P300 latency as an indicator of severity in major depressive disorder.

BACKGROUND: Depression is the most common mental health problem across all the age groups. Still diagnostic techniques and laboratory tests are awaited to confirm it. Some studies focus on P300 latency to aid in the diagnosis of depression. Hence, this study was conducted to know whether P300 latency is an indicator of major depressive disorder (MDD).
METHODS: This study was conducted both on patients admitted in the hospital and those attending outdoor clinic giving written informed consent and fulfilling inclusion/exclusion criteria from the Department of Psychiatry, S.N. Medical College and Hospital, Agra. The sample consisted of 30 consecutive patients suffering from MDD as per the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and 30 subjects as normal control. Sociodemographic and clinical history proforma, Hamilton Rating Scale for Depression (Ham-D), and P300 were administered on all 60 subjects. Data were analyzed using mean, standard deviation, and t-test.
RESULTS: Significant difference (P < 0.0001) has been found in HAM-D mean scores of depressed and nondepressed control group subjects. The mean score of depressed group was significantly high (18.066) compared to nondepressed control group (4.833). Significant difference (P < 0.0001) between the mean of P300 latency in depressed and nondepressed control subjects was also found. Mean score of P300 latency in depressed group was significantly high (346.918 ± 19.515) compared to the nondepressed control subjects (303.741 ± 6.378). There was a significant difference in the mean of P300 latency between mild and severe (P < 0.0001), mild and very severe (P < 0.0003), as well as moderate and severe (P < 0.0001) level of depression.
CONCLUSIONS: P300 latency may be used as an indicator of MDD and it is directly proportional to the severity of MDD.

Recently, depression affects more than 350 million people worldwide.[1] Current predictions indicate that by 2030, depression will be the leading cause of disease burden globally.[2] Hence, early detection and management of the depression is the most important issue to be addressed currently.

Most experts believe that biological,[345678910] psychological, and social[11121314] factors play an important role in causing depression, in what is often described as the bio-psycho-social model. There is much overlap and integration, and the precise causes vary depending on the individual and their circumstances.

The diagnosis of depression is based entirely on psychiatric history and mental state examination. Sometimes, psychological tests help in making the diagnosis. Before making the diagnosis of major depressive disorder (MDD), a medical practitioner generally performs a medical examination and selected investigations to rule out any medical illness consequent to the present symptoms. These include blood tests measuring thyroid-stimulating hormone to exclude hypo or hyperthyroidism; basic electrolytes to rule out a metabolic disturbance; and a full blood count including erythrocyte sedimentation rate to rule out a systemic infection or chronic disease.[15] Testosterone levels may be used to diagnose hypogonadism, a cause of depression in men. A computed tomography/magnetic resonance imaging scan can exclude brain pathology in those with psychotic, rapid onset, or otherwise unusual symptoms. No biological tests are available to confirm MDD. Investigations are generally not repeated for a subsequent episode unless there is a specific medical indication, such as serum sodium can rule out hyponatremia if the person presents with an increased frequency of passing urine, a common side effect of selective serotonin reuptake inhibitor antidepressants.

Measuring latency for the P300 response is a physiological means of examining the speed of psychomotor performance.[16] Depressed elderly patients had longer P300 latency than normal elderly subjects. In the depressed patients, P300 latency was related to deficits in initiation and errors in perseveration. Risk factors for vascular disease were associated not only with P300 latency, but also with deficits in initiation and errors in perseveration.[17] Himani et al.[18] reported that the latency of P300 was found to be significantly delayed in cases of major depression as compared to that of controls. On the basis of this study, they suggested that P300 latency is longer in the patients of MDDs, which could be due to constitutive altered “cognitive neuronal pool” or a neurotransmitter/neuropeptide imbalance.

Till date, there is no diagnostic technique and laboratory test to confirm the diagnosis of MDD. Recently, one of the leading areas of the interest for research in the field of psychiatry is neurophysiological studies.

The studies done so far had some lacunae such as small sample size, indoor patients of only severe category of depression, or were represented by only higher age group. To overcome the above lacunae, the present study also includes outdoor patients apart from indoor patients of age group 18–60 years and they belong to different categories of depression, namely mild, moderate, and severe. Keeping these facts in mind, the study was conducted on the patients of MDD who have not initiated antidepressant medication for current episode. For comparison, a matched normal population sample was also included in the study. The objectives of the study were (1) to study P300 latency in patients with MDD and normal control (2) to study the association of P300 latency with the severity of the depression.

The present study was carried out in the Department of Psychiatry, S.N. Medical College and Hospital, Agra, between January 2008 and October 2008.

METHODS

The present study was conducted both on patients admitted in the hospital and those attending outdoor clinic in the Department of Psychiatry, S.N. Medical College and Hospital, Agra. The patients were represented from and around Agra City and comprised the people of urban and rural origin and of all socioeconomic statuses.

The clinical sample consisted of 30 consecutive patients suffering from MDD and from normal population, fulfilling the inclusion/exclusion criteria. Cooperative persons and patients given written informed consent aged between 18 and 60 years, not having any mental illness for the control group, and patients fulfilling the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision[19] diagnostic criteria for MDD for case group were included in the study. Persons aged <18 or >60, patients having psychotic features meeting criteria for schizophrenia or schizoaffective disorder, with history of neurological disease or any other past or current physical disorder that could have affected the brain, substance abuse in past or present, history of electroconvulsive therapy in the last 6 months, having weight loss of more than 20% in the past 6 months, and having any kind of mental illness were excluded for control group.

Assessment tools

Detailed clinical history

Sociodemographic proforma.

Hamilton Rating Scale for Depression

This scale is considered to be the “gold standard” scale for assessing the severity of depression. In addition, this scale is the most sensitive of the commonly used scales for depression in detecting any change in the clinical condition of the patient. Although the Hamilton Rating Scale for Depression (HAM-D)[20] form lists 21 items, the scoring is based on the first 17 items. It generally takes 15–20 min to complete the interview and score the results. Eight items are scored on a 5-point scale; ranging from 0 = not present to 4 = severe. Nine items are scored from 0 to 2. It provides a simple way for assessing the severity of depression; the higher is the score, the more severe is the depression. Severity of depression was categorized on the basis of total HAM-D score into normal (score 0–7); mild (8–13); moderate (14–18); severe (19–22), and ≥23 was considered as very severe depression.

P300

The P300 was discovered originally by Samuel Sutton, Margery Braren, Joseph Zubin, and E. R. John as noted in Science magazine from November 26, 1965,[21] to unpredictable stimuli presented in an oddball paradigm. Although the electroencephalography (EEG) signal is most strongly acquired around the parietal electrodes, interactions involving the frontal and temporal regions as well as several deep brain loci have been suggested[22]

The P300 wave is an event-related potential (ERP), which can be recorded via EEG as a positive deflection in voltage at a latency of roughly 300 ms in the EEG. The signal is typically measured most strongly by the electrodes covering the parietal lobe. The presence, magnitude, topography, and time of this signal are often used as the metrics of cognitive function in decision-making processes

In practice, the P300 waveform must be evoked using a stimulus delivered by one of the sensory modalities. One typical procedure is the “oddball” paradigm, whereby a target stimulus is presented among more frequent standard background stimuli. A distracter stimulus may also be used to ensure that the response is due to the target rather than the change from a background pattern. The classic oddball paradigm has seen many variations, but in the end, most protocols used to evoke the P300 involved in some form of conscious realization or decision making. Attention is required for such protocols.

Applications

Scientific research often relies on the measurement of the P300 to examine ERPs, especially with regard to decision making. As cognitive impairment is often correlated with modifications in the P300, the waveform can be used as a measure for the efficacy of various treatments on cognitive function. Some have suggested its use as a clinical marker precisely for these reasons. There is a broad range of uses for the P300 in scientific research, ranging from the study of depression and drug addiction to anxiety disorders (obsessive compulsive disorder, posttraumatic stress disorder, etc.).[23]

Procedure

The patients and normal subjects fulfilling inclusion/exclusion criteria were included in the study. Sociodemographic detail and clinical history were gathered on a semi-structured proforma. HAM-D was administered to assess the severity of depression and P300 was done on all subjects. For P300 study, subjects were comfortably seated with neck musculature relaxed in a dark and quite room. Electrodes were applied and auditory stimuli were provided to the subjects. Finally, averaging was done of the recordings to find out the P300 waveform. Obtained data were analyzed using mean, standard deviation (SD), and t-test.

The raw data obtained of the MDD and controls were taken. The mean and SDs were obtained for the raw data. Further analysis was performed to detect, if any.

Sample

A total number of 60 patients were included for the study, out of them, 30 each from MDD and nondepressed controls from the normal population. Mean age of the MDD group was 30.8 ± 7.0 years and for controls, it was 31.5 ± 7.2 years. Significant difference was not found between the age of case and control groups (t = 0.11, P < 0.10). Similarly, there was an insignificant difference by gender between case and control groups (χ2 = 0.06, P < 0.10).

Table 1 shows significant difference (P < 0.0001) in HAM-D mean scores of depressed and nondepressed control group subjects. The mean score of depressed group was significantly high (18.066) compared to nondepressed control group (4.833). Significant difference (P < 0.0001) between the mean of P300 latency in depressed and nondepressed control subjects was also found. Mean score of P300 latency in depressed group was significantly high (346.918 ± 19.515) compared to the nondepressed control subjects (303.741 ± 6.378).

Table 1

Comparison of Hamilton Rating Scale for Depression scores and P300 latency mean between depressed and nondepressed (control group)

Table 2 shows that there was a highly significant difference in the mean of P300 latency between mild and severe (P < 0.0001), mild and very severe (P < 0.0003), moderate and severe (P < 0.0001), moderate and very severe (P < 0.001), and between severe and very severe (P < 0.01) level of depression. However, the difference was not significant between mild and moderate depressed patients (P < 0.0807).

Table 2

Distribution and comparison of mean of P300 latency according to severity of depression

DISCUSSION

The study was conducted with the objectives of (1) to study P300 latency in patients with MDD and normal control (2) to assess the association of P300 latency with the severity of the depression.

In this study, the subjects were assessed on HAM-D for depressive severity and P300 latency when they first contacted. Highly significant difference (P < 0.0001) in HAM-D scores of depressed and healthy control group shows that HAM-D score is very much consistent to rule out depressives from nondepressive population [Table 1].

In the present study, we have tried to find out changes in P300 latency, which is a positive deflection in the P300 waveform 300 ms poststimulus. Highly significant difference (P < 0.0001) between the P300 latency in depressed and nondepressed control population indicates that depressives can be differentiated from normal on the basis of P300 latency. In our study, the cutoff score of P300 latency for depressed was found to be 346.918 ± 19.515; however, for normal (nondepressed), it was 303.741 ± 6.378. It also shows that P300 latency is prolong or delayed in the patients of MDD as compared to normal healthy controls. The result is similar to the studies done by Kalayam et al.[17] and Himani et al.,[18] but it is in contrary to the study done by Kaustio et al.,[24] who reported that there was no statistically significant difference in P300 amplitude or latency between depressed and control subjects, although psychotic symptoms are associated with reduction in amplitude and prolongation of the P300 latency.[24] The available diagnostic criteria in the absence of any confirmatory laboratory tests for depression such as other psychiatric diagnoses sometimes leave psychiatrists in predicament. The ability of P300 in differentiating depression from the normal subjects will give some breathing space for the psychiatrists.

Table 2 shows the distribution and comparison of HAM-D mean scores and mean of P300 latency in patients of MDD. The P values obtained are indicative of significant difference in P300 latency between all the severity levels of depression except mild and moderate. This also indicates that the severity level of depression can be differentiated on the basis of P300 latency. Highly significant difference was obtained between severe and very severe (P < 0.0001) depressive patients. This shows that P300 latency is directly associated with the severity of depression. However, the difference was not significant between mild and moderate depressed patients (P < 0.0807). The present study shows that the severity of depression is consistent with the prolongation of the P300 latency. It contradicts the findings of a study,[25] in which correlation between P300 latency and severity of depression was not observed. It may be one of the areas for the researchers to have a look on this aspect of use of P300 in depression so that its role can be established as a prognostic indicator for the depression.

It is generally accepted that changes in the amplitude of the P300 are related to increases or decreases in the intensity, energy required, or level of arousal tied to a specific task.[23] Distinct from P300 amplitude, latency changes indicate that there is a correlation to the processing time necessary for task performance.[26] The present study determined that P300 latency is consistently associated with the depressive states. P300 waveform can be formed only when the subject is concentrated enough on the auditory stimuli. Depressed subjects have poor concentration that results in the delayed processing time which is evident in the form of the delayed P300 latency.

CONCLUSIONS

On the basis of the present study, it can be concluded that the P300 latency is delayed in depressed subjects than the healthy controls. The P300 latency is directly proportional to the severity of depression that can be useful as a prognostic indicator for the depression.

Limitations

Several factors may limit the credibility and generalization of the findings of this study.

Many factors may confound the association between depression and P300 study. Examples of such factors are general level of functioning, absence from work due to sickness, motivation in the test situation, quality of sleep, and use of psychotropic medication or other substances. All of these potential confounding factors may exist independently of depression

P300 study requires a high degree of concentration and attention. Many subjects could not understand the instructions given by the examiner, which results in unsatisfactory waveform formation, as it is averaging out of the waves during whole recording session

Our study was cross sectional. Only 1 time study was done on the subjects, although it requires study at several intervals. This study was performed only on the patients when they first contacted. Further study was not done to know alteration after initiation of the treatment

Sample size was small. Its findings could not be generalized to the general population

Sample was not representative of general population. Study is based on the patients who attend our hospital.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.