Impact of Modi cation to DSM-5 Criterion A for Hypomania/Mania in Newly Diagnosed/First Episode Bipolar Patients – Findings From the Prospective BIO Study


 Background: DSM-IV states that criterion A for diagnosing hypomania/mania is mood change. The revised DSM-5 now states that increased energy or activity must be present alongside mood changes to diagnose hypomania/mania, thus raising energy/activity to criterion A. We set out to investigate how the change in criterion A affects the diagnosis of hypomanic/manic visits in patients with a newly diagnosed / first episode bipolar disorder. Results: In this prospective cohort study, 373 patients were included (median age=32; IQR, 27-40). Women constituted 66% (n=245) of the cohort and 68% of the cohort (n=253) met criteria for bipolar type II, the remaining patients were diagnosed bipolar type I. Median number of contributed visits was 2 per subject (IQR, 1-3) and median follow-up time was 3 years (IQR, 2-4). During follow-up, 127 patients had at least one visit with fulfilled DSM-IV criterion A. Applying DSM-5 criterion A reduced the number of patients experiencing a hypomanic/manic visit by 62% at baseline and by 50% during longitudinal follow-up, compared with DSM-IV criterion A. Fulfilling DSM-5 criterion A during follow-up was associated with higher modified young mania rating scale score (OR=1.51, CL [1.34, 1.71], p <.0001) and increased number of visits contributed (OR=1.86, CL [1.52, 2.29], p <.0001). Conclusion: Applying the stricter DSM-5 criterion A in a cohort of newly diagnosed bipolar patients reduced the number of patients experiencing hypomanic/manic visit substantially, and was associated with higher overall young mania rating scale scores, compared with DSM-IV criterion A. Overall, fewer hypomanic/manic visits may be detected in newly diagnosed /first episode bipolar patients with applied DSM-5 criterion A. Consequently, with the DSM-5 criteria applied less severe bipolar disorders may be overlooked, especially early during the course of illness, and result in a diagnostic delay. Further studies are warranted on this issue.


Background
The introduction of the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) (1) has in many ways changed the diagnostic criteria for bipolar disorder (BD). Several iterations of the DSM, including DSM-IV, emphasized mood abnormalities (elevated, expansive or irritable mood) as the cardinal symptom (criterion A) for a hypomanic/manic episode, and listed psychomotor disturbances (activity) as one of the seven criterion B symptoms (2). However, the revised DSM-5, which was published in 2013, now states that increased energy or activity must be present alongside mood disturbances to diagnose a hypomanic/manic episode, thus raising psychomotor disturbances to criterion A (1) (see Table 1). The argument behind the modi cation of criterion A was that it might improve speci city when making the diagnosis of hypomania/mania, and consequently, BD.
The International Classi cation of Diseases (ICD) is following in the footsteps of the DSM de nitions.
The ICD-10 de nition of hypomania/mania highlighted mood abnormalities as criterion A (like DSM-IV) (3). However, the newly online released ICD-11, like DSM-5, includes increased energy or activity as criterion A alongside mood abnormalities (4).
Few studies have investigated the impact of the modi cation to DSM-5 criterion A for the diagnosis of hypomanic/manic episodes but only in cohorts of more chronic bipolar patients. The STEP-BD study (5) found that applying DSM-5 criterion A reduced the identi ed number of hypomanic/manic episodes by 48% when looking at baseline visits only (point prevalence), compared with DSM-IV criterion A. A study by our group of 907 chronic bipolar patients found a 34% reduction in the number of patients experiencing a hypomanic/manic visit during follow up when DSM-5 criterion A was applied (6). On the other hand, the BDRN study (7) found that up to 94% of patients with a lifetime diagnosis of DSM-IV BD also met lifetime DSM-5 criteria for BD. All three mentioned studies have in common that they investigated populations of more chronic bipolar patients. Results from the three mentioned studies suggest that the reduction in the diagnostic prevalence of hypomania/mania, and consequently BD, is highest earlier in the course of bipolar illness (a 34-48% reduction) but may diminish during lifetime (to a 94% reduction).
Thus, a knowledge gap remains, regarding how the introduction of DSM-5 criteria for BD affects the diagnostic prevalence of hypomanic/manic visits in newly diagnosed/ rst episode bipolar patients and potentially prolong the diagnostic gap from rst symptoms to diagnosis. Therefore, in a cohort of newly diagnosed patients with BD, we aimed to quantitatively determine the point prevalence of patients ful lling criterion A of a hypomanic/manic visit according to DSM-IV and DSM-5 at baseline and during longitudinal follow up. Furthermore, we aimed to investigate if any of the covariates available could predict DSM-5 diagnosis. Lastly, we explored the individual association between manic symptoms available from the Young Mania Rating Scale (YMRS) to understand the relationship between present manic symptoms and the transition from DSM-IV to DSM-5 diagnosis of hypomania/mania. We hypothesized that applying DSM-5 criterion A would lower the number of hypomanic/manic visits signi cantly, both at baseline and during follow-up and that no association between sex, age and DSM-5 diagnosis would be found. Lastly, we hypothesized that mood abnormalities (mood elevation and irritability) and energy/activity would show a strong association.
This study is of high importance as the consequences of modi cation to DSM-5 criterion A are still unknown and have never been looked at in a population of newly diagnosed/ rst episode bipolar patients. This study will help us understand the impact of the current modi cation to DSM-5 criterion A for newly diagnosed bipolar patients, and hopefully help us understand the patient's disease-trajectory in the light of DSM-5.

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The present study is a prospective cohort study investigating follow-up data on newly diagnosed patients with BD. The overall aim of the present study is to elucidate the clinical consequences of the modi cation to the current DSM-5 criterion A when focusing on newly diagnosed bipolar patients.

Setting of the study
The present study investigated data from the ongoing longitudinal Bipolar Illness Onset study (BIO), which aims to identify biomarkers for BD (8). Details on methods and procedures in the BIO-study are fully described elsewhere (8)

Participants
We included 373 patients with newly diagnosed BD. Recruitment of participants took place at the outpatient Copenhagen Affective Disorder Clinic from June 2015 to November 2019. The Clinic provides treatment for patients with newly diagnosed BD and receives patients from the Capital region of Denmark, an area covering 1,6 million and all the psychiatric centers in the Region (9). All patients referred to the clinic as newly diagnosed bipolar patients were routinely asked for inclusion in the BIOstudy.
At baseline, the initial diagnostic assessment of participants was conducted by an experienced specialist in psychiatry using the Structures Clinical Interview for DSM-IV-TR Axis I Disorders (10), categorizing patients into bipolar disorder I (BD I) or bipolar disorder II (BD II). The diagnosis of BD was con rmed in a semi-structured research-based interview by MDs or MScs in Psychology PhD students using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) providing an ICD-10 diagnosis (3).
Inclusion criteria were an ICD-10 diagnosis of BD or a single manic episode and age 15-70 years.
No attempts to balance the prevalence of bipolar subtypes were taken. Patients with BD not otherwise speci ed and patients with cyclothymia were not offered treatment in the Clinic and thus not included in the BIO-study. Exclusion criteria were organic BD secondary to brain injury.
Patients with BD received treatment as usual in the clinic without interference from study investigators.
Besides the clinical assessment at inclusion (baseline), patients were assessed during remitted depressive, manic or mixed phases and and once yearly for up to ve years of follow up.

Procedures
At each assessment the current affective state of each participant was evaluated according to ICD-10 (manic, hypomanic, depressive, mixed episode, remission). The severity of manic and/or depressive symptoms were evaluated using the 11-item clinician administered Young Mania Rating Scale (YMRS) (11) and the 17-item Hamilton Depression Rating Scale (HAMD-17) (12), respectively, covering the precceding three days. Both rating scales have been extensively validated for assessing manic and depressive symptoms, respectively (11,13). Patients were required to have a completed YMRS score at their rst visit (baseline) to be included in the present study, as this was the basis of inclusion criteria.

De nitions
We used the same methodology and de nitions as in our prior publication on patients with chronic BD (6). The individual ratings on item 1 (Mood), item 2 (Energy/Activity) and item 5 (Irritability) on the 11item YMRS allowed an evaluation of the presence of ful lled criterion A of hypomania/mania according to DSM de nition (see table 1).
A score equal or above 2 on item 1 (Mood) was considered re ective of increased/elevated mood. A score equal or above 2 on item 2 (Energy/Activity) was considered re ective of increased motor activity or energy. A score equal or above 4 on item 5 (Irritability) was considered re ective of increased irritability (see table 1).
Thus, study de nition of ful lling DSM-IV criterion A for a hypomanic/manic visit was de ned as item 1 (Mood) 2 and/or item 5 (Irritability) 4, presumably adequate to meet the DSM-IV de nition of criterion A.
Study de nition of ful lled DSM-5 criterion A for a hypomanic/manic visit was de ned as item 1 (Mood) 2 and/or item 5 (Irritability) 4 AND item 2 2 (Energy/Activity), presumably adequate to meet the DSM-5 de nition of criterion A (see table 1).
Depressive symptoms were de ned as an HAMD-17 total score 15.

Statistical analyses
A total of 849 visits by 373 participants were analyzed. Data analyses were performed based on participants (373 patients) using logistic regression models and based on visits (849 visits) using linear mixed-effects models.
Descriptive data were presented as median and interquartile range (IQR) or count and percentage (%). A power of 80% and a signi cance level of alfa=.05 were chosen for all statistical analyses. Results from analyses were presented as odds ratios with 95% con dence limits.
All statistical analyses were performed using software programs (SAS Enterprise Guide version 7.15, SAS institute, Cary, North Carolina).

Missing data
One subject had missing data on the variables "age of onset" and "age at rst hypomanic/manic episode" and additional one subject had missing data on "delay in diagnosis". These missing data were handled by single imputation with the median value of the cohort. Twelve subjects had missing data on family history of BD, 4 had missing data on no. of previous hospitalizations / admissions, and 4 had missing data on education years. These missing data were likewise handled by imputation before inclusion in the logistic regression model. A maximum of 7 missing values on the individual YMRS items were present throughout all visits (849) and were handled in the mixed model analysis.

Logistic regression
A modi ed YMRS score for each visit was calculated based on the total YMRS score, minus item 1, 2, and 5, as these items were used to de ne the outcome, i.e., DSM-IV and DSM-5 criterion A. The mean modi ed YMRS score was found for each participant as a mean of the modi ed YMRS scores across their visits.
Logistic regression models were performed in order to investigate if any of independent variables could predict DSM-5 Criterion A ful llment during follow-up. The outcome was de ned as ful lling DSM-5 criterion A at least once during follow-up in study (yes/no). Univariate and multivariable analyses were performed, and data were represented unadjusted and fully adjusted for bipolar subtype, sex, no. of visits contributed, age rst hypomanic/manic episode (years), no. of visits with depressed symptoms, mean modi ed YMRS total score, family history of BD, delay in diagnosis, education years. BD subtype, family history of BD, and sex were treated as binary variables, whereas the remaining variables were treated as continuous variables in the univariate and multivariable analysis. Variables included in the multivariable analysis were included based on clinical relevance and/or signi cance in univariate analysis (p<0.2).

Mixed models
Based on visits, we examined the association between individual items on the YMRS. Visits data (849 visits) represent repeated measures data and were analyzed accordingly, using generalized linear mixedeffects models, specifying each participant as random effect. The data represented zero-in ated data. Thus, the outcome was dichotomized, and the mixed models were speci ed as binomial.
The rst analysis investigated the individual YMRS items (predictors) and their association with experiencing increased mood (outcome variable). The outcome variable mood (item 1) was de ned as elevated (>0) and not elevated (=0). Univariate as well as multivariable linear mixed-effects models were conducted, and results presented unadjusted and fully adjusted for the other YMRS items. The analysis was repeated with irritability (item 5) as the outcome.
The analyses were speci ed with mood and irritability, respectively, as outcome variable, the individual YMRS items as predictors, and a random intercept for each participant to account for multiple observations made on the same subject.

Demographic and clinical characteristics
We included 373 patients (median age=32; IQR 27-40; 66% were female (n=245) and 32% (n=120) met criteria for BD I. A total of 849 visits by the 373 patients were included.

DSM-IV and DSM-5 criterion A
Baseline/ rst visit At baseline (the participant's rst visit), 86 patients ful lled criterion A of a hypomanic/manic visit according to DSM-IV criterion A (mood and/or irritability). Of the 86 patients, 33 patients ful lled DSM-5 criterion A (mood and/or irritability AND energy/activity) of a hypomanic/manic visit, a reduction of 62% at baseline (see table 2).
The median of the modi ed YMRS total score at baseline was 5 (IQR, 2-8) in the group of 86 patients who ful lled DSM-IV criterion A and 8 (IQR, 4-10) in the group of 33 patients who ful lled DSM-5 criterion A (see table 2).

Follow up
During follow-up, 127 subjects had at least one visit ful lling DSM-IV criterion A of a hypomanic/manic visit. Applying DSM-5 criterion A, 63 subjects had at least one visit ful lling DSM-5 criterion A of hypomania/mania corresponding to a reduction of 50% in the number of subjects who experienced a hypomanic/manic visit according to criterion A during follow-up in the study when applying DSM-5 criterion A (see table 2).

Multivariable logistic regression
We investigated if any of the demographic and clinical variables could predict DSM-5 diagnosis of hypomania/mania according to DSM-5 criterion A during follow-up. The multivariable logistic regression model revealed that the number of visits contributed and the mean modi ed YMRS total were associated with DSM-5 diagnosis according to criterion A during follow-up (see Delay in diagnosis, no. of visits with depressed symptoms, and education years all showed a vague association with DSM-5 diagnosis according to criterion A in univariate analysis but these associations did not withstand after adjustment in the multivariable analysis (see table 3).
We did not nd any associations between sex, age, bipolar subtype, no. of previous hospitalizations/admissions, family history of BD and DSM-5 diagnosis according to criterion A.
Sensitivity analyses were performed, stratifying based on bipolar subtype and sex, respectively, however, this did not change the results.

Mood
We investigated the individual hypomanic/manic symptoms (individual YMRS items) and their relationship with mood elevation. In the univariate analysis all items except item 11 (Insight) showed association with mood elevation before adjustment. After adjustment, only item 2 (Energy/Activity), item 3 (Sexual Interest), item 4 (Sleep), and item 6 (Speech), remained statistically signi cantly associated with item 1 (Mood) with a p-value below .05. For every 1-value increasement in Energy/Activity on item 2, the odds of experiencing elevated mood increased by 2.5 times in the adjusted model (adjusted OR [95% CL] = 2.5 [1.8, 3.4]).

Irritability
We investigated the individual hypomanic/manic symptoms (individual YMRS items) and their relationship with irritability. In the univariate analysis all items except item 11 (Insight) showed an association with irritability before adjustment. After adjustment, only item 4 (Sleep), item 7 (Language-Thought Disorder), and item 9 (Aggression), remained statistically signi cantly associated with irritability with a p-value below .05. For every 1-value increasement in aggression on item 9, the odds of experiencing increased irritability was increased 2. Discussion DSM-5 criterion A for hypomania/mania now includes the requirement of increased energy or activity in addition to mood change. The clinical consequences of the modi cation to the current DSM-5 criterion A for hypomania/mania has never been investigated in newly diagnosed bipolar patients. Elucidating the consequences of applied DSM-5 criterion A for newly diagnosed bipolar patients can help us understand the disease-trajectory of newly diagnosed bipolar patients in the light of DSM-5, and soon ICD-11 criteria.
In the present study of 373 newly diagnosed / rst episode BD patients we revealed 3 overall ndings. First, we found that applying DSM-5 criterion A reduced the number of patients experiencing a hypomanic/manic visit by 62% at baseline and by 50% during longitudinal follow-up, compared with DSM-IV criterion A. Second, ful lling DSM-5 criterion A for a hypomanic/manic visit during follow-up was associated with higher scores on the YMRS and associated with increased number of contributed visits. Third, the individual association between manic symptoms available from the Young Mania Rating Scale showed a strong association between elevated mood (item 1) and energy/activity (item 2), sexual interest (item 3), decreased need for sleep (item 4), and speech (item 6). Irritability (Item 5) showed a strong association with decreased need for sleep (item 4), language-thought disorder (item 7), and aggression (item 9).
The decrease in diagnostic prevalence (62% at baseline and by 50% during follow-up) with applied DSM-5 criterion A is clinically signi cant in a cohort of newly diagnosed bipolar patients. Previous studies of more chronic bipolar patients also point toward a decrease in both baseline prevalence and longitudinal diagnostic prevalence with applied DSM-5 criterion A for hypomania/mania, however the decrease in the prevalence of BD using DSM-5 compared with DSM-IV was smaller (34% (6) and 48% (5)) than in our study of newly diagnosed patients with BD (62% at baseline).
More severe manic symptoms (i.e., higher YMRS score) were associated with DSM-5 diagnosis during follow-up. These results may indicate that the stricter DSM-5 criterion A captures the more severe and evident hypomanic/manic visits but cuts off 50% of previously detected visits by DSM-IV criterion A.
Number of contributed visits per patient was associated with ful llment of DSM-5 criterion A, suggesting that patients over time, were more likely to have a hypomanic/manic visit detected according to DSM-5 criterion A.
These results are in line with ndings from our previous study on chronic bipolar patients also showing that both higher YMRS scores and number of contributed visits were associated with DSM-5 diagnosis according to criterion A (6). Consequently, with the DSM-5 criterion A less severe BD may be overlooked, especially early during the course of illness. This may inevitably result in a longer diagnostic delay (14,15), as patients may not ful ll criteria for BD until later stages of the illness. Consequently, treatment interventions will be delayed likely with poorer outcomes (16)(17)(18). Nevertheless, it should be noted that in the present study we did not prove a direct association between delay in diagnosis and ful lling DSM-5 criterion A.
The individual association between manic symptoms available from the YMRS showed a strong association between mood and energy/activity after adjustment, however, irritability and energy/activity did not prove any signi cant association after adjustment. This could potentially be part of the explanation of why some of the DSM-IV diagnosed hypomanic/manic visits (elevated, expansive, or irritable mood) no longer ful ll DSM-5 criterion A (elevated, expansive, or irritable mood AND energy or activity), as irritability and energy/activity did not prove an association in our data after adjustment. Interestingly, sleep disturbances (item 4), was the only item that showed a signi cant association with both mood elevation and irritability, respectively, after adjustment.

Strengths and limitations
Our study is based on updated data from the ongoing longitudinal BIO-study, including a large cohort of well-characterized patients with newly diagnosed BD. Our cohort seems representative of newly diagnosed bipolar patients with a median age of illness onset of 18 years and a median delay in diagnosis of 5 years (14,15).
The decrease in prevalence of hypomanic and manic visits from DSM-IV to DSM-5 criterion A was larger than in previous studies, this could be explained by the present study had predominance of BD II patients (68%), and the comparable studies had a majority of BD I patients (5,6).
Standardized, validated rating scales were used to evaluate both manic and depressive symptoms, YMRS and Hamilton 17-items, respectively, as undertaken by trained MDs or MScs in Psychology PhD students. The assessment of ful lled DSM-IV and DSM-5 criterion A were based solely on the YMRS scores on individual items, thus individual YMRS scores served as a proxy for evaluating the presence/absence of a hypomanic/manic visit, although the YMRS rating scale is not designed as a diagnostic tool but rather a rating scale measuring the overall symptom severity of individual manic symptoms. In this regard, it should be noted that the majority of patients included in the study did not present with a mood episode at baseline (see Table 2) and the ndings were based on limited observations of patients (median visits = 2; IQR, 1-3) and a period of observation with the use of scales during approximately yearly visits of a 3 days look-back.
It is evident from these and our prior data (6) that inclusion during a mood episode and more frequent visits and a longer follow-up period would have resulted in a higher concordance between DSM-5 and DSM-IV diagnoses of hypomania/mania and BD. Furthermore, the present study only evaluated hypomania/mania according to criterion A and did not incorporate the time frame or the criterion B symptoms in the assessment of hypomania/mania. However, criterion A is the gate criterion to evaluate the presence/absence of a manic/hypomanic state according to DSM and thus must be ful lled in order to continue to criterion B.
Lastly, the present study incorporated an explorative analysis of associations between DSM-5 criterion A ful llment and clinical characteristics / demographics. Our logistic regression models included multiple testing and thus an increased risk of a random signi cant nding (type I error). On the other hand, several of our predictors showed borderline signi cance in the logistic regression model, which can either be a random nding, or the result of a too small sample size to detect an actual difference (type II error). Nevertheless, our ndings are consistent with results from a cohort of more chronic bipolar patients published by our study group (6).

Conclusions
In this prospective cohort study, applying DSM-5 criterion A for hypomania/mania reduced the diagnostic prevalence of hypomanic/manic visits by 62% at baseline and by 50% during longitudinal follow-up, compared with DSM-IV criterion A. Ful lling DSM-5 criterion A was associated with more severe manic symptoms and increased during follow-up. Compared with the DSM-IV, the DSM-5 and the upcoming ICD-11 will inevitably result in longer diagnostic delay of BD.

Declarations
Ethics approval and consent to participate

Consent for publication
Written informed consent was provided by all participants.

Availability of data and materials
Data are not available.

Competing interests
Lars Vedel Kessing has in the past three years been a consultant for Lundbeck. Maj Vinberg has in the past three years been a consultant for Lundbeck, Janssen Cilag and Sunovion. Trisha Suppes has in the past three years reported: Grants from Merck, National Institute on Drug Abuse, National Institute of Health, VA Cooperative Studies Program, and VA OR&D PRIME Care, Palo Alto Health Sciences, Stanley Medical Research Institute, Pathways Genomics. Consulting fees from Allergan, Inc., Intracellular Therapies, Sunovion Pharmaceuticals, Inc., and Impel NeuroPharma Inc. Honoraria from CME Institute (Physicians Postgraduate Press, Inc.) and CMEology. Royalties from American Psychiatric Association Publishing, Hogrefe Publishing, Jones and Bartlett, and Wolters Kluwer Health (UpToDate). Travel reimbursement from Sunovion Pharmaceuticals, Inc.
The remaining authors declare no con icts of interest.