Quantitative electroencephalography (QEEG) and event-related potentials (ERPs), such as loudness dependence of auditory evoked potentials (LDAEP) and mismatch negativity (MMN), are noninvasive and clinically useful tools [1-3]. However, no study has compared the difference between QEEG and ERP in the same patients in each bipolar depressive manic. and euthymic phase. This study compares the changes in QEEG, LDAEP, and MMN in the case of bipolar depression, mania, and euthymia in a single patient.

The study was approved by the Inje University Ilsan Paik Hospital Ethics Committee (IRB 2022-02-032). In-formed consent was waived because of the retrospective nature of the study.

A 20-year-old female patient who started experiencing depression in the first year of high school was admitted to a closed ward owing to exhibiting depressed mood, anxiety, and suicidal ideation. There was a clear depressive episode satisfying the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5). Simultaneously, it was observed that her negative thoughts were constantly running in the head, and that she was restless and wandering around the hospital room. Additionally, the patient was engrossed in a computer game. Therefore, the patient was diagnosed with bipolar depression with mixed features. The Baseline Hamilton Depression Rating (HAMD) and Young Mania Rating Scales (YMRS) had 36 and 17 points respectively. First, considering QEEG, the z-score of absolute power in the frontal lobe alpha band increased (Z > 2), and the z-score of the absolute power of the occipital beta band decreased (Z < −3) (Fig. 1). MMN at Fz was −3.3 and LDAEP at Cz was 1.35 (Table 1, Fig. 2). The patient was discharged to the outpatient clinic following remission. At discharge, she was treated with 600 mg lithium, 10 mg aripiprazole, 75 mg quetiapine, and 0.5 mg of clonazepam. In October of the following year, she became talkative, had decreased sleep drive, increased confidence, self-esteem, and sexual desire, and grandious de-lusions. There was a clear mania episode satisfying DSM-5, guilt and suicidal ideation. Therefore, she was diagnosed with bipolar mania with mixed features. The baseline YMRS and HAMD had 34 and 27 points respectively. Considering QEEG, the z-score of absolute power in the delta, theta, and beta bands decreased in the occipital, temporal, and parietal lobes (Z < −3) (Fig. 1). The z-score of the absolute power in the frontal alpha band increased slightly. The range was very small (Fig. 1). MMN at Fz was −1.7 and LDAEP at Cz was 1.67 (Table 1, Fig. 2). She was discharged to the outpatient clinic because her condition had improved to the euthymic phase. At discharge, she was treated with 600 mg lithium, 600 mg valproate, 16 mg blonanserin, 20 mg propranolol, and 1.0 mg clonazepam.

In summary, the characteristic of QEEG in this patient with mixed depression was an increase in alpha; in mixed mania, there was little increase in alpha, and the decrease in delta, theta, and beta was noticeable. LDAEP increased more in the manic phase than in the depressive phase. In contrast, MMN decreased more in the manic than in the depressive phase. After remission of mania, QEEG, LDAEP, and MMN were re-measured. Compared with the manic phase, the decrease in delta, theta, and beta bands in the occipital, temporal, and parietal lobes improved significantly. The LDAEP decreased from LDAEP 1.67 to 0.97. However, in spite of the euthymic phase, MMN amplitude showed a further decrease, from −1.7 to −0.9.

In terms of mood alone, manic and depressive episodes are opposite to each other; therefore, it can be expected that QEEG will be opposite. However, in this case, the QEEG results showed that the alpha power of the frontal lobe increased in the depressive phase, whereas that of the frontal lobe did not decrease in the manic phase. Additionally, the decrease in delta and beta was in her depressive phase and intensified in her manic phase. Therefore, the manic phase can be considered a version with advanced psychopathology, rather than the opposite of the depressive phase. A recent animal study also reported that tryptophan depletion induced mania [4], while other studies reported depression [5,6]; this condition improved with valproate [4]. This means that bipolar depression and mania may have the common biological background. However, this patient did not have a pure manic or depressive state but a mixed state. Thus, more research will be needed to reach a conclusion.

However, to date, there have been no consistent results of bipolar disorder in EEG studies. Some studies show that compared with normal controls, alpha power decreased during the euthymic phase [7]. However, other studies show that alpha power increased [8]. Another study shows that delta and theta bands also decreased in some areas [9]. However, in this study, the phase was not classified separately, and the average Beck Depression Inventory was 17.8 points, which applies to mild depression.

LDAEP generated using the evoked potential induced by an auditory stimulus has been considered a noninvasive tool for indicating CNS serotonin intensity [1]. LDAEP studies on bipolar disorder are rare [10]. Previous studies show that LDAEP is inversely related to CNS serotonin intensity, with low LDAEP reflecting high serotonergic neurotransmission and vice versa [1,11]. Based on this, the patient in this case had a lower serotonin intensity during the mania phase than during the depression phase; after remission of mania, the serotonin intensity increased more than during the depression phase. However, in one study, compared with three-phase patients with bipolar disorder and normal controls, LDAEP was the lowest in the manic phase. In other words, serotonin intensity was significantly higher in the manic phase than in normal controls [12]. However, that study was small, including 15 manic patients, 10 depressive patients, 10 euthymic patients, and 22 normal controls. Therefore, it is necessary to analyze the LDAEP among a larger number of subjects per phase in the future.

MMN is considered a trait marker in schizophrenia and is associated with working memory [13]. A recent study of three groups of major depressive disorder (MDD), bipolar II disorder (BIID), and bipolar I disorder (BID) also found that the size of the MMN among patients with BID was smaller than that among patients with MDD [14]. However, in this case, the MMN of mania was smaller than that of depression and the MMN of remission after mania was smaller than that of mania. This was different from LDAEP returning to the normal range at remission state This suggests that the cognitive function of bipolar disorder is worse in mania than in depression. However, unlike serotonin intensity, it does not return to normal even if mania improves to remission.

In conclusion, using QEEG, LDAEP, and MMN can help clinicians predict a patient’s bipolar state and evaluate serotonin intensity and cognitive function, enabling customized treatment. However, there are still few consistent research results; therefore, there is a need to utilize a larger sample size.

I thank Sol Han, Bonu Jo, and Jooyoung Son for data acquisition.

This study was supported by a grant from the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (2020R1F1A1073188).

No potential conflict of interest relevant to this article was reported.