaches to psychopathology, in which disorders result from the causal and complex symptoms interplay over time with feedback loops that cross the borders of traditional diagnostic entities [19].

Despite the limitations, however, the findings of this study confirm the presence of consistent and meaningful homotypic and heterotypic trajectories in psychiatric patients, thus suggesting that the evolution of lifetime diagnoses should become a main focus in theoretical and practical approaches to psychiatric disorders that, in real-world circumstances, seem to blur into each other according to dimensional rather than categorical patterns, reflecting different psychopathological domains (internalizing, externalizing, and psychotic) and patterns of sequential comorbidity. There is a clear need to strengthen our knowledge within this field of research, and further studies are needed to accurately address the complex problems that hinder the understanding of lifetime comorbidity, diagnostic overlaps, and heterogeneity of courses and outcomes across psychiatric disorders.

Conclusions

The traditional, symptom-based nosological systems may not reflect the true neurobiological boundaries of disease entities that should be better conceptualized in terms of dimensions, networks, dynamical systems in which transitions possibly derive from multiple interactions among vulnerable endophenotypes, neurodevelopment, and environmental contributions, including early experiences, learning, and life events [20]. Finally, especially in the case of severe and chronic mental illnesses, a staging approach aimed at differentiating earlier clinical features from illness progression markers may prove useful for selecting specific treatments and predicting outcome and for helpfully guiding clinicians to understand the complexity of patients’ life histories, to provide personalized treatment, early diagnoses, and appropriate prevention strategies.