misdiagnosis of bipolar disorder is a potentially serious problem for patients , which sometimes leads to inappropriate treatment.1 however , it is not unusual for bipolar disorder to be misdiagnosed as a major depressive disorder.2 previous studies have shown that the proportion of cases of bipolar disorder misdiagnosed as a major depressive disorder is 20.8%40%.24 nevertheless , there are few biomarkers for accurate diagnosis .
if patients become depressive for the first time and have never experienced a manic episode , it is difficult to determine whether that depressive episode is unipolar or bipolar depression , and the risk of a manic switch is unknown .
near - infrared spectroscopy ( nirs ) is a noninvasive and useful method that uses near - infrared light to measure hemoglobin concentration changes in the cortical surface area .
although changes in the nirs signals measured on the forehead during the word fluency task may be partially associated with changes in skin blood flow,5 the changes in oxygenated hemoglobin ( [ oxyhb ] ) are associated with changes in the regional cerebral blood volume .
nirs enables the assessment of brain function , and recent studies have shown that the frontal hemodynamic patterns detected by nirs can be a biomarker for the diagnosis of major psychiatric disorders.6,7 in the present case , nirs during the word fluency task was measured during the clinical course of bipolar disorder . in brief , [ oxyhb ] and deoxygenated hemoglobin ( [ deoxyhb ] ) were measured with a 52-channel nirs machine ( hitachi etg-4000 ; hitachi medical corporation , tokyo , japan ) at two wavelengths of near - infrared light ( 695 and 830 nm ) , the absorption of which was measured , and [ oxyhb ] and [ deoxyhb ] were calculated as previously described.8 the distance between pairs of source - detector probes was set at 3.0 cm and each measured area between pairs of source detector probes was defined as a  channel  .
the probes of the nirs machine were fixed with 3  11 thermoplastic shells , with the lowest probes located along the fp1-fp2 line according to the international 1020 system used in electroencephalography .
we used the word fluency task because it is easy to understand and execute , and it is also an executive task that produces distinct differences in performance and neuroimaging data among each diagnostic group of psychiatric disorders.7 additionally , plasma levels of homovanillic acid ( hva ) , a dopamine metabolite , and 3-methoxy-4hydroxyphenylglycol ( mhpg ) , a noradrenaline metabolite , were measured longitudinally using high performance liquid chromatography . in our hospital , we measured both plasma levels of monoamine metabolites ( every 3 weeks in principle ) and nirs ( before and after the treatment ) in psychiatric inpatients with mood disorders to investigate the association between plasma monoamine metabolites and nirs signals .
this protocol was approved by the ethics committee of fukushima medical university , and the patient consented to participate after having been informed of the purpose of the study .
the patient was a 22-year - old man who had no history of psychiatric illness .
he was admitted to our hospital due to major depression that was diagnosed according to the diagnostic and statistical manual for mental disorders , fourth edition , with moderate sadness , agitation , retardation , and difficulty in concentrating .
we treated the patient with paroxetine and lorazepam for about 4 weeks , but treatment was not successful . on day 4 ,
his montgomery sberg depression rating scale ( madrs ) score was 44 , and his plasma levels of hva and mhpg were 4.6 ng / ml and 1.9 ng / ml , respectively .
figure 2 shows the waveform of [ oxyhb ] during the cognitive activation of the word fluency task .
nirs signal changes were measured during a 10 second pretask baseline period , a 60 second task period , and a 55 second posttask baseline period .
the initial syllables assigned were changed every 20 seconds ( /a/ , /ka/ , and /sa/ , respectively ) during the 60 second task period . during the task period ,
the patient was instructed to generate as many japanese words beginning with the designated syllable as possible . in the pretask and the posttask baseline periods ,
the patient was instructed to repeat a train of syllables ( /a/ , /i/ , /u/ , /e/ , and /o/ ) .
he sat on a chair in a room with daylight with his eyes open throughout the measurements .
we focused on increases in [ oxyhb ] , because this appears to reflect task - related cortical activation more directly than decreases in [ deoxyhb].7 we defined the patterns of nirs waveforms using the grand average waveforms in the frontal region ( ch 2528 , ch 3638 , and ch 4649 ; figure 3 ) and two simple visual indices,7 integral value , and centroid value . the integral value describes the size of the hemodynamic response during the 60 second activation task period , whereas the centroid value serves as an index of time course changes throughout the task , with periods representing the timing of the hemodynamic response.7 a recent study reported that the optimal threshold of the centroid value of the frontal region between major depressive disorder and two other disorders ( schizophrenia and bipolar disorder ) is 54 seconds ( major depressive disorder < other 2 disorders).7 on day 4 , the centroid value of the grand average in the central region was 68.6 seconds ( figure 2 ) , and the nirs waveforms showed an [ oxyhb ] reincrease in the posttask period ( ch 34 , 35 , 36 , 39 , 45 , 46 , 47 , and 49 ; figure 2 ) , which is characteristic of schizophrenia.6,7,911 on day 25 , his madrs score was 40 , his plasma hva level was markedly higher at 49.3 ng / ml , and his plasma mhpg level was 1.6 ng / ml . on day 27 , he was voluntarily discharged from the hospital , but was still in a depressive state . on day 30 , 3 days after leaving the hospital , he became manic and was readmitted to our hospital .
he was in a state of psychotic mania with elevated mood , grandiosity , aggression , auditory hallucination , and thought broadcast , with a young mania rating scale ( ymrs ) score of 48 .
we subsequently treated him with lithium , risperidone , and zotepine for approximately 3 weeks , and his manic state improved . on day 46 , his ymrs score was 29 , and plasma levels of hva and mhpg were 17 ng / ml and 1.3 ng / ml , respectively .
however , he refused drugs because of extrapyramidal symptoms and became manic with psychotic symptoms again . therefore , we tried a combination of lithium , olanzapine , and zotepine , and the treatment was successful . on day 77 , the nirs waveforms turned to a negative pattern ( figure 2 ) , which was defined by an integral value of the grand average in the central region < 0 , whereas there were [ oxyhb ] reincreases in the posttask period ( ch 33 , 41 , 42 , 43 , 44 , 51 , and 52 ) . on day 99
, his ymrs score decreased to 3 , and his plasma levels of hva and mhpg were 8.7 ng / ml and 1.9 ng / ml , respectively .
nine months later , he was off medication , became manic again , and was admitted to another psychiatric hospital .
to the best of our knowledge , this is the first case report to measure both nirs and plasma levels of monoamine metabolites in a patient with bipolar disorder , although the clinical course in this patient was not usual as the mania occurred within the first weeks of the initiation of serotonin selective reuptake inhibitor ( ssri ) treatment . in this case
, it was difficult to diagnose bipolar depression from only clinical symptoms at his first admission .
we could not predict the subsequent manic switch with psychotic features , which was likely caused by paroxetine .
however , the results of nirs on day 4 showed a pattern of schizophrenia , characterized by a smaller [ oxyhb ] increase during the first half of the task and an [ oxyhb ] reincrease in the posttask period,4,911 but not a unipolar depression pattern , which is characterized by only a smaller [ oxyhb ] increase during the first half of the period.4,9,12,13 care must be taken to interpret these findings as patterns of diseases because of the small number of studies .
an [ oxyhb ] reincrease in the posttask period is considered as inefficient activation of the prefrontal cortex,4,9,11 which is one of the quantitative abnormalities in schizophrenia.14 these results may have predicted a possible risk of a manic switch in this patient .
a recent study7 reported that the frontal hemodynamic patterns detected by nirs accurately distinguished between patients with major depressive disorder and those with bipolar disorder or schizophrenia with depressive symptoms .
although the clinical status of bipolar depression may be different from that of unipolar depression,1 it is not easy to clearly distinguish without a previous manic episode .
in fact , most bipolar disorder patients with depressive symptoms are initially diagnosed as having major depression.2 because there are few biomarkers for diagnosis , nirs findings may help for distinguishing unipolar and bipolar disorders . however , nirs signals changed after treatment with antipsychotics and lithium in this patient .
although it is believed that nirs waveforms are a possible trait marker , nirs signals may change with the state or the medication .
interestingly , nirs findings in this case showed a pattern of schizophrenia , not a pattern of bipolar disorder , which is characterized by a smaller [ oxyhb ] increase during the early period , and larger [ oxyhb ] increase during the late period of this task.15 this result is consistent with a manic episode in this case that included psychotic symptoms such as hallucination and thought broadcast .
furthermore , 5 days before the manic switch , the patient s plasma hva level was almost ten times higher than just after admission . because the hva level change occurred in tandem with the manic symptoms during the clinical course , it is estimated that the manic episode in this case was associated with dopaminergic function .
plasma hva levels have been considered as a possible indicator in the treatment of schizophrenia16,17 and bipolar disorder.18,19 furthermore , because ssris act on dopaminergic and serotonergic neural systems,20 the increase in the plasma hva level in this patient may have been induced by paroxetine .
a previous study reported that psychosis or mania induced by ssris showed a pattern of increased plasma hva levels.21 this is consistent with our findings of the changes in plasma hva levels in this patient . taken together , the nirs findings in this patient may be based on dopaminergic dysfunction .
however , the changes in the nirs may not be directly associated with the changes in plasma hva levels , because nirs findings are based on frontal brain functions , whereas plasma hva levels are related to psychotic symptoms,22 which seem to be a reflection of the mesolimbic dopamine system .
in this case , nirs findings in a depressive state may predict the possible risk for a manic switch .
longitudinal monitoring of plasma hva levels may be useful in the treatment of bipolar disorder , in particular in patients with psychotic symptoms like this case .
 misdiagnosis of bipolar disorder is a serious , but not unusual problem for patients . nevertheless , there are few biomarkers for distinguishing unipolar and bipolar disorder . 
 near - infrared spectroscopy ( nirs ) is a noninvasive and useful method for the measurement of hemoglobin concentration changes in the cortical surface area , which enables the assessment of brain function . 
 we measured nirs and plasma monoamine metabolite levels in a patient with bipolar disorder . 
 a 22-year - old man was admitted due to major depression . at admission 
 , nirs findings showed oxygenated hemoglobin reincrease in the posttask period , which is characteristic of schizophrenia . 
 after treatment with paroxetine , he became manic with psychotic symptoms . 
 his plasma level of homovanillic acid just before the manic switch was ten times higher than that just after paroxetine initiation . 
 treatment with lithium and antipsychotics was successful , and plasma homovanillic acid decreased after treatment . in this case , the nirs findings may predict a possible risk of a manic switch , which is likely induced by paroxetine . 
 nirs may be able to help distinguish unipolar and bipolar disorder in clinical settings . 
Introduction
Case report
Discussion
Conclusion