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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 35  |  Issue : 1  |  Page : 22-38

Cognitive and clinical correlates of hippocampus volume, an MRI 2-year follow-up study


1 Department of Psychiatry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo, Egypt
3 Department of Psychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt
4 Department of MRI, Hadi Hospital, State of Kuwait, Kuwait

Date of Submission10-Feb-2012
Date of Acceptance20-Mar-2012
Date of Web Publication18-Feb-2014

Correspondence Address:
Mamdoh El Gamal
Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1105.127273

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  Abstract 

Background
Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode psychosis. Many studies examining brain structure changes in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether reduction in hippocampal volume is a morphological trait in such a group of patients in an attempt to find its clinical and cognitive correlates for patients with different diagnoses of first-episode psychosis both at their first contact and at short-term follow-up.
Patients and methods
We obtained high-resolution three-dimensional T-weighed MRI scans of the hippocampus for 90 patients with first-episode psychosis (49 patients with schizophrenia, 21 patients with bipolar psychoses, and 20 patients with depressive psychosis) as well as 23 healthy controls both at the baseline and after 2 years of assessment. Assessment of the clinical picture was carried out using the structured SCID interviews, HDRS, YMRS, and PANSS. Cognitive function and intellectual abilities were examined using WMS-III, the Trail Making Test, and WAIS.
Results
A greater reduction in hippocampal volume was evident in the schizophrenia group than the bipolar and depressive psychosis groups compared with the healthy controls both at baseline and after 2 years, indicative of being a morphological trait for such patients. Negative symptoms were related to hippocampal volume reduction in the schizophrenia group. The initial assessment of untreated patients revealed reduction in their hippocampus volume which correlated with the longer duration of untreatment. After 2 years of follow-up, recurrent hospitalization was found to be related to further volume reduction. Impaired working memory, verbal memory, and baseline intellectual abilities were related positively to structural hippocampal changes. Cognitive and clinical correlation with a reduction in hippocampal size was less evident in the bipolar psychosis group, which may highlight different structural changes in other areas in the striatum.
Conclusion and recommendation
Hippocampal volume reduction may be considered as morphological traits for some patients with first-episode psychosis, and linked to some clinical and cognitive impairment. Study of the shape, localized regions of the hippocampus as well as other brain areas may help to clarify the circuits shared in the pathophysiology of psychoses of different types. Early detection of structural changes with the study of high-risk patients may aid effective treatment and improve outcomes.

Keywords: Cognitive impairment, first-episode psychosis, hippocampus, magnetic resonance imaging


How to cite this article:
ELTayebani M, El Gamal M, Bassim R, Abdelaal MS. Cognitive and clinical correlates of hippocampus volume, an MRI 2-year follow-up study. Egypt J Psychiatr 2014;35:22-38

How to cite this URL:
ELTayebani M, El Gamal M, Bassim R, Abdelaal MS. Cognitive and clinical correlates of hippocampus volume, an MRI 2-year follow-up study. Egypt J Psychiatr [serial online] 2014 [cited 2021 Jun 19];35:22-38. Available from: http://new.ejpsy.eg.net/text.asp?2014/35/1/22/127273


  Introduction Top


Magnetic resonance imaging (MRI) studies have shown the presence of structural brain abnormalities in multiple brain regions in chronic schizophrenia patients compared with healthy controls (Shenton et al., 2001). Although volume changes have also been observed in various brain regions in first-episode schizophrenia patients (ElIison-Wright et al., 2008), only hippocampal volume reduction and ventricular enlargement are consistently present, as shown in recent meta-analysis (Steen et al., 2006; Vita et al., 2006).

Inconsistencies among studies are probably because of differences in methods, sample sizes, and sample composition (e.g. studies vary in the inclusion criteria of previous exposure to antipsychotic medications and substance abuse or dependence).

Numerous studies point toward hippocampal involvement in schizophrenia (Boos et al., 2007; Gur et al., 2007). Volumetric reductions in the hippocampus, however, are not pathognomonic for schizophrenia, but they have been associated with numerous neuropsychiatric disorders, including substance abuse (Geuze et al., 2005). Moreover, typical and atypical antipsychotics may affect hippocampal volumes differently (Chakos et al., 2005). In antipsychotic-naive patients, significant hippocampal reductions have been reported (Salgado-Pineda et al., 2003), although not consistently (Laakso et al., 2001). The clinical implications of hippocampal involvement in antipsychotic-naive schizophrenia patients are unclear. However, hippocampal reductions may be associated with the duration and psychopathology of illness (Matsumoto et al., 2001).

Memory deficits are one of the most consistently reported cognitive difficulties in both symptomatic and remitted patients with major depressive illness (Porter et al., 2003; Weiland-Fiedler et al., 2004; Bearden et al., 2006). Given the central role of the hippocampus in the formation and consolidation of new memories (Eichenbaum and Fortin, 2005), as well as its importance in the regulation of motivation and emotion (Davidson et al., 2002, hippocampal pathology is likely to be involved in the pathophysiology of the illness. Indeed, reduced hippocampal volume has been reported by many, but not all, neuroimaging studies of major depressive disorder (MDD) (Campbell and MacQueen, 2004; Videbech and Ravnkilde, 2004). The results of a recent meta-analysis indicated that differences in hippocampal volume were only apparent among MDD patients with a duration of illness longer than 2 years or among those who had more than a single disease episode, suggesting that hippocampal volume reduction typically occurs after disease onset in MDD patients (MCKinnon et al., 2009).

Structural changes already observed in antipsychotic-naive schizophrenia patients are likely not because of hospitalization, chronicity, or antipsychotic treatment. However, schizophrenic patients commonly have a past or a current history of substance abuse or dependence. Both alcoholism (Pfefferbaum et al., 1998; Nagel et al., 2005) and cannabis abuse (Raise et al., 2008; Yucel et al., 2008) have been associated with gray matter changes in the frontal, temporal, and subcortical regions as well as ventricular changes. Some studies have dealt with this issue by excluding patients with comorbid substance abuse or dependence (Keshavan et al., 1998; Shihabuddin et al., 1998; Lang et al., 2001). However, the criteria used are not uniform among studies and encompass exclusion because of substance dependence (Crespo-Pacorro et al., 2007), 'significant abuse' (Gunduz et al., 2002), or abuse within a 6-month period as well as no mention of abuse (Corson et al., 1999; Shihabuddin et al., 2001).

In the current study, patients with a history of or current substance abuse or dependence or even during the study were excluded.

The primary aim of our study was to determine whether the presence of hippocampal reduction is a morphological trait in drug-naive first-episode psychosis patients, as well as its association with cognitive and clinical presentation at baseline and after 2 years of follow-up.


  Patients and methods Top


Place

All participants were part of a prospective outcome study of drug-naive first-contact patients with first-episode psychosis treated in the psychological Medicine Hospital, State of Kuwait (three million inhabitants). This is the only and official hospital that provides psychiatric services at the tertiary level.

The research was approved by the research and ethics committee. Before participation, all patients had to sign an informed consent either by themselves or their caregivers who live with them.

Patients

Inclusion criteria

  1. Kuwaiti, first-contact drug-naive patients with first-episode psychosis.
  2. Age between 18 and 65 years.
  3. Patients of both sexes were included.
  4. Right handed.


Being accompanied by at least one close relative who live with the patient was a prerequisite for accurate assessment of history.

Only Kuwaiti patients were recruited, not only to facilitate the process of follow up but also to avoid any cultural differences in the clinical presentation of psychosis

Exclusion criteria

  1. Patients with any neurological disorders, seizure, mental subnormality, or history of head trauma with loss of consciousness more than 10 min.
  2. Current major medical illness.
  3. History or current substance abuse or dependence.
  4. Patients with metal implants.
  5. Claustrophobia.


Control participants

Healthy individuals were recruited from the Radiology Department after signing a written consent of participation after fulfilling the inclusion and exclusion criteria. On the basis of the SCID interview, they had no history of or current Axis I psychiatric disorder.

Process and design

The study was designed to have two parts:

  1. Baseline assessments: All drug-naive patients with first-contact psychosis admitted in the period between January 2008 and December 2009 were assessed by clinical, psychometric, and MRI studies.
  2. Follow-up after 2 years: Repeated assessments and MRI were performed using the same clinical and psychometric scales as those used at baseline. The study was completed at the end of 2011.


By the end of recruitment, we had 176 patients with first-episode psychosis; only 139 were Kuwaiti, and 18 of them did not fulfill the inclusion criteria and 11 refused to participate in the study. In all, 110 patients completed the baseline study. On follow-up, 90 patients were available. Of the 90 eligible patients, 49 patients (54.4%) were diagnosed with schizophrenia spectrum disorders; 21 patients had bipolar disorder (23.3%) with psychosis and 20 (22.2%) patients were diagnosed with psychotic unipolar depression.

Clinical assessment

Consensus diagnoses were established by members from the clinical and research team using the structured clinical interview SCID of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) (First et al., 1996), and all available collateral information from families and/or previous caregivers, medical records, and information provided by the clinical and research team. This information generally included not only the initial symptoms but also direct and ancillary information obtained over the course of 6-8 weeks of initial treatment. Repeated assessments on clinical bases every 6 months or at the time of rehospitalization were also carried out.

For each patient, the following measures were applied.

Hamilton Depression Rating Scale (Hamilton, 1960, 1967)

The original version of 17 items [Hamilton Depression Rating Scale (HDRS 17)] related to symptoms of depression experienced over the past week. A score of 0-7 is generally considered to be within the normal range (or in clinical remission), 8-13 as indicating mild depression, 19-22 as moderate depression, and more than 23 as very severe degree of depression.

Young Mania Rating Scale (Young et al., 1978)

Young Mania Rating Scale (YMRS) is an 11-item clinician-rated scale designed to assess the severity of manic symptoms over the previous 48 h both for baseline assessment and for follow-up of treatment response.

Four of the YMRS items were scored on a 0-8 scale, with the remaining five items being rated on a 0-4 scale. A score of 12 or less indicates remission of symptoms.

Positive and Negative Syndrome Scale (Kay et al., 1987)

Positive and Negative Syndrome Scale (PANSS) has 30 items along three subtests (positive, negative, and general psychopathology). Items are scored along a continuum of severity between 1 (asymptomatic) and 7 (extreme symptom severity). Analysis was carried out on both total and subscale scores.

Cognitive tests

Cognitive ability was examined by dividing various neuropsychological tests into six cognitive domains as suggested by the National Institute of Mental Health measurement and treatment research to improve cognition in schizophrenia (Nuechterlein et al., 2004, 2008; Kern et al., 2004, 2008).

All participants were tested and scored both at baseline assessment and at the end of 2 years of follow-up.

The following domains were derived:

  1. Working memory: spatial span subtests of the Wechsler Memory scale-3rd ed. (WMS-III) (Wechsler, 1997) and the Digit span subtests of Wechsler Adult Intelligence Scale-3rd ed. (WAIS-III) (Wechsler, 1997).
  2. Verbal learning and memory: the logical memory subtest of WMS-III.
  3. Visual learning and memory: visual reproduction subtests of WMS-III.
  4. Reasoning and problem solving: the trial making-B and Block Design subtest of WAIS-III.
  5. Speed and processing: the trial-making test A (completion time (Reitan, 1992) and the digit symbol subtest of WAIS-III.
  6. Attention: the spatial span and digit span forward subtest of WAIS-III.
  7. Intellectual ability using WAIS:


Using the two-subtest of version of WAIS (verbal and performance subtest), it was measured both at baseline and at the end of follow-up (2 years).

Duration of untreated psychosis (DUP): defined as the number of weeks between the first expression of psychosis and study recruitment.

Duration of untreated illness (DUI): defined as the number of weeks between the start of any behavioral changes and/or pathological changes and study recruitment.

MRI study

All participants were examined using an MRI study at baseline and at the end of 2 years of follow-up. The patients at baseline were examined according to schedule after patients were clinically assessed to be stable.

Imaging protocol and volume measurements

Measurement of the hippocampus started by tracing the outline of the temporal lobe on each section followed by tracing the borders of each right (RT) and left (LT) hippocampus.

MRI acquisition and processing

MRI was obtained, for all patients and control at the initial assessment and 2 years later, using a single 1.5-T scanner (Sigma Horizon; General Electric Medical System (Montreal, Quebec, Canada).

Straps were used across the chin and forehead and a foam pad was supporting the head of the patient to minimize movement.

Right and left hippocampal volumes were measured using a manual tracer around their borders. One rater Abdelaal MS, performed all tracings. About 60, three -dimensional contiguous coronal oblique slices, 3 mm each, perpendicular to the hippocampus were performed after exclusion of any organic lesions.

Statistical methodology

Data were collected and coded, and then entered into an IBM compatible computer using SPSS, version 17 for Windows (SPSS Inc., Chicago, Illinois, USA). The data entered were checked for accuracy and then for normality using the Kolmogorov-Smirnov test.

Qualitative variables were expressed as numbers and percentages, whereas qualitative variables were expressed as means (X) and SD.

The arithmetic means (X) was used as a measure of central tendency whereas the SD was used as a measure of dispersion.

The following statistical tests were used:

  1. Independent-samples t-test was used as a parametric test of significance for comparison between two sample means after carrying out Levene's test for equality variances.
  2. Independent-samples Mann-Whitney's U-test (or Z test) was used as a nonparametric test of significance for comparison between two sample medians.
  3. The χ2 -test (or log-likelihood ratio was used as a nonparametric test of significance for comparison between the distribution of two qualitative variables.
  4. The Kruskal-Wallis test (χ2 -value) was used as a nonparametric test of significance for one-way comparison between more than two sample means, when the one-way analysis of variance test was not appropriate.
  5. Spearman's rank correlation coefficient was used as a nonparametric measure of the mutual relationship between two non-normally distributed qualitative or ordinal variables.
  6. A 5% level was chosen as a level of significance in all statistical significance tests used.



  Results Top


Group comparison of hippocampal volume among patients with first-episode psychosis showed a highly significant difference in the total hippocampal volume reduction (F = 9.810, P < 0.001), where the hippocampus was the largest among the controls, followed by Bipolar patients and then patients with depressive psychosis, and finally the schizophrenia group had the smallest overall hippocampal volume [Table 1] and [Figure 1].
Figure 1:

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Table 1: Group comparison of hippocampus volume and clinical characteristics of different diagnostic groups and healthy control patients

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There was no significant difference among groups in RT (F = 0.366, P > 0.05) or LT side (F = 0.587, P > 0.05) hippocampal volume.

Patients with depressive psychoses were significantly older (F = 17.49, P < 0.001), with delayed age at onset (F = 537.201, P < 0.001), higher rate of hospitalization (F = 13.508, P<0.01), and longer DUI (F = 11.6, P < 0.001) than schizophrenia and bipolar patients as well as the control group. On the other hand, patients with schizophrenia spectrum were mostly males (F = 3, P = 0.03) with longer DUPAQ17 (F = 18.6, P = 0.001) compared with other groups [Table 1].

As expected, [Table 2] and [Figure 2] show that patients with depressive psychosis had higher mean scores of HDRS (19.40 ± 3.79), but lower mean scores of YMRS (6.50 ± 3.10) and PANSS [Figure 2] (positive =8.70 ± 0.86, negative = 17.40 ± 1.82, general psychopathology = 40.40 ± 6.13, and total score =58.70 ± 8.55) compared with schizophrenia and bipolar patients both at baseline and after 2 years.
Figure 2:

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Table 2: Mean scores of HDRS, YMRS, PANSS in schizophrenia, bipolar, and depressive psychoses at baseline and after 2 years of follow-up

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[Table 3] and [Figure 3],[Figure 4] and [Figure 5] show the cognitive functions and intellectual abilities among controls and patients with different types of psychoses (schizophrenia, bipolar, and depressive), where the control group had higher cognitive mean scores both at baseline and at the 2-year follow-up compared with patients, where the mean scores of depressed patients were better than those of bipolar patients, whereas patients with schizophrenia had the lowest mean cognition scores.
Figure 3:

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Figure 4:

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Figure 5:

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Table 3: Cognitive functions at baseline in different diagnostic groups of first-episode psychosis

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Hippocampal volume and clinical characteristics

Schizophrenia spectrum

At baseline assessment, the total hippocampal volume showed significant negative correlations with age, rate of hospitalization, DUI, and the mean scores of the negative PANSS subtest (the latter was consistent after 2 years). This means that hippocampal volume reduction was associated with more severe negative symptoms both at baseline and the short-term outcome, which may highlight the sensitivity of the hippocampus to negative symptoms. This was also true for RT and LT hippocampal volume at the end of the study [Table 4] and [Figure 6].
Figure 6:

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Table 4: Correlations of hippocampal volume with clinical characteristics in the schizophrenia group (n = 49)

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In addition, total hippocampal volume showed a significant positive association with more severe positive psychotic features as well as general psychopathology mean scores (P = 0.04 and 0.02, respectively).

Age at onset, DUP, HDRS scores, YMRS scores, and the total PANSS score were not correlated significantly with hippocampal volume at baseline or after a short outcome (2 years).

Bipolar psychosis

In bipolar patients, hippocampal volume reduction was associated with older age, delayed onset, repeated hospitalization, and longer DUI (P < 0.0001; [Table 5]).
Table 5: Hippocampal volume associations with clinical characteristics for patients with bipolar psychoses (n = 21)

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The current results did not show any other significant relation between hippocampus volume and (HDRS, YMRS, PANSS, and DUP) at baseline assessment of bipolar patients.

After 2 years, the RT and total hippocampal volume were further reduced despite the significant improvement in all PANSS scores, except the negative subtype.

Also, there was a positive significant correlation between percent change of RT and total hippocampal volume and change in the HDRS score percent at the end of the 2-year assessment.

In summary, at baseline, the hippocampal volume of drug-naive psychotic bipolar patients was significantly sensitive to age, age at onset, and DUI, but not to clinical picture, whereas after 2 years, repeated hospitalization and both psychotic and affective depressive symptoms had a high impact on hippocampal volume.

Depressive psychosis

At baseline assessment, the hippocampus volume of patients with depressive psychosis showed an inverse relation with their age, age at onset, DUI, and with their scores of the three psychometric scales HDRS, YMRS, as well as all PANSS scores and subscores. This finding may suggest that hippocampal volume is likely to be reduced with earlier and more severe untreated symptoms [Table 6].
Table 6: Association of hippocampal volume at baseline and after 2 years of assessment with clinical characteristics in patients with depressive psychosis (n = 20)

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After 2 years, the hippocampal volume still consistently showed a significant negative relation with the YMRS scores and general psychopathology as well as the total PANSS scores.

This means that at onset, there was a severe hippocampal volume reduction in patients with depressive psychosis, who were older, with delayed age at onset, higher rate of hospitalization, longer duration of untreated illness, and more severe symptoms. The volume reduction of the hippocampus was consistently found to be associated with repeated hospitalization and more severe bipolar or psychopathological symptoms on short-term outcome.

There was no impact of DUP (P > 0.05) on hippocampal volume both at baseline and in terms of short-term outcome in depressed patients with psychotic features.

Sex had no impact on hippocampal volume for all diagnostic groups (schizophrenia, bipolar, and depression) of first-episode psychosis both at baseline and in terms of short-term outcome (P > 0.05).

Hippocampus volume and cognition

Schizophrenia spectrum group

At first contact, the total hippocampal volume showed significant positive correlations with the working memory subtest (spatial span back, P = 0.001), and the mean scores of verbal memory subtests [logical memory immediate subtest (P = 0.04) and logic memory recall (P = 0.000)], as well as the mean scores of verbal WAIS (P = 0.01) [Table 7].
Table 7: Correlation of hippocampal volume with cognitive function at baseline and percent change after 2 years in the schizophrenia spectrum group (n = 49)

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There were no other significant correlations between hippocampal volume and other cognitive functions.

Assessment after 2 years showed that the percent change in hippocampal volume (RT and total) was correlated negatively with the mean scores of working memory and verbal memory subtests [Table 7].

No other significant correlation was observed between hippocampal volume and other cognitive functions in patients with schizophrenia.

In other words, drug-naive patients with schizophrenia had cognitive dysfunctions early in the disease process, which was significantly associated with reduced hippocampus volume. This reduction was consistently present after 2 years despite improved working and verbal memory.

Bipolar psychosis

At baseline assessment, there were no significant correlations between hippocampal volume and cognitive functions. This was also found on assessment of short-term outcome [Table 8].
Table 8: Hippocampal volume correlation with cognition at baseline and percent change after 2 years in the bipolar psychosis group (n = 21)

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Depressive Psychosis

Assessment at first contact showed a highly significant (P<0.001) direct correlation between hippocampal volume with the mean scores of spatial span back (working memory), as well as verbal, performance, and total WAIS scores. In contrast, a highly significant negative correlation was observed between hippocampal volume and trail making A and B, that is executive function [Table 9].
Table 9: Hippocampal volume correlation with cognition at baseline and 2 years' percent change in patients with depressive psychosis (n = 20)

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On short-term assessment, the mean percent change in the digit symbol subtest score showed a highly significant negative correlation (P < 0.001) with percent change of hippocampal volume.

There were no other significant correlations between hippocampus volume and other cognitive functions both at baseline and at short-term assessment.

In summary, patients with depressive psychosis who had higher scores of working memory, executive functions, and intellectual abilities had larger hippocampus volume.


  Discussion Top


Hippocampus as morphological trait

The hippocampus is a highly stress sensitive brain region (Thomas et al., 2007). Preclinical studies suggest that stress can result in structural changes to the hippocampus (Vermetton and Bremner, 2002; Malberg and Duman, 2003; Pham et al., 2003). As we hypothesized, there was a reduction in the hippocampal volume in comparison with healthy controls among patients with first-episode psychosis. This was a significant reduction in the overall hippocampal volume, with greater reduction in patients with schizophrenia and a modest reduction in the bipolar and depressive group in comparison with the healthy participants.

RT and LT hippocampal volume reduction was also observed in all patients, but did not reach statistical significance in comparison with the healthy participants.

The above-mentioned results were consistent with other studies that reported hippocampal volume reduction at onset of schizophrenia (EL Tayebani et al., 2006; Steen et al., 2006; Vita et al., 2006; Boos et al., 2007). Meta-analysis of Campbell et al. (2004) as well as Videbech et al.(2004) confirmed a reduction in hippocampal volume in depression as well.

Despite significant hippocampal volume reduction in healthy individuals over time, and the relative increase in hippocampal volume in all patients after 2 years of initiating treatment, the patients' hippocampi were still smaller than that of the control individuals.

This progressive hippocampal volume reduction, especially on the LT side, was clear in all groups, especially in schizophrenia.

The consistent reduction of hippocampal volume in short-term assessment (2 years) in comparison with the controls is an indicator of its value as a morphological trait for different groups of patients with first-episode psychosis.

The effect of a relative increase in hippocampus volume on treatment (except the size of the hippocampus in the schizophrenia group) did not exclude the possibility of continuous reduced hippocampus volume on short-term follow-up and was consistent with the conclusion that exposure of patients with first-episode psychosis to antipsychotics may not protect against progressive reduction (Chakos et al., 2005).

The significant overall reduction in hippocampal volume but not specific RT or LT side could be explained by the hypothesis that the reduction in volume may be somewhat localized. The identification of regional alterations in the hippocampal structure may thus help to elucidate the pathophysiology and functional systems associated with first-episode psychosis, especially with difficult to detect hippocampal differences in small, heterogeneous samples using global methods (McDonald et al., 2004). Many studies have reported localized volume reduction in the hippocampus, especially in depressed patients, as tail (Maller et al., 2007), head (MacQueen et al., 2008), or subiculum reduction (Ballmaier et al., 2008; Bearden et al., 2009).

Clinical importance of reduced hippocampus

It is unclear whether a reduction in the hippocampal volume in antipsychotic-naive schizophrenia, bipolar, and depressive psychotic patients is associated with psychopathology and clinical variables. Important inconsistencies exist with respect to clinical variables across studies.

In the current sample, including healthy controls, there was an inverse relation between volume reduction of the hippocampus and age, which means that greater hippocampal reduction is evident in older patients with schizophrenia or affective psychosis.

One explanation is the reduced burden of illness in young adults compared with older participants (Monkul et al., 2007); this was confirmed in our results with the high significant positive association between DUI and age (P < 0.001) and the inverse association between DUI and hippocampal volume in all patient groups (P < 0.001), that is older patients had longer DUI, which in turn may have a negative impact on hippocampal size.

The above mentioned results support the hypothesis that the longer duration of untreatment may lead to reduction of hippocampal volume, and that older people have greater illness burden (Sheline and Gado, 2003), in other words, young adults have a period of reduced vulnerability. Especially, hypercortisolemia - because of exposure to prolonged stress - was linked to hippocampal volume in prolonged depressive illness (Sapolsky, 2000), which occurs more commonly with advanced age (O'Brien et al., 1996), rendering the aged hippocampus particularly vulnerable to the effect of protracted stress (Seckl and Olsson, 1995).

In our sample, patients with first-episode schizophrenia had a younger mean age and smaller hippocampal size, which might be explained by the hypothesis of a nonlinear relation between age and hippocampus size and psychotic illness as stress is a process of all related aging, where differences between patients and controls are the greatest in middle adulthood, and then they plateau as both patients and healthy individuals age.

Another possible explanation is that the hippocampal volume reduction is because of multiple interacting factors such as DUI (Matsumoto et al., 2001), suggesting that changes may occur during the transition to psychosis (Velakoulis et al., 2006), or because of the effect of illness itself, especially with repeated hospitalization, where younger patients with psychosis and limited disease exposure are yet to experience the pattern of hippocampal loss reported in patients with protracted illness (Videbech and Ravnkilde, 2004). Age at onset may play an interacting role, where the more delayed the age at onset, the smaller the hippocampus size; this may be because of the impact of DUI, which was associated positively with age at onset in both our bipolar and depressive psychosis patients (P = 0.002 and 0.01, respectively). The same results were obtained by Janssen et al. (2007) and Steffens et al. (2000).

Other studies, however, did not find evidence of an effect of illness duration on the hippocampus, especially in depression (Posener et al., 2003; Frodl et al., 2004; Lloyd et al., 2004; Xia et al., 2004; Hickie et al., 2005; Frodl et al., 2006; MacMaster et al., 2008). These negative findings could be attributed to the small sample size and the heterogeneity of the patient group; the patients were younger in age and had a low number of illness episodes.

An association between the severity of affective (depressive and bipolar) symptoms and hippocampal volume was absent both in patients with schizophrenia and in those with bipolar psychosis, but it was present in patients with depression. The association between depression and hippocampal volume was consistent with those of Saylam et al. (2006) and Vakili et al. (2000); such an association may reflect a genetic predisposition for depression. This association could be explained by the polymorphism in the serotonin (5HT) transporter gene 5HRTPR (Taylor et al., 2005) and in the brain-derived neurotropic factor gene at position 66 (Frodl et al., 2007), or it could be due to the hypersensitivity of the hippocampus to damage effect of hypercortisolemia linked more with depression (Kessler, 1997; MacQueen et al., 2003; Sheline and Gado, 2003). It has also been proposed that impaired neurogenesis may result in depression (Sapolsky, 2004).

In terms of psychotic symptoms at baseline, there was a relation between hippocampal volume and negative symptoms in schizophrenia as well as in depression. In patients with schizophrenia, hippocampal volume reduction was related to the severity of negative symptoms at baseline and in the short term. This notion supports the conclusion of many studies indicating the importance of negative symptoms as a predictor for outcome of schizophrenia and also highlights the importance of studying the functional circuits between the hippocampus and different areas of front temporal connections (Davidson and McGlashan, 1997; Ho et al., 1998; Miller et al., 2005).

In the current study, reduced hippocampal volume was related significantly to higher positive symptom scores in depressed patients but not in patients with schizophrenia. The impact of positive symptoms was not significant in the short term in both groups. The above finding indicates that change in hippocampus volume is not sensitive to positive symptoms in patients with first-episode psychosis. The association between structural abnormalities and clinical variables presumably reflects underlying pathophysiologic disturbances in neurotransmission, metabolism, and genetic variances, and different mechanisms may underline positive and negative symptoms (Nesvag et al., 2009).

Hippocampus and cognition

The current results revealed that all patients with first-episode psychosis, independent of their diagnosis, functioned worse than healthy controls in all cognitive tests and were even more evident in patients with schizophrenia. This conclusion is consistent with aforementioned studies that have consistently shown global cognitive deficits for all patients with first-episode psychosis (Bilder et al., 2000; Moritz et al., 2000; Townsend et al., 2001; Verdoux et al., 2002; Addington et al., 2003; Addington et al., 2005). This could be explained by the fact that single patient groups were compared with either normative values or with values of a healthy control group without considering the heterogeneity of treatment responses or outcome.

Our results support a previous result of Joyce et al. (2005), who suggested that cognitive heterogeneity is likely present at the onset of illness of first-episode psychosis. Also, the possibility of cognitive deficit starting before the clinical presentation may be valid, but longitudinal studies of such a group of patients at risk are needed.

The above conclusion was reported by Woodberry et al. (2010), who observed that a clinical risk sample showed a significant difference in the overall magnitude of neuropsychological impairment. Individuals who subsequently developed psychotic level symptoms showed a huge impairment in verbal IQ, verbal memory, and olfactory identification comparable with the magnitude of first-episode samples (Keefe et al., 2006; Eastvold et al., 2007).

In the present study, reduced hippocampal volume was associated with lower scores of working and verbal memory as well as verbal IQ in the schizophrenia group and with lower working memory as well as executive functions as well as low verbal performance and total WAIS scores in patients with depressive psychoses.

After 2 years, the percent change in working and verbal memory was not consistent with (RT and total) hippocampus volume reduction. In addition, an inverse relation of executive function percent change with hippocampus size was present in the depressive group, indicating a progressive reduction in hippocampal volume despite clinical and cognitive improvement.

The above results may highlight the importance of verbal, working memory baseline intellectual abilities as well as reduced hippocampal volume as being morphological traits and predictors of outcome in the subgroup of patients with first-episode psychosis (schizophrenia and depressive patients), but not in bipolar patients.

The above observations were consistent with Bodnar et al. (2008) and Woodberry et al. (2010) (for verbal and working memory), Lesson et al.( 2009) (for IQ as a predictor), Bearden et al. (2009) (for the relation between impaired verbal memory and brain regional atrophy.

The lack of correlations of hippocampal volume reduction with the cognitive or clinical picture in the bipolar group may indicate that other areas may be specific for such patients as a morphological trait or the reflection of phenomenological state.


  Conclusion and recommendations Top


  1. Hippocampal volume reduction is considered a morphological trait for schizophrenia and depressive psychosis and to a lesser extent for bipolar patients.
  2. Hippocampal reduction was observed at baseline assessment and this reduction progressed over time.
  3. Cognitive and clinical association was evident with hippocampal reduction in schizophrenia and depressive psychosis patients.
  4. Study of the shape of the hippocampus may help to identify specific areas of functional and pathophysiological changes with first-episode psychosis.
  5. Combining structural, functional, and clinical study for patients with psychosis may help localize areas of brain dysfunction reflecting clinical presentation and predicting drug response as well as outcome.
  6. Longitudinal studies for patients at a high risk or those in their first episode may highlight the importance of early effective management and may help differentiate poor outcome groups.
  7. Genetic studies for patients with psychosis and hippocampal volume reduction may help confirm the importance of hippocampal volume in the course of their illness.



  Strengths Top


  1. It is a prospective study that attempted to examine the relation between structural, clinical, and cognitive changes in first-episode psychosis groups.
  2. Studying drug-naive patients on their first contact, the first-episode state can overcome the effect of medications, chronicity, and hospitalization. It can also highlight the changes associated with schizophrenia, bipolar, and depressive psychoses.
  3. Only Kuwaiti patients were recruited to overcome the impact of culture differences.
  4. MRI scans using manual tracing with thinner slices perpendicular to the interesting anatomical areas can yield accurate results on volumetric changes.



  Limitations Top


  1. Infrequent follow-up assessments and not following a fixed schedule may miss some of the early clinical and structural changes.
  2. The study did not correlate hippocampal volume with whole-brain volume.
  3. We only examined restricted anatomical areas, not the whole brain, for such groups of psychoses with heterogeneous presentation and outcome.
  4. This study focused on the volume but not the shape of the hippocampus, which may not provide information about specific localized regions and specific functional circuits shared in the pathophysiology of patients with their first psychotic episode.
[91]


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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    Tables

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