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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 21  |  Issue : 2  |  Page : 151-157

Hippocampal volume alteration in medication-naive depression patients in comparison to healthy individuals: An Indian perspective


1 Classified Specialist Psychiatry, Department of Psychiatry, 151 Base Hospital, Assam, India
2 Professor, Department of Psychiatry, INHS Asvini, Mumbai, Maharashtra, India
3 Classified Specialist, Pathology, Department of Pathology, 151 Base Hospital, Assam, India

Date of Submission06-Apr-2019
Date of Acceptance19-Sep-2019
Date of Web Publication07-Oct-2019

Correspondence Address:
Lt Col (Dr) Barun Kumar Chakrabarty
Classified Specialist, Pathology, Department of Pathology, 151 Base Hospital, Guwahati, Assam
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmms.jmms_19_19

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  Abstract 


Context: Depression is the most common mental health problem in all the age groups. However, the exact pathophysiology of this devastating disorder remains an enigma. Many hitherto conflicting studies have focused on volumetric measurement of the hippocampus using magnetic resonance imaging (MRI), but few studies have been conducted in our country. Thus, our study envisages comparing hippocampal volumes of medication-naïve depressed individuals against healthy controls. Materials and Methods: This study was conducted both on patients admitted to the hospital and those attending outdoor clinic fulfilling inclusion/exclusion criteria in a tertiary care hospital. The sample consisted of 25 patients freshly diagnosed as Depressive Episode as per the International Classification of Diseases (ICD-10) and 25 healthy controls. Sociodemographic and clinical history pro forma and Hamilton Rating Scale for Depression were administered on all individuals before obtaining the volumetric measurements of the hippocampi of all individuals using a 1.5 Tesla MRI scanner. Results: Our study indicated right hippocampal volumes (RHVs) of depressed individuals were significantly reduced more so with advancing age. It hinted to the lesser effect of severity of depression on RHVs than in the left hippocampal volumes (LHVs). We found that female patients are more predisposed to RHV loss. However, our study did not reveal any significant difference in LHVs or total hippocampal volumes between depressed individuals and healthy controls. Conclusions: It is one of the exclusive studies which have attempted to shed light on the pathophysiology of depression in relation to its severity and hippocampal volumes in the Indian context.

Keywords: Depression, hippocampus, India, magnetic resonance imaging, medication-naïve, volume


How to cite this article:
Sud K, Goyal S, Chakrabarty BK. Hippocampal volume alteration in medication-naive depression patients in comparison to healthy individuals: An Indian perspective. J Mar Med Soc 2019;21:151-7

How to cite this URL:
Sud K, Goyal S, Chakrabarty BK. Hippocampal volume alteration in medication-naive depression patients in comparison to healthy individuals: An Indian perspective. J Mar Med Soc [serial online] 2019 [cited 2019 Dec 9];21:151-7. Available from: http://www.marinemedicalsociety.in/text.asp?2019/21/2/151/268614




  Introduction Top


The application of neuroimaging technology in clinical neuroscience research holds the potential to transport psychiatry into an era in which pathophysiology, rather than signs and symptoms, guides the nosology of psychiatric disorders.[1]

Intense curiosity in brain function dates back many thousands of years to the earliest writings of Indian and Arabic physicians, through the speculations of ancient Greek philosophers, to Descartes and the rational philosophers, to the great neurologists of 19th century paris, to Freud and Harvey Cushing and countless other psychiatrists; psychologists, neurologists, neuroscientists, and neurosurgeons. Never have we been hitherto so technically equipped with means and resources to study in a systemic as well as scientific manner the structural and functional aspects of neuroimaging laying foundations for future generations of brain scientists.

Modern neuroimaging such as single-photon emission computed tomography, magnetic resonance (MR) volumetry, and functional MR imaging (MRI) has effectively advanced research on etiology, pathogenesis, and therapy options of depressive disorders. During the processing of emotional cues, depressive patients show different activation patterns in the regions of the frontal lobe and the amygdala.[2]

Depression is a worldwide health problem affecting about 1 in 20 people worldwide and leading to about 1 million lives lost due to suicide every year.[3] It is not a homogeneous disorder, but a complex phenomenon, which has many subtypes and probably more than one etiology. The pathogenesis of depressive states can be traced to two major components:first, reactive emotional, and behavioral responses to adverse life events and second, inborn differences in biology and physiology of the brain.[4] Several promising lines of research are underway, but imaging technology has not lived up to the hopes invested in it in the 1990s – labeled the “Decade of the Brain” by the American Psychiatric Association when many scientists believed that brain scans would turn on the lights in what had been a locked black box.[5]

Now, with imaging studies being published at a rate of more than 500 a year, and commercial imaging clinics opening in many parts of the country, some experts say that the technology has been oversold as a psychiatric tool. Other researchers remain optimistic, but they wonder what the data adds to, and whether it is time for the field to rethink its approach and its expectations. The results of such studies are guiding the clinical neurosciences field toward models of depression, in which both functional and structural factors play a role in the pathogenesis of mood disorders.[6],[7]

In this study, we have assessed hippocampal volumes in medication-naïve patients with depression using MRI and compared results so obtained with healthy population.


  Materials and Methods Top


The study was a single-center, comparative observational study carried out in a psychiatry unit of a large teaching hospital. The study sample was drawn from 20 to 65 years old unipolar, moderate-to-severe medication-naive cases of depression without psychotic symptoms diagnosed according to International Classification of Diseases (ICD)-10 criteria. Mentally retarded patients, recurrent/bipolar depression cases, patients those who had a serious acute or chronic medical illness including any cardiovascular, respiratory, endocrinological or neurological disease, cases suffering from other psychiatric disorders, patients with a history of old head injury, cerebrovascular accident, or epilepsy were excluded from the study. Informed consent was taken from all the patients. All 43 treatment-naive cases of suspected depression reported to the outpatient department (OPD) were initially screened at baseline during the study. Finally, 25 treatment naïve cases of depression were included in the study based on inclusion criteria. The patients who have the duration of illness more than 2 weeks were included. Age- and gender-matched 25 healthy individuals who were relatives and friends of other patients and who had accompanied the patients to the hospital were chosen only after taking a written informed consent provided they did not have a diagnosis of depressive episode (as per ICD-10) after clinical assessment. Ethics committee approval was obtained prior to recruitment of test subjects.

All cases recruited in the study were interviewed, evaluated, and diagnosed by a competent psychiatrist. Sociodemographic information, details of presenting psychiatric complaints, medical illness, family history, and history of substance abuse/dependence were collected in detail and recorded. A detailed general physical examination and systemic examination including neurological examination were performed. The patients were also screened for any comorbid psychiatric disorder utilizing a thorough, detailed history.

Socioeconomic rating scale (Gupta and Sethi- 1978)[8] was used for the assessment of the socioeconomic status. The categories are grouped into five social classes, namely very high, upper-middle, middle, lower-middle, and very low. The Hamilton Rating Scale for Depression (HRSD) developed by M. Hamilton, which is one of the most widely utilized rating scales for depressive symptoms, was used to assess the severity of symptoms of depression. The items are rated on either a 0–4 spectrum (0 = none/absent and 4 = most severe) or a 0–2 spectrum (0 = absent/none and 2 = present). After these preliminaries, the individuals underwent both multiplanar and multisequence MRI brain scans at the department of radiology of the hospital. MRI was used to measure volume of hippocampus using a 1.5 Tesla MAGENETOM Symphony MRI (SIEMENS) System. Volumes were obtained by 1 mm thickness slices in T1-weighted coronal section.

The imaging data were analyzed using the Medical Image Processing and Visualization (MIPAV) Software Package Version 7.0.1 (Center for Information Technology, National Institutes of Health, Bethesda, Maryland, USA) by a single radiologist who was blind to subject information. The hippocampus was manually traced in the coronal plane using three-dimensional spoiled gradient recalled acquisition in steady-state coronal sections. Intracranial volumes of the hippocampi were calculated by summing areas of successive coronal slices and multiplying by slice thickness, using the most anterior slice in which the temporal stem was first visible. The most anterior slice showing the mammillary bodies was used as the hippocampal boundary. Dorsally and laterally, the alveus used as a landmark for the hippocampal head and outlined up to the origin of the fornices medially. The ambient fissure and uncal sulcus defined the medial border of the hippocampus. The superior border of the hippocampus was bounded anteriorly by the temporal horn and posteriorly by the fornix. Our measurement of the hippocampal formation included the cornu ammonis, dentate gyrus, and subiculum [Figure 1].
Figure 1: Magnetic resonance imaging of left hippocampus outlined with manual tracing of boundaries of the left hippocampus

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The data obtained were analyzed by Statistical Package for Social Sciences (SPSS) version 20 (IBM Corp., Armonk, NY, USA). Descriptive statistics were used for the demographic data and variables therein. The t-test was deployed to check the statistical difference in the hippocampal volumes and the mean age between both the groups. Pearson's correlation was used to check the relationship between HRSD scores and hippocampal volumes in the cases.


  Results Top


The study groups were age- and sex-matched. The various demographic parameters of both the study groups for the variables such as handedness, education, occupation, socioeconomic status, and marital status were grossly comparable [Figure 2].
Figure 2: Demographic details

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In depressed individuals, it was found that left hippocampal volumes (LHV) decreases with age. In this study, left-handed depressed individuals had lesser hippocampal volume loss. The study showed that there was a greater tendency for hippocampal volume loss in females during the depression. The Hamilton Depression Rating Scale (HDRS) scores of the cases showed that LHVs tends to reduce with increased severity of depression [Table 1].
Table 1: Comparison between left hippocampal volume and mean age, handedness, gender, and Hamilton Depression Rating Scale scores amongst study groups

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It was observed that in depressed patients, right hippocampal volume (RHV) decreases with age. The reduction of RHVs was more in right-handed patients. Our study indicated that female patients are more predisposed to RHV loss during depression. It hinted at a possibility of lesser effect of severity on RHVs unlike seen in LHVs [Table 2].
Table 2: Comparison between right hippocampal volume and mean age handedness, gender, and Hamilton Depression Rating Scale scores among study groups

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With advancing age, it was found that there was a trend of reduction of total hippocampal volumes (THVs) in depressed individuals. Our study results indicated there could be a chance of greater THV loss in depressed individuals who are left-handed and also revealed a possibility of higher preponderance among female patients for hippocampal volume loss. The study pointed to a possibility of hippocampal volume reduction with increasing severity of illness [Table 3].
Table 3: Comparison between total hippocampal volume and mean age handedness, gender, and Hamilton Depression Rating Scale scores among study groups

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About 76% of the healthy persons studied had LHVs in the range of 2.00–2.99 cc 3. LHVs were in the similar range among right- and left-handed normal population. The study revealed that males in the general population have larger LHVs than females. In controls, it was found the there was a loss of RHV with advancing age and suggested the possibility of smaller RHVs in right-handed persons in the general population. The study showed that RHVs of males were larger than those of females in the general population. THV ranges in healthy controls again indicated hippocampal loss as the age increases and that right-handed people have larger hippocampi. It can be deduced from THV results that females probably have smaller hippocampal volumes as compared to males. There appears to be a statistically nonsignificant trend of reduction of hippocampal volume in depressed individuals as compared to those who are not depressed [Figure 3].
Figure 3: Mean left hippocampal volumes, right hippocampal volumes and total hippocampal volumes of depressive patients versus healthy study group

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No statistically significant correlation was observed between LHV, RHV, THV, and the HDRS scores of the depressed cases. Although there was no statistically significant correlation found between LHV, RHV, THV, and the age of the healthy population group, Pearson's correlation (r) was found to be significant in depressed patients, implying that as age increases the RHV decreases [Table 4].
Table 4: Correlation between left hippocampal volumes, right hippocampal volumes, total hippocampal volumes, and Hamilton Depression Rating Scale scores

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It follows that there is no significant difference between the mean LHVs between both the study groups (P = 0.30). However, there was a statistically significant difference between the mean RHVs between the groups (P = 0.02), implying that the mean RHV of the healthy population higher than the depressed patients. It was observed that there is no statistically significant difference between the mean THVs of studied groups (P = 0.16).


  Discussion Top


Depressive disorder is a complex condition of multifactorial etiology. To understand the neurobiology of depression, brain morphological alterations have been observed, using MRI and voxel-based morphometry (VBM) techniques with variable results. Abnormalities are commonly located in anterior cingulate cortex, frontal cortex, orbitofrontal cortex, ventral striatum, thalamus, and hippocampus. Morphometric reduction in the hippocampus is one of the most consistent findings in major depressive disorder, with both a region of interest approach and VBM. The correlation between hippocampus size and depression has been implicated in pathogenesis of depression,[9] predicting response to treatment,[10] age of onset of depression,[11] and effect of depression on hypothalamo-pituitary-adrenergic axis leading to reduced hippocampal size.[12]

According to literature, 50% depressive disorder patients have an onset of illness between the ages of 20 and 50[13] which is also reflected in our study group. Studies have consistently shown depression occurring twice as much in females than in males.[14] However, in our study, the high proportion of males may be due to sociocultural limitations.

A majority of the individuals in both the groups were right-handed. Accumulated data from studies implicating left-sided brain lesions in depression have provided support for the hypothesis of abnormal cerebral lateralization in unipolar depression.[15] However, no significant differences between the two groups were detected as far as handedness of the subjects.

In our study, it was observed a trend of decreasing LHV with increased age increases in the depressed population consistent with previous studies. We found that LHVs of depressed individuals was seemingly reduced as compared to their healthy counterparts. These findings are commensurate with researchers who have not found any significant changes in LHVs.[16],[17],[18] However, some authors,[19],[20] have found reduced LHVs in depressed individuals. The present study reveals that RHV decreases as age progresses. This observation is in agreement, with some other studies.[11],[21]

Our study reflects that there is an obvious reduction in RHV of cases as compared to healthy population group indicating that there was indeed an RHV loss in people afflicted with depression. Many workers support this outcome.[22],[23] Our study further corroborated with previous research findings by demonstrating overall reduction in hippocampal volume with more loss of volume toward the right side than the left.[24],[25]

The apparent trend of THV loss with increasing age in depressed patients was not found statistically significant. Lloyd et al. found that participants with late-onset depression had bilateral hippocampal atrophy compared with those with early-onset depression and controls.[11] A trend of reduction of THV in patients than nondepressed individuals though not statistically significant seemed to emerge (P = 0.16). Hence, like many other workers, our study also did not reveal any statistically significant loss of THV.[16],[17],[18] However, several researchers have noted bilateral hippocampal volume declines in depressed individuals, with the magnitudes ranging from 8% to 19% relative to healthy controls.

There is not much literature available which evaluates the severity of depression and its relation to hippocampal volume. However, many researchers have argued that the duration of illness,[23] and number of episodes [17] has a more profound impact on the hippocampus volume. Hence, ours is perhaps one of the unique studies which have tried to shed light on the relation between depression severity (based on HDRS scores) and hippocampal volumes.

Various hypotheses have been proposed for this observed finding. The most accepted notion is the neurotoxicity hypothesis [26] which implicates hippocampal cell death leading to a loss of hippocampal volume might occur as a consequence of repeated stress with associated glucocorticoid excess. An alternative vulnerability hypothesis, suggests that reduced hippocampal volume is a pre-existing risk factor for stress-related disorders induced by genetics and early exposure to stress.[27] Recent studies [28] have found depressive disorder to be a significant risk factor for subsequent Alzheimer dementia (AD). Studies also suggested that the hippocampal complex (HC) volume loss may be arrested by antidepressant treatment.[29]

There is emerging data coming up establishing hippocampal neuroplasticity in depressive disorder. Neuroplasticity theory hypothesized that external or internal stimuli continuously modifies neural circuits and connections. Adult neurogenesis mainly occurs in the dentate gyrus of the HC throughout life. It has been suggested that depressive disorder results in hippocampal microdamage due to cortisol induced disruption of neurogenesis that followed by tissue regeneration encompassing neurotrophins and neurogenesis. Therefore, stress axis deviation is related to affective disorders that consecutively affect HC volume.[30]

Although the study was designed in the best possible manner, it had certain limitations. The study population was small. The small sample size is a limitation to the external validity of the study. However, given the strict inclusion and exclusion criteria to increase the internal validity of the study, a universal sampling method was adopted, and all treatment-naive cases of suspected depression reporting to the OPD during the study were included. The study was a cross-sectional study and data derived were extrapolated to derive relationship of hippocampal volume loss with age. The early and late-onset cases were not separated due to small sample size. Other hitherto unknown causes and individual variations which could affect hippocampal volume were not included in the exclusion criteria. Some or all of these could have been confounding variables. There could be methodological differences in MRI acquisition techniques. Hence, in our study, statistical trends were established; nevertheless, further longitudinal studies covering larger populations need to be replicated to validate the findings of this study.


  Conclusion Top


The hippocampus of patients with unipolar depression has been studied since 1993 using MRI techniques. Conflicting findings have accumulated over the years, and in India, comparable studies are rare. Our study was an endeavour to contribute to this ever-growing area of interest by probing into the depths of Hippocampal volume changes in depressed individuals as related to age and severity by comparing with matched healthy population. We found that RHVs were statistically significantly reduced in depressed individuals, and this decreased RHVs correlated negatively with age. However, our study did not reveal any significant difference in LHVs or THVs between those who were depressed and those who were not. Although, there was a wide range of agreement and disagreement among our results and those of other workers globally, our attempt at investigating these parameters did yield valuable inputs. Nevertheless, despite variation in measurement techniques and patient samples, this study has paved the way for others to embark on a quest to ascertain the neuro-biological substrate of depression. The summations of these observations would not only culminate into a more exhaustive understanding of the complex nature of this debilitating disorder but would also elucidate the mechanisms by which these changes can be ameliorated by newer drugs.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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