Bipolar disorder (BD) affects 2-4% of the population and is one of the major causes of disability. The course of bipolar disorder is cyclical and identified by episodes of depression and (hypo)mania with or without mixed features, accompanied by or in the absence of interepisodic euthymia [1]. Alterations in biological rhythms (BR) may have a role in the pathophysiology of BD and may serve as a possible marker in the identification of early stages and relapses of this disturbance as well [2]. Many studies have assumed that identifying the link between biological rhythm disturbances and BD might help better clarify its etiology [3]. Indeed, a vast amount of literature explains the relationship between disruptions of biological rhythms and the maintenance, remission and treatment of bipolar episodes [4-8].

The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) was developed to clinically approach disturbances in biological rhythm, especially in patients with mental disorders [9, 10]. Hence, a biological rhythm assessment is not only cardinal for identifying the cause of clinical symptoms but as well for the psychiatric treatment and clinical research of mood disorders. The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) is an 18-item interviewer administered instrument that focuses on appraising four main areas related to circadian rhythm disturbance, concretely: sleep, activities, social rhythms and eating patterns. Items are estimated using a 4-point scale, (1)=no difficulty, (2)=mild difficulty, (3)=moderate difficulty, and (4)=severe difficulty. The BRIAN scores, therefore, range from 1 to 72, where the higher scores indicate serious circadian rhythm disturbance [11].

The objective of this study was to examine the reliability and validity of the Macedonian version of the BRIAN by investigating the relevance of the scale for identifying circadian rhythm abnormalities in subjects with BD compared with the healthy subjects in a Macedonian population.

The 1995 Declaration of Helsinki and its revisions [12] have been followed in the carrying on of this study. Approval to the study protocol has been granted by the Institutional Review Board (IRB) of Public Health Institution (PHI)-Psychiatric Hospital Demir Hisar in Demir Hisar and PHI-Psychiatric Hospital Negorci in Negorci, Gevegelija, North Macedonia, with the authorization signed on 15.06.2021 and 13.09.2021, respectively.

No difference by gender or age was noticed (Table 1). Patients differed from controls in education and occupation. These differences are expected because people with bipolar disorder, due to the nature of the disease, have obstacles and limitations in using their potential for higher education levels (university), and also are limited in the constancy in workplaces. Data violated normality for some of the BRIAN scales in patients (Kolmogorov-Smirnov with Lilliefors corrections ‘ s p < 0.05 for Sociality and Rhythms subscales); data violated normality for all BRIAN scales in controls. However, the t-test is pretty robust to depart from the normality assumption.

Reliability, as measured with Cronbach’s alpha, was good in BD subjects, except for the Rhythms subscale; reliability in controls was less good, especially for the Sleep and Rhythms subscales (Table 2).

Furthermore, the tool was able to discriminate patient groups with controls, with large differences on all subscales (Table 3). However, since the reliability was suboptimal for some subscales, these differences cannot be entirely trusted.

The BRIAN distinguished people with high AUC (0.95; 95%CI: 0.91 – 0.99) diagnosed with BD from putatively healthy controls (Fig. 1). The best threshold for the differentiation of BD subjects from controls was 46. Sensitivity and specificity at the best threshold were 86% and 96%. BRIAN showed a poorer NPV (87.3%) than its PPV (95.5%). The positive diagnostic likelihood ratio was high: 21.5. In the investigated samples, just 2 controls (4%), as against 43 patient groups (86%), scored at or above the cut-off on the BRIAN (χ²_Yates=64.6; df=1; p<0.0001). The ROC analysis does not assume the normality distribution of the numerical variable.

Fig. (1). ROC analysis curve of Macedonian version of BRIAN.

We studied the validity and reliability of the Macedonia version of BRIAN, which has been used to measure biological rhythm in psychiatric backgrounds. In particular, individuals with BD, which is known to relate closely with circadian rhythm disturbances, were estimated with control subjects, and a remarkable intergroup difference was verified. The reliability of the Macedonian version of BRIAN, validated through this study, was similar to that determined in earlier studies of BRIAN [22, 23]. The Cronbach’s alpha values for the entire scale and for each subscale were very good and additionally confirmed the good reliability of this tool. Otherwise, the traditional approach of measuring biological rhythm implies continuous measurement of the core body temperature; however, most studies measure behavioral and molecular circadian rhythms [24-26]. Molecular-level assessment may be the most precise; however, this method is invasive and is complex to apply to many subjects [27, 28].

A biological rhythm measurement based on the BRIAN scale is subject to recall bias and dependent on the reliability of answers [29, 30] but can be easily evaluated at any time; furthermore, the ability to assess 5 subdomains makes this scale an attractive clinical and research tool. This result can be interpreted in the context of previous studies, which reported a close relationship between biological rhythm disturbances and more frequent and severe depressive features in patients with BD. In the present study, the BRIAN score was importantly higher in people with BD than in normal control subjects. This is compatible with previous studies putting forward that individuals with BD show more disturbed biological rhythms as determined by the BRIAN [31-35]. Further investigation into the association between the prevalence and intensity of mood symptoms and the BRIAN will be required in the future. This finding contributes important confirmation concerning an approach established on biological rhythms in clinical practices and research of mood disorders. As the main reason for the significant difference in occupation between subjects with bipolar disorder and controls is the reduced ability for consistency and continuity in the workplace, which leads to the loss of the same and obtaining the status of an unemployed person. As well sleep rhythms are thought to depend on the occupation. Moreover, the human circadian rhythm cannot easily adapt to these fast shifts in bipolar disorder. Indeed, in inter-episode bipolar disorder, lower and more variable sleep efficiency and variability in falling asleep time are related to worse illness course and outcome [36]. Relative to the inter-episode phase, sleep disturbance escalates just before an episode, worsens during an episode and does not always resolve with medication [37, 38]

The potential application of this tool based on validity, as a screener, should also be addressed. From this point of view, the authors considered that a screener, in fact, can be convenient if it does not produce false positives and hence is efficient in producing a high predictive value. Actually, if the test is low-priced, noninvasive and adaptable, it can lead to a second evaluation only on positives with a more precise diagnostic tool. It is obvious that this study was conducted by comparing bipolar subjects to people without psychiatric diagnoses. Practically, a screening tool should be able to distinguish, especially among people with various pathologies. From this perspective, it has to look deeper into the fact that the disturbances of biological rhythms have recently been revealed not only in bipolar disorder but as well in other psychiatric disorders such as schizophrenia, autism, major depression, stress related disorders [39-42]. Very interestingly, even on the level of genetic determinants, an association between dysregulation of biological rhythms and bipolar disorder has been observed [43].

The BRIAN showed to be able to distinguish patients diagnosed with BD from putatively healthy controls, with good accuracy (when measured with AUC) and a very good informative positive diagnostic likelihood ratio (around 21). On the basis of the PPV and the NPV, the BRIAN is a screener that is good at confirming the presence of a BD, although it can also contribute to excluding its presence.

Few studies applied the receiver operating characteristic curve (ROC) to the BRIAN to determine its screening capacity. In a study on 60 newly diagnosed Japanese patients with delayed sleep-wake phase disorder, a threshold of 40 on the BRIAN discriminated patients from controls with a sensitivity of 80.0% and a specificity of 75.6% [44]. Since the study was on a condition different from BD, we cannot compare the threshold we have found with the one of the Japanese studies. On the other hand, the study of validation of the Italian version of BRIAN showed good accuracy in screening between BD (44 subjects) and non-BD (38 subjects). It was noticed quite good performance in specificity, for example, at cutoff 16, with a sensitivity of 68.2% and excellent specificity of 92.5% [9].

The limited sample size and the preliminary nature of the data represent obvious limitations of the study, which was designed to validate the Macedonian version of the BRIAN, not to test its screening effects. Despite their preliminary nature, the reported findings purport an innovative approach in the development of screening tools aimed at detecting the consequences of the symptoms (on circadian rhythms) rather than simply counting their occurrence. As evidenced by past studies, the tool emerges as a very practical tool for evaluating the bipolar disorder phenotype because it focuses on biological rhythms, contrasting other scales that only indirectly consider biological rhythm by evaluating seasonality or chronotype. In the future, this version of the scale will probably be used for biological rhythm measurements in different psychiatric areas and for active research and clinical practice concerning mood disorders.

Due to the significance of monitoring biological rhythms with a relevant and consistent instrument, BRIAN can be an applicable tool both in research and clinical practice with bipolar patients. The study suggests that the Macedonian version of this instrument has acceptable psychometric characteristics and also encourages the chance of developing mixed screening tools by incorporating elements of biological rhythm dysregulation into the routine evaluation of mood.