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A pilot study on predictors of brainstem raphe abnormality in patients with major depressive disorder
Journal of Affective Disorders 209 (2017) 66–70
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Research paper
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A pilot study on predictors of brainstem raphe abnormality in patients with major depressive disorder ⁎
Milutin Kostića, , Ana Munjizaa, Danilo Pesica, Amir Peljtoa, Ivana Novakovica,b, Valerija Dobricicb, Dusica Lecic Tosevskia,c, Milija Mijajlovicb,c a b c
Institute of Mental Health, Belgrade, Serbia Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia School of Medicine, University of Belgrade, Belgrade, Serbia
A R T I C L E I N F O
A BS T RAC T
Keywords: Transcranial sonography Serotonin transporter gene Anxiety Depression 5-HTTLPR
Background: Hypo/anechogenicity of the brainstem raphe (BR) structures has been suggested as a possible transcranial parenchymal sonography (TCS) marker associated with depression. Aim: The aim of this study was to analyze possible association of the abnormal BR echogenicity in patients with major depression when compared to healthy controls, and to evaluate its clinical and genetic correlates. Methods: TCS was performed in 53 patients diagnosed as major depressive disorder (MDD) without psychotic symptoms and in 54 healthy matched controls. Results: The TCS detected BR abnormalities were significantly more frequent in MDD patients (35 out of 53; 66%) in comparison to matched controls (5 out of 56; 9%). The prevalence of short allele (s) homozygocity in the length polymorphism of the promoter region of the serotonin transporter gene (5-HTTLPR) was significantly higher in MDD patients relative to those with normal BR echogenicity. A stepwise statistical discriminant analysis revealed statistically significant separation between MDD patients with and without BR abnormalities groups based on the four predictors combined: the Hamilton Anxiety Rating Scale item 5 („difficulty in concentration, poor memory“), presence of social phobia, s allele homozygocity of the 5-HTTLPR polymorphism, and presence of generalized anxiety disorder. Limitations: Cross-sectional design and heterogenous treatment of depressed patients. Conclusions: Reduced BR echogenicity in at least a subgroup of MDD patients may reflect a particular phenotype, characterized by more prevalent comorbid anxiety disorders, associated with particular genetic polymorphisms and neurotransmitter(s) deficits, most probably altered serotonergic mechanisms.
1. Introduction Major depressive disorder accounts for significant global morbidity, including medical comorbidities, mortality, and disability (Belmaker and Agam, 2008), but our understanding of its pathophysiology is still limited. Genetic factors conferred a moderate contribution of 37% to unipolar depression (Sullivan et al., 2000). One of the most studied genes in depression, and the first gene to show gene-environment interaction in this disorder was the serotonin transporter gene, namely the polymorphism of its promoter region (5-HTTLPR) (Caspi et al., 2003). Transcranial parenchymal sonography (TCS), which displays brain tissue echogenicity through the intact skull, gathered increased attention, since it enabled studies of not only midbrain structures, but also echogenicity of the basal ganglia, as well as the transverse diameter of the third and of the frontal horn of the lateral ventricle (Berg et al.,
⁎
2008). It has been explored as a diagnostic method for neuropsychiatric disorders for more than two decades (Becker et al., 1994). In particular, hypo/anechogenicity of the brainstem raphe (BR) structures has been suggested as a possible TCS marker associated with depression (Berg et al., 2008). Brainstem raphe (BR) was normally depicted as a highly echogenic line, with an echogenicity identical to that of the nucleus ruber (Mijajlović, 2010). Although hypoechogenicity of the BR was present in 8–28% of healthy controls (Becker et al., 1995; Walter et al., 2007a; Mijajlović, 2010), such abnormality (hypo/anechogenicity) was particularly prevalent in patients with unipolar depression (50–70%), with some studies showing abnormal BR echogenicity in up to 90% of patients (Becker et al., 1995; Walter et al., 2007a; Budisic et al., 2010; Ghourchian et al., 2014; Krogias and Walter, 2016). Hypo/ anechogenicity was hypothesized to reflect structural disruption of the BR, resulting in impaired serotonergic innervations (Becker et al., 2001). This abnormality was also frequent in depressed patients with
Corresponding author.
http://dx.doi.org/10.1016/j.jad.2016.11.034 Received 29 August 2016; Received in revised form 26 October 2016; Accepted 15 November 2016 Available online 22 November 2016 0165-0327/ © 2016 Elsevier B.V. All rights reserved.
Journal of Affective Disorders 209 (2017) 66–70
M. Kostić et al.
2.2. Clinical assessment
Parkinson’s disease (PD; 40–60%) or Huntington’s disease (Walter et al., 2007b; Krogias et al., 2011a). However, BR alterations were not found in patients with bipolar affective disorder (10–36%) or in patients with schizophrenia (Mijajlović, 2010; Krogias et al., 2011b). The aim of this study was to analyze possible association of the abnormal BR echogenicity in patients with major depression when compared to healthy controls, and to evaluate clinical and genetic correlates of such an association.
Detailed interview on socio-demographic and clinical data, including treatment course and family history of mental disorders, was obtained from all patients and HC, as well as family members when necessary. Participants fulfilled the self-reporting Beck Depression Inventory (BDI) (Beck et al., 1961), and interviewers filled in the Hamilton Depression Rating Scale (HDRS) (Hamilton et al., 1960) and the Hamilton Anxiety Rating Scale (HARS) (Hamilton et al., 1959). Blood samples were taken for genetic studies. 2.3. Genetic testing
2. Methods DNA was extracted from blood using standard protocols. The 5HTTLPR deletion (L/S) polymorphism was assayed using gel electrophoresis of PCR products as previously reported (Alexander et al., 2009). Additionally, all samples containing the L allele were genotyped for SNP rs25531 (A/G) by restriction fragment length polymorphism analysis with HpaII restriction enzyme. We analyzed two length polymorphisms of 5-HTTLPR: a short (s) and a long (l) allele, but due to a limited number of patients we divided patients into two genetically-driven groups: (a) s allele homozygotes, and (b) l allele carriers (ll+ls) (Table 1).
2.1. Patients Our study comprised 58 consecutive inpatients treated for Major depressive disorder (MDD) without psychotic symptoms (both first episode and recurrent), recruited at the Institute of Mental Health (Belgrade, Serbia). The diagnosis was established using the Structured Clinical Interview for Axis–I (SCID-I) for DSM-IV (First et al., 2002). Patients were excluded if they were (a) < 18 and > 65 years old; (b) had any other central nervous system disease or other causes of focal or diffuse brain damage, including signs of small vessel disease of the brain on MRI examination; (c) had any psychiatric comorbidity within the Axis I, except for panic disorder, social anxiety disorder and generalized anxiety disorder (GAD), as well as personality disorders; and (d) the Mini Mental State Examination score < 27 (Folstein et al., 1975). All patients were treated with antidepressant drugs and adjunct therapy such as stabilizers, antipsychotics, benzodiazepines or hypnotic drugs (Table 1). Fifty-four age- and sex-matched healthy controls (HC) were also included in the study. The study was done in accordance with the latest version of the Declaration of Helsinki and approved by the Ethics Committee of the Institute of Mental Health. Patients and HC were included in the study after signing an informed written consent.
2.4. Transcranial sonography For TCS we used a color-coded phased-array ultrasound system, equipped with a 2.5 MHz transducer (ProSound Alpha 10, Aloka, Japan). The ultrasound parameters chosen were penetration depth of 14–16 cm and a dynamic range of 45–50 dB. Image brightness, contrast and time-gain compensation were adjusted to get the best image. The examination was performed through a preauricular acoustic bone window scanning supra and infratentorial brain areas in axial planes by tilting the probe. Echogenicity of the pontomesencephalic brainstem raphe (BR) was evaluated by bilateral TCS investigation (the side with better visible structure was used for further analyses). Using the red nucleus (RN) or basal cisterns echogenicity as a reference, the BR echogenicity was semiquantitatively classified as normal (equal signal intensity with the RN and/or basal cisterns) or abnormal if (a) the raphe signals were missing (not visible), or (b) were of reduced echogenicity (the echogenic line of the BR was interrupted or appears abnormally slight and thin) on both sides of insonation (Walter et al., 2002; Krogias et al., 2011a). All TCS assessments were performed by two experienced examiners who were blinded to the clinical data. In case of discrepant assessments, a consensus was accomplished between the examiners.
Table 1 Demographic and clinical features of patients with major depressive disorder (MDD) with (MDD-BR+) and without (MDD-BR-) brainstem raphe abnormality on the transcranial sonography.
a
Number of patients Age (years)* Male/female ratioa Education* Age at onset (years)* HDRS* BDI* HARS* Duration of problems (months)* Duration of psychiatric treatment (months)* SNRIsa SSRIsa TCAsa TeCAsa Benzodiazepinesa Mood stabilizersa Antipsychotics, 1st generationa Antipsychotics, 2nd generationa Number of hospitalization* 5-HTTLPR frequency ss/ls/ll'a 5-HTTLPR ss/ls+ll'a
MDD-BR-
MDD-BR+
p
18 45.6 ± 10.3 3/15 3.2 ± 0.9 37.8 ± 12.1 22.8 ± 3.5 33.6 ± 13.5 22.6 ± 8.7 92.3 ± 88.2 59.4 ± 73.1 3 10 2 1 14 7 6 4 1.7 ± 1.1 1/13/4 1/17
35 42.1 ± 9.8 11/24 3.0 ± 0.8 34.6 ± 10.9 23.3 ± 5.8 30.8 ± 13.3 23.9 ± 6.9 89.8 ± 86.8 63.7 ± 75.1 8 14 8 4 33 17 9 5 3.0 ± 3.2 10/21/4 10/25
– 0.238 0.248 0.500 0.332 0.762 0.479 0.544 0.902 0.840 0.597 0.281 0.301 0.441 0.072 0.502 0.559 0.466 0.111 0.121 0.048
2.5. Statistics Differences of demographic and clinical characteristics between groups with or without BR abnormalities were assessed using analysis of variance for continuous and non-parametric stististics (Chi square test and Mann-Whitney test) for categorical data. A discriminant forward step wise analysis was used to develop a model for predicting presence/absence of the BR abnormalities, with gender, presence of GAD, social phobia, panic attacks, the HARS item 5 and HTLPR frequency as predictors. Predictors were ranked by the probability of the Wald chi-square test. Results were considered statistically significant at p≤0.05. Interrater reliability for the BR TCS was assessed by Cohen’s kappa. Statistical analysis was performed with SPSS (v.16.0 for Windows; SPSS Inc., Chicago, IL).
*
Values presented as means ± SDs; Values presented as number of patients; BDI: Beck Depression Inventory; HARS: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; MDD: Major Depressive Disorder; SNRIs: serotonin-norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants; TeCAs: tetracyclic antidepressants; S′/S′ (S) vs L′ carriers (L) for the serotonin transporter gene a
3. Results The inadequate temporal acoustic bone windows were found in 5 patients (8.6%). Therefore, 53 MDD patients and 54 HC were included 67
68
53 MDD patients+54 HC Our study
MDD: Major Depressive Disorder; ADDM: Adjustment Disorder with Depressed Mood; HC: Healthy Controls; BR: brainstem raphe; SCID: Structured Clinical Interview for Axis–I (SCID-I) for DSM-IV
Reduced BR echogenicity in 66% of MDD patients vs. 9% of HC (p=0.003) 2-point scale
Reduced BR echogenicity (≤ grade 3) in 85% of patients with depression vs. 5% of HC (p=0.05) 4-point scale 41 depressed inpatients+43 HC
Ghourchian et al. Zhang et al.
Budišić et al.
Walter et al.
Cut-off scores of depression scales DSM-IV (SCID-I)
Reduced BR echogenicity in 36.7% of MDD patients vs. 10% of HC (p=0.015) 2-point scale DSM-IV-R
3-point scale DSM-IV
Reduced BR echogenicity in 53% of MDD and ADDM patients vs. 9% of HC (p < 0.001) 2-point scale DSM-IV (SCID-I)
Significant decrease in the echogenicity score in MDD patients vs. HC (1.3 ± 0.47 and 2.8 ± 0.64, respectively; p < 0.001) Significant decrease in the echogenicity score in MDD patients vs. HC (1.4 ± 0.6 and 2.8 ± 0.5, respectively; p < 0.00001) No difference in the echogenicity score in MDD patients vs. HC (2.07 ± 1.39 and 2.57 ± 1.16, respectively; p=0.37) Reduced BR echogenicity in 54% of MDD and ADDM patients vs. 8% of HC (p < 0.001) scale scale scale scale
Comments Quantification of BR echogenicity
4-point 4-point 4-point 3-point DSM-III-R DSM-III-R DSM-IV DSM-IV (SCID-I)
20 MDD inpatients+20 HC 40 MDD inpatients+40 HC 15 MDD patients+14 controls 52 inpatients (37 with MDD and 15 with ADDM)+50 HC 40 MDD and 15 ADDM patients+55 HC 31 MDD patients (14 with suicidal ideation)+40 HC 30 MDD patients+30 controls Becker et al. Becker et al. Steele et al. Walter et al.
The first of the main findings of our study (e.g. significantly more frequent BR hypo/anechogenicity in MDD patients than in HC) was in continuation with the majority of previous studies (Table 2) (Becker et al., 1994, 1995; Walter et al., 2007; Walter et al., 2007a; Budisic et al., 2010; Ghourchian et al., 2014). It has not been clarified what was the nature of BR echogenicity changes in depression, but an alteration of the BR microarchitecture was indicated (Becker et al., 2001). Hypothesized structural pathology has been backed by an increase of the brainstem midline signal intensity on the T2-weighted MRI in MDD patients when compared to controls, but also patients with bipolar disorder (Berg et al., 1999). Lack of correlation between BR echogenicity and severity of depression in majority of previous studies (including our own) (Table 2) (Becker et al., 1994, 1995; Walter et al., 2007a, 2007c), led Walter et al. (2007a) to imply that TCS findings of the BR hypo-/anechogenicity might indicate “a vulnerability factor for development of depressive states”.
Psychiatric diagnosis according to:
4. Discussion
Number of participants
Table 2 Review of published studies dealing with the brainstem raphe echogenicity in patients with major depressive disorder.
in the final analysis. The interrater reliability for the BR TCS was high (Cohen’s kappa 0.86; p < 0.001). In order to reach a consensus two raters conducted an extensive discussion on 5 cases. The TCS detected BR abnormalities were significantly more frequent in MDD patients (35 out of 53 or 66%; in 26 patients the BR was not visible, while 9 had slightly reduced echogenicity) in comparison to age- (43.3 ± 19.9 and 42.8 ± 10.2 years, respectively) and sex-matched HC (5 out of 56 or 9%; in one subject the BR was not visible, while in 4 echogenicity was slightly reduced) (Chi square=8.57, df=1, p=0.003). There were no differences between MDD patients with (MDD-BR+) and without (MDD-BR-) TCS brainstem raphe abnormality regarding sex, age, duration of education, age at onset, duration of problems and psychiatric treatment, distinction between the first or recurrent episodes, presence of the GAD, panic attacks, social phobia, heredity of depression, suicides and suicidal attempts, alcoholism and drug addiction, psychiatric treatment heredity (Table 1). Mean number of hospitalization was higher in MDD-BR+ group than in MDD-BRgroup (3.0 vs. 1.7, respectively), but the difference was not statistically significant. There was no difference regarding distribution of ss, ls and ll genotypes of the 5-HTTPLR polymorphisms between the MDD-BR+ and MDD-BR- groups (p=0.121) ( Table 1). However, the prevalence of short allel (s) homozygocity of the 5-HTTLPR polymorphism was significantly higher (p < 0.048) in MDD-BR+ relative to MDD-BRpatients. Also, there were no differences between these two groups regarding the total BDI, HDRS and HARS scores, as well as in their items scores, with the exception of the HARS item 5 („difficulty in concentration, poor memory“), that appeared to be worse in MDD-BR+ patients (F(1,51)=1.179; p=0.029). Interestingly enough, MDD patients with abnormal BR echogenicity when compared to those with normal BR had more frequently comorbid anxiety (at least one of the following diagnoses: GAD, panic attacks, social phobia and agoraphobia), but this two-fold difference did not reach statistical significance (15 out of 35 patients [43%] and 4 out of 18 patients [22%], respectively; p=0.138). This was also true for the most prevalent comorbid GAD (12 out of 35 patients [34%] and 3 out of 18 patients [17%], respectively; p=0.177). A stepwise statistical discriminant analysis was performed using 5 variables (GAD, social phobia, panic attacks, the HARS item 5 and 5HTTLPR polymorphism frequency) as predictors of membership in the two groups (MDD-BR- and MDD-BR+). There was statistically significant separation between MDD-BR- and MDD-BR+ groups based on the four predictors combined: the HAMA item 5 (F(1.47)=9.812; p=0.002), presence of social phobia (F(1.47)=6.72, p=0.012), short allele (s) homozygocity of 5-HTTLPR (F(1.47)=6.17; p=0.016) and presence of GAD (F(1.47)=5.69; p=0.021).
Reduced BR echogenicity in 47% of MDD patients vs. 15% of HC (p < 0.01)
Journal of Affective Disorders 209 (2017) 66–70
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Journal of Affective Disorders 209 (2017) 66–70
M. Kostić et al.
abnormal BR echogenicity included also higher scores of the item 5 of the HAMA („difficulty in concentration, poor memory“). Among the limitations of our study, besides those linked to the methodology of TCS itself, were cross-sectional design and heterogenous treatment of depressed patients. The sample size was among the largest in similar studies (Table 2), but it was still small regarding clinical and genetic correlations performed. Considering clinical, genetic and morphological heterogeneity of depression, the presence of reduced BR echogenicity on TCS in at least a subgroup of MDD patients may reflect a particular phenotype, characterized by more prevalent comorbid anxiety disorders, associated with particular genetic polymorphisms and neurotransmitter(s) deficits, most probably altered 5-HT mechanisms. Therefore, TCS may be an interesting and promising tool in defining possible distinct subtypes of depressive disorder, which in turn can lead to better defined treatment targets and objectives.
Changes in BR echogenicity have been proposed through several lines of evidence to be linked to 5-HT transmission (Meyer et al., 2006). Clusters of 5-HT neurons in the dorsal (DRN) and median raphe nucleus (MRN)) are the main source of ascending 5-HT projections throughout the forebrain to limbic, striatal and cortical regions (Becker et al., 2001; Brooks and Piccini, 2006). Study using single photon emission computed tomography found reduced 5-HT 1A receptor binding in the midbrain raphe (Malison et al., 1998), accompanied in a later positron emission tomography studies with the finding of decreased 5-HTT availability in the same structure of MDD patients (Drevets et al., 1999; Parsey et al., 2006). In one study with the highly specific ligand for 5-HTT, [11C]-DASB, statistically significant decreases in binding potentials of the 5-HTT were observed in various brain regions, including brainstem (Selvaraj et al., 2011). Finally, in a pathoanatomic study of the DRN of depressed suicide victims, a decrease in 5-HT 1A receptors was found, as well as in the number of neurons expressing 5-HTT mRNA in comparison to controls (Arango et al., 2001). In favor of serotonergic “connection” was also the finding that reduced BR echogenicity indicated good responsivity to selective serotonin reuptake inhibitors (SSRI), with a positive predictive value of 88% (Walter et al., 2007a). However, the echogenic midline of the mesencephalon and upper pontine brainstem identified by TCS represent a cross-road region of not only serotonergic, bidirectional pathways that are central components of limbic network forming basal limbic system (Becker et al., 2001). Therefore, mood changes associated with alterations of the BR echogenicity depicted by TCS might not be interpreted solely as a consequence of abnormalities in 5-HT transmission, but more general as a consequence of an impairment of the basal limbic system. Another important result of our study was that discriminant analysis revealed as significant predictors for the abnormal BR echogenicity combined presence of comorbid anxiety disorders, higher scores on the HAMA item 5 („difficulty in concentration, poor memory“), and a short allele homozygocity for the 5HTTLR polymorphism. Comorbid anxiety disorders were approximately twice as common in MDD-BR+ than in MDD-BR- patients, but this difference, partly due to the small sample size, did not reach statistical significance. Similar observation has been previously published in patients whose PD was associated with depression: anxiety was more frequently present in those with than in those without abnormal BR echogenicity (41% and 29% of patients, respectively) (Stanković et al., 2015). Besides major depression, several lines of evidence also implicated decreased serotonergic activity in anxiety disorders (Eison and Eison, 1994). The DRN was selectively activated by anxiety-related stimuli and is interconnected with forebrain structures controlling anxiety states (Lowry et al., 2008). The presence of s allele was included in a combination of factors that predicted abnormal BR+ echogenicity and also its homozygocity was significantly more frequent in MDD-BR+ than in MFF-BR- patients (p=0.048). Genetic polymorphisms in 5HTTLPR affected 5-HTT mRNA transcription (i.e. reduced 5-HTT expression for the s allele) (Praschak-Rieder et al., 2007) and have been associated with depression, but also with many anxiety disorders, such as generalized anxiety disorder (You et al., 2005) and social anxiety disorder (Reinelt et al., 2014). These associations were weak and not always reproducible, suggesting that serotonin might be a predisposing factor rather than a cause of depression or anxiety (Karg et al., 2011). Subject carrying s allele exhibited more depressive symptoms and major depression after stressful life events (Caspi et al., 2003). Lesch et al. (1996) were the first to report an association between the s allele and depression-, anxiety-, and aggression-related general personality traits. Also, Blom et al. (2011) found a relation between avoidant behavioral personality traits, associated with high rates of comorbid depression and anxiety (Oldham et al., 1995; McGlashan et al., 2000), and this allele. Some studies linked the s allele to decline in working memory (Weiss et al., 2014), as well as memory performance in women (Price et al., 2013). Interestingly enough, combination of predictors for
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research paper
crossmark
A pilot study on predictors of brainstem raphe abnormality in patients with major depressive disorder ⁎
Milutin Kostića, , Ana Munjizaa, Danilo Pesica, Amir Peljtoa, Ivana Novakovica,b, Valerija Dobricicb, Dusica Lecic Tosevskia,c, Milija Mijajlovicb,c a b c
Institute of Mental Health, Belgrade, Serbia Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia School of Medicine, University of Belgrade, Belgrade, Serbia
A R T I C L E I N F O
A BS T RAC T
Keywords: Transcranial sonography Serotonin transporter gene Anxiety Depression 5-HTTLPR
Background: Hypo/anechogenicity of the brainstem raphe (BR) structures has been suggested as a possible transcranial parenchymal sonography (TCS) marker associated with depression. Aim: The aim of this study was to analyze possible association of the abnormal BR echogenicity in patients with major depression when compared to healthy controls, and to evaluate its clinical and genetic correlates. Methods: TCS was performed in 53 patients diagnosed as major depressive disorder (MDD) without psychotic symptoms and in 54 healthy matched controls. Results: The TCS detected BR abnormalities were significantly more frequent in MDD patients (35 out of 53; 66%) in comparison to matched controls (5 out of 56; 9%). The prevalence of short allele (s) homozygocity in the length polymorphism of the promoter region of the serotonin transporter gene (5-HTTLPR) was significantly higher in MDD patients relative to those with normal BR echogenicity. A stepwise statistical discriminant analysis revealed statistically significant separation between MDD patients with and without BR abnormalities groups based on the four predictors combined: the Hamilton Anxiety Rating Scale item 5 („difficulty in concentration, poor memory“), presence of social phobia, s allele homozygocity of the 5-HTTLPR polymorphism, and presence of generalized anxiety disorder. Limitations: Cross-sectional design and heterogenous treatment of depressed patients. Conclusions: Reduced BR echogenicity in at least a subgroup of MDD patients may reflect a particular phenotype, characterized by more prevalent comorbid anxiety disorders, associated with particular genetic polymorphisms and neurotransmitter(s) deficits, most probably altered serotonergic mechanisms.
1. Introduction Major depressive disorder accounts for significant global morbidity, including medical comorbidities, mortality, and disability (Belmaker and Agam, 2008), but our understanding of its pathophysiology is still limited. Genetic factors conferred a moderate contribution of 37% to unipolar depression (Sullivan et al., 2000). One of the most studied genes in depression, and the first gene to show gene-environment interaction in this disorder was the serotonin transporter gene, namely the polymorphism of its promoter region (5-HTTLPR) (Caspi et al., 2003). Transcranial parenchymal sonography (TCS), which displays brain tissue echogenicity through the intact skull, gathered increased attention, since it enabled studies of not only midbrain structures, but also echogenicity of the basal ganglia, as well as the transverse diameter of the third and of the frontal horn of the lateral ventricle (Berg et al.,
⁎
2008). It has been explored as a diagnostic method for neuropsychiatric disorders for more than two decades (Becker et al., 1994). In particular, hypo/anechogenicity of the brainstem raphe (BR) structures has been suggested as a possible TCS marker associated with depression (Berg et al., 2008). Brainstem raphe (BR) was normally depicted as a highly echogenic line, with an echogenicity identical to that of the nucleus ruber (Mijajlović, 2010). Although hypoechogenicity of the BR was present in 8–28% of healthy controls (Becker et al., 1995; Walter et al., 2007a; Mijajlović, 2010), such abnormality (hypo/anechogenicity) was particularly prevalent in patients with unipolar depression (50–70%), with some studies showing abnormal BR echogenicity in up to 90% of patients (Becker et al., 1995; Walter et al., 2007a; Budisic et al., 2010; Ghourchian et al., 2014; Krogias and Walter, 2016). Hypo/ anechogenicity was hypothesized to reflect structural disruption of the BR, resulting in impaired serotonergic innervations (Becker et al., 2001). This abnormality was also frequent in depressed patients with
Corresponding author.
http://dx.doi.org/10.1016/j.jad.2016.11.034 Received 29 August 2016; Received in revised form 26 October 2016; Accepted 15 November 2016 Available online 22 November 2016 0165-0327/ © 2016 Elsevier B.V. All rights reserved.
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2.2. Clinical assessment
Parkinson’s disease (PD; 40–60%) or Huntington’s disease (Walter et al., 2007b; Krogias et al., 2011a). However, BR alterations were not found in patients with bipolar affective disorder (10–36%) or in patients with schizophrenia (Mijajlović, 2010; Krogias et al., 2011b). The aim of this study was to analyze possible association of the abnormal BR echogenicity in patients with major depression when compared to healthy controls, and to evaluate clinical and genetic correlates of such an association.
Detailed interview on socio-demographic and clinical data, including treatment course and family history of mental disorders, was obtained from all patients and HC, as well as family members when necessary. Participants fulfilled the self-reporting Beck Depression Inventory (BDI) (Beck et al., 1961), and interviewers filled in the Hamilton Depression Rating Scale (HDRS) (Hamilton et al., 1960) and the Hamilton Anxiety Rating Scale (HARS) (Hamilton et al., 1959). Blood samples were taken for genetic studies. 2.3. Genetic testing
2. Methods DNA was extracted from blood using standard protocols. The 5HTTLPR deletion (L/S) polymorphism was assayed using gel electrophoresis of PCR products as previously reported (Alexander et al., 2009). Additionally, all samples containing the L allele were genotyped for SNP rs25531 (A/G) by restriction fragment length polymorphism analysis with HpaII restriction enzyme. We analyzed two length polymorphisms of 5-HTTLPR: a short (s) and a long (l) allele, but due to a limited number of patients we divided patients into two genetically-driven groups: (a) s allele homozygotes, and (b) l allele carriers (ll+ls) (Table 1).
2.1. Patients Our study comprised 58 consecutive inpatients treated for Major depressive disorder (MDD) without psychotic symptoms (both first episode and recurrent), recruited at the Institute of Mental Health (Belgrade, Serbia). The diagnosis was established using the Structured Clinical Interview for Axis–I (SCID-I) for DSM-IV (First et al., 2002). Patients were excluded if they were (a) < 18 and > 65 years old; (b) had any other central nervous system disease or other causes of focal or diffuse brain damage, including signs of small vessel disease of the brain on MRI examination; (c) had any psychiatric comorbidity within the Axis I, except for panic disorder, social anxiety disorder and generalized anxiety disorder (GAD), as well as personality disorders; and (d) the Mini Mental State Examination score < 27 (Folstein et al., 1975). All patients were treated with antidepressant drugs and adjunct therapy such as stabilizers, antipsychotics, benzodiazepines or hypnotic drugs (Table 1). Fifty-four age- and sex-matched healthy controls (HC) were also included in the study. The study was done in accordance with the latest version of the Declaration of Helsinki and approved by the Ethics Committee of the Institute of Mental Health. Patients and HC were included in the study after signing an informed written consent.
2.4. Transcranial sonography For TCS we used a color-coded phased-array ultrasound system, equipped with a 2.5 MHz transducer (ProSound Alpha 10, Aloka, Japan). The ultrasound parameters chosen were penetration depth of 14–16 cm and a dynamic range of 45–50 dB. Image brightness, contrast and time-gain compensation were adjusted to get the best image. The examination was performed through a preauricular acoustic bone window scanning supra and infratentorial brain areas in axial planes by tilting the probe. Echogenicity of the pontomesencephalic brainstem raphe (BR) was evaluated by bilateral TCS investigation (the side with better visible structure was used for further analyses). Using the red nucleus (RN) or basal cisterns echogenicity as a reference, the BR echogenicity was semiquantitatively classified as normal (equal signal intensity with the RN and/or basal cisterns) or abnormal if (a) the raphe signals were missing (not visible), or (b) were of reduced echogenicity (the echogenic line of the BR was interrupted or appears abnormally slight and thin) on both sides of insonation (Walter et al., 2002; Krogias et al., 2011a). All TCS assessments were performed by two experienced examiners who were blinded to the clinical data. In case of discrepant assessments, a consensus was accomplished between the examiners.
Table 1 Demographic and clinical features of patients with major depressive disorder (MDD) with (MDD-BR+) and without (MDD-BR-) brainstem raphe abnormality on the transcranial sonography.
a
Number of patients Age (years)* Male/female ratioa Education* Age at onset (years)* HDRS* BDI* HARS* Duration of problems (months)* Duration of psychiatric treatment (months)* SNRIsa SSRIsa TCAsa TeCAsa Benzodiazepinesa Mood stabilizersa Antipsychotics, 1st generationa Antipsychotics, 2nd generationa Number of hospitalization* 5-HTTLPR frequency ss/ls/ll'a 5-HTTLPR ss/ls+ll'a
MDD-BR-
MDD-BR+
p
18 45.6 ± 10.3 3/15 3.2 ± 0.9 37.8 ± 12.1 22.8 ± 3.5 33.6 ± 13.5 22.6 ± 8.7 92.3 ± 88.2 59.4 ± 73.1 3 10 2 1 14 7 6 4 1.7 ± 1.1 1/13/4 1/17
35 42.1 ± 9.8 11/24 3.0 ± 0.8 34.6 ± 10.9 23.3 ± 5.8 30.8 ± 13.3 23.9 ± 6.9 89.8 ± 86.8 63.7 ± 75.1 8 14 8 4 33 17 9 5 3.0 ± 3.2 10/21/4 10/25
– 0.238 0.248 0.500 0.332 0.762 0.479 0.544 0.902 0.840 0.597 0.281 0.301 0.441 0.072 0.502 0.559 0.466 0.111 0.121 0.048
2.5. Statistics Differences of demographic and clinical characteristics between groups with or without BR abnormalities were assessed using analysis of variance for continuous and non-parametric stististics (Chi square test and Mann-Whitney test) for categorical data. A discriminant forward step wise analysis was used to develop a model for predicting presence/absence of the BR abnormalities, with gender, presence of GAD, social phobia, panic attacks, the HARS item 5 and HTLPR frequency as predictors. Predictors were ranked by the probability of the Wald chi-square test. Results were considered statistically significant at p≤0.05. Interrater reliability for the BR TCS was assessed by Cohen’s kappa. Statistical analysis was performed with SPSS (v.16.0 for Windows; SPSS Inc., Chicago, IL).
*
Values presented as means ± SDs; Values presented as number of patients; BDI: Beck Depression Inventory; HARS: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; MDD: Major Depressive Disorder; SNRIs: serotonin-norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants; TeCAs: tetracyclic antidepressants; S′/S′ (S) vs L′ carriers (L) for the serotonin transporter gene a
3. Results The inadequate temporal acoustic bone windows were found in 5 patients (8.6%). Therefore, 53 MDD patients and 54 HC were included 67
68
53 MDD patients+54 HC Our study
MDD: Major Depressive Disorder; ADDM: Adjustment Disorder with Depressed Mood; HC: Healthy Controls; BR: brainstem raphe; SCID: Structured Clinical Interview for Axis–I (SCID-I) for DSM-IV
Reduced BR echogenicity in 66% of MDD patients vs. 9% of HC (p=0.003) 2-point scale
Reduced BR echogenicity (≤ grade 3) in 85% of patients with depression vs. 5% of HC (p=0.05) 4-point scale 41 depressed inpatients+43 HC
Ghourchian et al. Zhang et al.
Budišić et al.
Walter et al.
Cut-off scores of depression scales DSM-IV (SCID-I)
Reduced BR echogenicity in 36.7% of MDD patients vs. 10% of HC (p=0.015) 2-point scale DSM-IV-R
3-point scale DSM-IV
Reduced BR echogenicity in 53% of MDD and ADDM patients vs. 9% of HC (p < 0.001) 2-point scale DSM-IV (SCID-I)
Significant decrease in the echogenicity score in MDD patients vs. HC (1.3 ± 0.47 and 2.8 ± 0.64, respectively; p < 0.001) Significant decrease in the echogenicity score in MDD patients vs. HC (1.4 ± 0.6 and 2.8 ± 0.5, respectively; p < 0.00001) No difference in the echogenicity score in MDD patients vs. HC (2.07 ± 1.39 and 2.57 ± 1.16, respectively; p=0.37) Reduced BR echogenicity in 54% of MDD and ADDM patients vs. 8% of HC (p < 0.001) scale scale scale scale
Comments Quantification of BR echogenicity
4-point 4-point 4-point 3-point DSM-III-R DSM-III-R DSM-IV DSM-IV (SCID-I)
20 MDD inpatients+20 HC 40 MDD inpatients+40 HC 15 MDD patients+14 controls 52 inpatients (37 with MDD and 15 with ADDM)+50 HC 40 MDD and 15 ADDM patients+55 HC 31 MDD patients (14 with suicidal ideation)+40 HC 30 MDD patients+30 controls Becker et al. Becker et al. Steele et al. Walter et al.
The first of the main findings of our study (e.g. significantly more frequent BR hypo/anechogenicity in MDD patients than in HC) was in continuation with the majority of previous studies (Table 2) (Becker et al., 1994, 1995; Walter et al., 2007; Walter et al., 2007a; Budisic et al., 2010; Ghourchian et al., 2014). It has not been clarified what was the nature of BR echogenicity changes in depression, but an alteration of the BR microarchitecture was indicated (Becker et al., 2001). Hypothesized structural pathology has been backed by an increase of the brainstem midline signal intensity on the T2-weighted MRI in MDD patients when compared to controls, but also patients with bipolar disorder (Berg et al., 1999). Lack of correlation between BR echogenicity and severity of depression in majority of previous studies (including our own) (Table 2) (Becker et al., 1994, 1995; Walter et al., 2007a, 2007c), led Walter et al. (2007a) to imply that TCS findings of the BR hypo-/anechogenicity might indicate “a vulnerability factor for development of depressive states”.
Psychiatric diagnosis according to:
4. Discussion
Number of participants
Table 2 Review of published studies dealing with the brainstem raphe echogenicity in patients with major depressive disorder.
in the final analysis. The interrater reliability for the BR TCS was high (Cohen’s kappa 0.86; p < 0.001). In order to reach a consensus two raters conducted an extensive discussion on 5 cases. The TCS detected BR abnormalities were significantly more frequent in MDD patients (35 out of 53 or 66%; in 26 patients the BR was not visible, while 9 had slightly reduced echogenicity) in comparison to age- (43.3 ± 19.9 and 42.8 ± 10.2 years, respectively) and sex-matched HC (5 out of 56 or 9%; in one subject the BR was not visible, while in 4 echogenicity was slightly reduced) (Chi square=8.57, df=1, p=0.003). There were no differences between MDD patients with (MDD-BR+) and without (MDD-BR-) TCS brainstem raphe abnormality regarding sex, age, duration of education, age at onset, duration of problems and psychiatric treatment, distinction between the first or recurrent episodes, presence of the GAD, panic attacks, social phobia, heredity of depression, suicides and suicidal attempts, alcoholism and drug addiction, psychiatric treatment heredity (Table 1). Mean number of hospitalization was higher in MDD-BR+ group than in MDD-BRgroup (3.0 vs. 1.7, respectively), but the difference was not statistically significant. There was no difference regarding distribution of ss, ls and ll genotypes of the 5-HTTPLR polymorphisms between the MDD-BR+ and MDD-BR- groups (p=0.121) ( Table 1). However, the prevalence of short allel (s) homozygocity of the 5-HTTLPR polymorphism was significantly higher (p < 0.048) in MDD-BR+ relative to MDD-BRpatients. Also, there were no differences between these two groups regarding the total BDI, HDRS and HARS scores, as well as in their items scores, with the exception of the HARS item 5 („difficulty in concentration, poor memory“), that appeared to be worse in MDD-BR+ patients (F(1,51)=1.179; p=0.029). Interestingly enough, MDD patients with abnormal BR echogenicity when compared to those with normal BR had more frequently comorbid anxiety (at least one of the following diagnoses: GAD, panic attacks, social phobia and agoraphobia), but this two-fold difference did not reach statistical significance (15 out of 35 patients [43%] and 4 out of 18 patients [22%], respectively; p=0.138). This was also true for the most prevalent comorbid GAD (12 out of 35 patients [34%] and 3 out of 18 patients [17%], respectively; p=0.177). A stepwise statistical discriminant analysis was performed using 5 variables (GAD, social phobia, panic attacks, the HARS item 5 and 5HTTLPR polymorphism frequency) as predictors of membership in the two groups (MDD-BR- and MDD-BR+). There was statistically significant separation between MDD-BR- and MDD-BR+ groups based on the four predictors combined: the HAMA item 5 (F(1.47)=9.812; p=0.002), presence of social phobia (F(1.47)=6.72, p=0.012), short allele (s) homozygocity of 5-HTTLPR (F(1.47)=6.17; p=0.016) and presence of GAD (F(1.47)=5.69; p=0.021).
Reduced BR echogenicity in 47% of MDD patients vs. 15% of HC (p < 0.01)
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abnormal BR echogenicity included also higher scores of the item 5 of the HAMA („difficulty in concentration, poor memory“). Among the limitations of our study, besides those linked to the methodology of TCS itself, were cross-sectional design and heterogenous treatment of depressed patients. The sample size was among the largest in similar studies (Table 2), but it was still small regarding clinical and genetic correlations performed. Considering clinical, genetic and morphological heterogeneity of depression, the presence of reduced BR echogenicity on TCS in at least a subgroup of MDD patients may reflect a particular phenotype, characterized by more prevalent comorbid anxiety disorders, associated with particular genetic polymorphisms and neurotransmitter(s) deficits, most probably altered 5-HT mechanisms. Therefore, TCS may be an interesting and promising tool in defining possible distinct subtypes of depressive disorder, which in turn can lead to better defined treatment targets and objectives.
Changes in BR echogenicity have been proposed through several lines of evidence to be linked to 5-HT transmission (Meyer et al., 2006). Clusters of 5-HT neurons in the dorsal (DRN) and median raphe nucleus (MRN)) are the main source of ascending 5-HT projections throughout the forebrain to limbic, striatal and cortical regions (Becker et al., 2001; Brooks and Piccini, 2006). Study using single photon emission computed tomography found reduced 5-HT 1A receptor binding in the midbrain raphe (Malison et al., 1998), accompanied in a later positron emission tomography studies with the finding of decreased 5-HTT availability in the same structure of MDD patients (Drevets et al., 1999; Parsey et al., 2006). In one study with the highly specific ligand for 5-HTT, [11C]-DASB, statistically significant decreases in binding potentials of the 5-HTT were observed in various brain regions, including brainstem (Selvaraj et al., 2011). Finally, in a pathoanatomic study of the DRN of depressed suicide victims, a decrease in 5-HT 1A receptors was found, as well as in the number of neurons expressing 5-HTT mRNA in comparison to controls (Arango et al., 2001). In favor of serotonergic “connection” was also the finding that reduced BR echogenicity indicated good responsivity to selective serotonin reuptake inhibitors (SSRI), with a positive predictive value of 88% (Walter et al., 2007a). However, the echogenic midline of the mesencephalon and upper pontine brainstem identified by TCS represent a cross-road region of not only serotonergic, bidirectional pathways that are central components of limbic network forming basal limbic system (Becker et al., 2001). Therefore, mood changes associated with alterations of the BR echogenicity depicted by TCS might not be interpreted solely as a consequence of abnormalities in 5-HT transmission, but more general as a consequence of an impairment of the basal limbic system. Another important result of our study was that discriminant analysis revealed as significant predictors for the abnormal BR echogenicity combined presence of comorbid anxiety disorders, higher scores on the HAMA item 5 („difficulty in concentration, poor memory“), and a short allele homozygocity for the 5HTTLR polymorphism. Comorbid anxiety disorders were approximately twice as common in MDD-BR+ than in MDD-BR- patients, but this difference, partly due to the small sample size, did not reach statistical significance. Similar observation has been previously published in patients whose PD was associated with depression: anxiety was more frequently present in those with than in those without abnormal BR echogenicity (41% and 29% of patients, respectively) (Stanković et al., 2015). Besides major depression, several lines of evidence also implicated decreased serotonergic activity in anxiety disorders (Eison and Eison, 1994). The DRN was selectively activated by anxiety-related stimuli and is interconnected with forebrain structures controlling anxiety states (Lowry et al., 2008). The presence of s allele was included in a combination of factors that predicted abnormal BR+ echogenicity and also its homozygocity was significantly more frequent in MDD-BR+ than in MFF-BR- patients (p=0.048). Genetic polymorphisms in 5HTTLPR affected 5-HTT mRNA transcription (i.e. reduced 5-HTT expression for the s allele) (Praschak-Rieder et al., 2007) and have been associated with depression, but also with many anxiety disorders, such as generalized anxiety disorder (You et al., 2005) and social anxiety disorder (Reinelt et al., 2014). These associations were weak and not always reproducible, suggesting that serotonin might be a predisposing factor rather than a cause of depression or anxiety (Karg et al., 2011). Subject carrying s allele exhibited more depressive symptoms and major depression after stressful life events (Caspi et al., 2003). Lesch et al. (1996) were the first to report an association between the s allele and depression-, anxiety-, and aggression-related general personality traits. Also, Blom et al. (2011) found a relation between avoidant behavioral personality traits, associated with high rates of comorbid depression and anxiety (Oldham et al., 1995; McGlashan et al., 2000), and this allele. Some studies linked the s allele to decline in working memory (Weiss et al., 2014), as well as memory performance in women (Price et al., 2013). Interestingly enough, combination of predictors for
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