CHAPTER 3
Plasma β-amyloid levels in drug-resistant bipolar depressed patients receiving electroconvulsive therapy (Neuropsychobiology 2013; 67(4):185-191)
Authors: Piccinni A, Veltri A, Vizzaccaro C, Catena Dell’Osso M, Medda P, Domenici L, Vanelli F, Cecchini M, Franceschini C, Conversano C, Marazziti D, Dell'Osso L.
ABSTRACT
Aims: Alterations of plasma amyloid-β (Aβ) peptides have been related to a high risk for cognitive impairment and dementia. The present study aimed to measure plasma Aβ peptides (Aβ40, Aβ42) and the Aβ40/Aβ42 ratio in a sample of drug-resistant bipolar depressed patients, as well as to explore the possible correlation between biological parameters and clinical changes along an electroconvulsive therapy (ECT) course. Methods: Aβ40 and Aβ42 were measured by means of an ELISA assay in 25 drug-resistant bipolar depressed patients before (T0) and 1 week after (T1) the end of ECT. The patients were clinically evaluated by means of the Hamilton Rating Scale for Depression, 21-item (HRSD-21), the Mini-Mental State Examination, and the Clinical Global Impressions-Severity of Illness Scale. Results: Plasma Aβ levels and the Aβ40/Aβ42 ratio were similar at T0 and T1. The Aβ40/Aβ42 ratio correlated positively with the HRSD total score at both T0 and T1. At T0, a negative correlation was found between the Aβ40/Aβ42 ratio and the improvement of depressive and cognitive symptoms. Moreover, remitters (n = 9; HRSD ≤ 10) showed a significantly lower Aβ40/Aβ42 ratio at T0 than non-remitters. Conclusion: The present data suggest that a low Aβ40/Aβ42 ratio might characterize a subgroup of depressed patients who respond to ECT, while higher values of this parameter seem to be typical of more severe cases of patients with cognitive impairment.
INTRODUCTION
The risk for dementia and cognitive deterioration is greater in patients affected by mood disorders than in the general population (Geerlings et al., 2008; Gualtieri and Johnson, 2008; Barnes et al., 2012), and it has been related to the number of affective episodes, manic polarity, and the presence of psychotic symptoms (Kessing and Andersen, 2004; Robinson et al., 2006; Torres et al., 2007). The cognitive decline in mood disorders has been interpreted as the result of a common neuropathological mechanism, or as the expression of a greater vulnerability of some affective patients towards neurodegenerative phenomena (Aznar and Knudsen, 2011)
Amyloid-β (Aβ) deposition in Alzheimer’s disease (AD) is characterized by the presence of fragments of various lengths. In particular, the Aβ42 aminoacid peptide is the main component of senile plaques and is considered the most neurotoxic (Selkoe 2006), whereas the Aβ40 amino acid peptide represents a component of amyloid-associated brain angiopathy (Zhang-Nunes et al., 2006). Indeed, an increase in Aβ40 plasma levels has been associated with microvascular brain pathology, white matter hyperintensities, and lacunar infarcts (van Dijk et al., 2004; Gurol et al., 2006), all conditions related to cognitive decline in the elderly (Longstreth et al., 1996), risk for dementia (Vermeer et al., 2003), and depressive symptoms (de Groot et al., 2000). Most of the studies in AD and mild cognitive impairment reported a reduction of plasma Aβ42 and an increase of Aβ40 and Aβ40/Aβ42 ratio (Van Oijen et al., 2006; Graff-Radford et al., 2007; Xu et al., 2008). However, a few data are available regarding the relationship between depression and peripheral levels of Aβ peptides. Higher levels of Aβ40, lower levels of Aβ42, and a greater Aβ40/Aβ42 ratio have been reported in elderly patients with depression, as compared with healthy control subjects (Qiu et al., 2007; Sun et al., 2007, 2008). Moreover, the study by Sun et al. (2008) highlighted how the so-called ‘amyloid-associated’ depression (with high Aβ40/Aβ42 ratio) is characterized by a more severe deficit in memory, visual-spatial skills, and executive functions. In another study (Kita et al., 2009), depressed patients showed an enhanced Aβ40/Aβ42 ratio, but no differences in Aβ42 levels, when compared with age-matched control subjects. In our recent study on bipolar depressed patients, a negative correlation was found between Aβ42 plasma levels and duration of illness, and a positive one between the Aβ40/Aβ42 ratio and the number of affective episodes (Piccinni et al., 2012).
Since over 70 years, electroconvulsive therapy (ECT) represents one of the most effective treatments for unipolar (Pagnin et al., 2004) and bipolar depression (Zomberg and Pope 1993; Daly et al., 2001) with an effectiveness rate greater than 60%, although its mechanism of action is still unknown. Several factors including sex, age, diagnosis, presence of psychosis, duration of the index episode, medication treatment failure prior to ECT, and medications during the ECT course, have been proposed as predictors of response to ECT in patients suffering from depression (Bloch et al., 2005; Kho et al., 2005; Pluijms et al., 2006), although some disagreements exist (Dombrovski et al., 2005). On the contrary, data on potential biological predictors for the efficacy of ECT are scarce.
Given the paucity of available data, the aim of the present study was to assess plasma Aβ40 and Aβ42 levels and the Aβ40/Aβ42 ratio in bipolar depressed patients who failed to respond
to medications and received ECT. Possible correlations between biological parameters and clinical changes after the ECT course were examined.
METHODS Subjects
Twenty-five patients (13 men and 12 women; mean age ± SD: 44.1 ± 11.9 years) suffering from bipolar I or II depressive episodes with or without psychotic symptoms according to DSM-IV-TR criteria, were selected at the outpatients’ ward and hospital of the Department of Psychiatry of the University of Pisa. Subjects were eligible if they were over 18 years of age, were not suffering from a major neurological or medical illness that limited the use of ECT, and had no history of substance abuse in the last 6 months. Inclusion criteria were failure to respond to at least three mood disorder treatments, comprising an adequate trial with a tricyclic antidepressant (TCA) (Thase and Rush, 1997; Fava, 2003). More specifically, treatment nonresponsiveness in patients with bipolar depression was defined as persisting depressive symptoms despite two trials of at least 8 weeks, consisting of one trial with mood stabilizer(s) plus a TCA (200 mg/day of imipramine or the equivalent, or the maximum tolerable dose) and one trial with a selective serotonin reuptake inhibitor (40 mg/day of fluoxetine or the equivalent) combined with mood stabilizer(s) and a TCA. Diagnosis was confirmed by means of the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998). For each patient, a senior psychiatrist recommended ECT according to clinical judgment based on the patient’s failure to respond to medication trials and severity or urgency of illness. A written informed consent was obtained from all subjects, which was approved by the Ethics Committee of the University of Pisa, after procedure and effects were fully explained.
Clinical assessment
Severity of depression was assessed by means of the Hamilton Rating Scale for Depression, 21-item (HRSD-21) (Hamilton, 1960) and the Clinical Global Impressions-Severity of Illness Scale (CGI-S) (Guy, 1976). Remission was considered when HRSD total scores were ≤ 10 at the last two consecutive assessments (Lecrubier, 2002). The sample was screened for significant cognitive impairment by means of the Mini-Mental State Examination (MMSE) (Folstein et al., 1975).
Patients were clinically evaluated by means of HRSD-21, CGI-S, and MMSE before the first ECT session (T0) and 1 week after (T1) the last ECT session. Together with clinical assessment, a blood sample was collected to measure plasma Aβ40 and Aβ42 levels. We
decided to collect blood at T0 within 30 min before the ECT session to avoid a possible acute effect of electroconvulsion on peripheral Aβ levels. In a previous study, Zimmermann et al. (Zimmermann et al., 2012) hypothesized that the acute variations of peripheral Aβ levels after ECT could depend not only on an increased release from neurons, but also from peripheral sources, like thrombocytes or muscles. This last effect could represent a confounding factor and an important bias.
In order to measure the amount of time the patients spent being ill, the parameter ‘duration of illness’ was assessed according to the following equation: (current age – onset age) × 100/current age, developed by us.
Moreover, two parameters were elaborated by our statistician to assess the changes of depressive and cognitive symptoms: the percentage of depression improvement (PDI) calculated according to the following equation: [(HRSD total score)T0 – (HRSD total score)T1] × 100/(HRSD total score)T0, and the percentage of cognitive improvement (PCI) calculated as: [(MMSE total score) T1 – (MMSE total score)T0] × 100/30-(MMSE total score)T0.
ECT treatment procedures
Before undergoing ECT, each patient was screened for general medical conditions by means of an accurate clinical evaluation including collection of a detailed medical history, a physical and neurological examination, blood and urine tests, electrocardiogram, chest X-ray, and a cerebral computed tomography scan. Anesthesia was induced with intravenous thiopental (2–4 mg/kg i.v.) and succinylcholine (0.5–1 mg/kg i.v.). Bilateral brief-pulse, square-wave stimuli were delivered using a Mecta Spectrum 5000 (Mecta Corporation, Lake Oswego, Oreg., USA) twice a week between 7:00 and 9:00 a.m. Stimulus setting was initially based on age, and the length of the seizures, measured by an electroencephalogram, was kept above 25 s. If the duration of the seizure fell below 25 s, the stimulus was raised (1.5 times) at the next session. For all patients, the electrode positioning and stimulus dosing were similar. Other physiological parameters were monitored by means of a pulse oximetry and an electrocardiogram. Patients were ventilated with 100% oxygen until resumption of spontaneous respiration. ECT treatment was completed on the basis of the clinical judgment of the treating clinicians. The mean number of treatments received was 8.3 (range 6–10). Patients were maintained on the same treatment for at least 4 weeks before and throughout the entire study period. Mood stabilizers were discontinued for 3 days before starting ECT and were withheld until the end of ECT treatment.
Aβ assay
All study participants were subjected to a blood draw (16-ml test tube) for the measurements of Aβ plasma levels. Samples were centrifuged at 2,500 rpm × 10 min. The plasma was divided into aliquots and preserved at –80 ° C. Analyses of the Aβ40 and Aβ42 levels were carried out using specific ELISA kits (Invitrogen, Camarillo, Calif., USA). Briefly, samples were incubated with the monoclonal antibody specific for the NH2-terminus region of human Aβ that was coated onto the microplate wells. During the first incubation, standard, control, and unknown samples were pipetted into the wells and co-incubated with a rabbit antibody specific for the COOH-terminus of the 1–42 or 1–40 Aβ sequence. Bound rabbit antibody was detected by the use of a horsera dish peroxidase-labeled anti-rabbit antibody. After washing, horseradish peroxidase-labeled anti-rabbit antibody (enzyme) was added. After a second incubation and washing to remove all unbound enzyme, a substrate solution was added, which is acted upon by the bound enzyme to produce color. The intensity of this colored product is directly proportional to the concentration of human Aβ42 or Aβ40 present in the original specimen. Absorption was read at 450 nm using a microplate reader (iMARK; Biorad Laboratories). Samples were quantitated by the standard curve generated from the recombinant Aβ42 or Aβ40 included with the kit.
Statistical analysis
Data were recorded in a specifically designed database and elaborated by means of SPSS software (version No. 17). The comparison between quantitative variables of non-Gaussian distribution was performed with nonparametric statistical tests: in particular, the Mann-Whitney test was used for the comparison of independent samples, while the Wilcoxon test was used to compare the paired data. Correlations between the variables were examined by means of Spearman’s coefficient. The χ 2 test was used to compare categorical variables, while the paired data with Gaussian distribution were compared by paired samples Student’s t-test.
RESULTS
Although all patients showed a clinical improvement, as assessed by the changes in rating scale scores, only 9 patients reached the clinical remission after ECT (HRSD ≤ 10). The HRSD total score (mean values ± SD) significantly decreased from T0 to T1 (T0: 30.5 ± 4.30; T1: 11.4 ± 2.6; t = –30.085, p < 0.0001), and the same was true for the CGI-S score (mean values ± SD) (T0: 5.8 ± 0.4; T1: 2.9 ± 0.8; t = –18.437, p < 0.0001).
On the contrary, the MMSE total score (mean values ± SD) significantly increased from T0 to T1 (T0: 23.4 ± 2.1; T1: 24.6 ±1.9; t = 4.748, p = 0.0001).
As shown in Table 1 , plasma Aβ40 levels, Aβ42 levels and the Aβ40/Aβ42 ratio were similar at T0 and T1.
Correlation analyses showed that the Aβ40/Aβ42 ratio correlated positively with the HRSD total score at both T0 (rs = 0.562, p = 0.003) and T1 (rs = 0.738, p < 0.001), and negatively with the MMSE total score at T1 only (rs = –0.559, p = 0.004). A significant and positive correlation was also detected between plasma Aβ40 levels and the HRSD total score at both T0 (rs = 0.510, p = 0.009) and T1 (rs = 0.531, p = 0.006).
Finally, a significant and negative correlation was found between plasma Aβ40 levels and the MMSE total score at both T0 (rs = –0.542, p = 0.006) and T1 (rs = –0.548, p = 0.006).
In addition, the sample was characterized by a duration of illness (mean ± SD) of 36.10 ± 17.37% and by a number of episodes (mean ± SD) of 4.12 ± 1.83. Plasma Aβ42 levels were negatively correlated with the duration of illness (rs = − 0.413, p = 0.04), while the Aβ40/Aβ42 ratio was positively correlated with the number of affective episodes (rs = 0.540, p = 0.005). As far as the ECT response was concerned, the Aβ40/Aβ42 ratio at T0 was negatively correlated with PDI (rs = –0.463, p = 0.02) and PCI (rs = –0.637, p = 0.001) (Table 2).
Moreover, remitters (HRSD ≤ 10, n = 9) at the end of the ECT course, were those with a lower Aβ40/Aβ42 ratio at T0 than the others (z = –2.46, p = 0.014) (Fig. 1).
Figure 1 - Aβ40/Aβ42 ratio (T0) in remitter and non-remitters. At baseline (T0), the group of remitters showed a mean Aβ40/Aβ42 ratio significantly lower than that of non-remitters. * Mann-Whitney test: z = –2.46, p = 0.014.
DISCUSSION
Our study aimed to assess plasma Aβ peptides in a sample of bipolar depressed patients before and after an ECT course. Our findings showed no changes in Aβ42 or Aβ40 levels, as well as in the Aβ40/Aβ42 ratio at the different assessment times. The stability of the Aβ levels, despite the clinical improvement following ECT, could suggest the need for further investigation in
order to understand if the alterations of peripheral Aβ peptides in patients suffering from bipolar depression might represent a trait rather than a state biomarker. This finding can be considered in line with that of a recent study demonstrating only a slight (between 5 and 10%) and transient (reversible within 2 h) increase of plasma Aβ peptide concentrations after single sessions of ECT. This might be due to a decreased integrity of the blood-brain barrier permeability, an increased release of Aβ from the neurons, or from peripheral sources, like thrombocytes or muscles (Zimmermann et al., 2012). However, to the best of our knowledge, our study is the first evaluating Aβ levels before and after ECT. In the literature, just a few indirect observations are available, like lower Aβ40 levels in patients receiving antidepressants (Sun et al., 2007), or no differences in plasma Aβ42 levels between patients with or without antidepressants (Sun et al., 2007; Pomara et al., 2006). Recently, no influence of antidepressants, lithium, or valproate treatments on the Aβ40/Aβ42 ratio was described in a large sample of depressed patients (Baba et al., 2012).
Our results showed that both Aβ40 levels and the Aβ40/Aβ42 ratio were positively correlated with the severity of depressive and cognitive symptoms, that is to say, the higher the biological parameters, the most severe the patient, and vice versa. According to some authors, the presence of depressive symptoms associated with a high Aβ40/Aβ42 ratio would represent a prodromal manifestation of AD (Sun et al., 2008). However, other hypotheses could be suggested, such as the existence of a primarily ‘amyloid-associated’ mood disorder (characterized by Aβ disturbances unrelated to prodromal AD) with resistance to treatment and risk for cognitive decline (Pomara and Murala Doraiswamy, 2003; Pomara and Sidtis, 2010). Alternatively, Aβ-mediated neurodegenerative processes could be triggered by recurrence of affective episodes representing an epiphenomenon in all patients with mood disorders. Interestingly, in both this study and in another of our group (Piccinni et al., 2012) a positive correlation was detected between the Aβ40/Aβ42 ratio and the number of affective episodes, while highlighting how the changes of blood Aβ levels could characterize a subgroup of bipolar patients with worse illness course.
In the present study, high values of the Aβ40/Aβ42 ratio were associated with a poor outcome of depressive and cognitive symptoms. Moreover, remitters presented a significantly lower Aβ40/Aβ42 ratio at baseline, as compared with non-remitters. Further studies are, however, needed to investigate whether the Aβ-mediated neurotoxicity might contribute to the worsening and subsequent poor response to treatments in affective patients. Although the mode of action of ECT is still elusive, different data show that electroconvulsive seizures may provoke a robust neurotrophic effect by increasing the levels of brain-derived neurotrophic
factor (BDNF) mRNA, proteins, and the tyrosine kinase receptor B mRNA in the rat hippocampus. Further, chronic electroconvulsive seizure administration blocked the downregulation of BDNF mRNA in the same area in response to restraint-induced stress (Lindefors et al., 1995; Nibuya et al., 1995; Angelucci et al., 2002). Some studies in depressed patients showed that ECT similarly to antidepressants (Piccinni et al., 2008; Sen et al., 2008) may increase the amount of serum and plasma BDNF (Bocchio-Chiavetto et al., 2006; Marano et al., 2007; Taylor, 2008) particularly in responders (Okamoto et al., 2008; Piccinni et al., 2009). These results suggest that one of the putative mechanisms of ECT might be mediated by BDNF and related substances (Taylor, 2008). It is therefore plausible that Aβ may exhibit a functional interference with BDNF actions. In fact, in cortical neuron cultures, subtoxic concentrations of Aβ impair the transduction pathways activated by BDNF signalling (Tong et al., 2001) and, at higher concentrations, the synthesis of BDNF (Arvanitis et al., 2007; Arancio and Chao, 2007). In rats, a BDNF pretreatment is able to prevent neuronal damage induced by Aβ injection (Arancibia et al., 2008), and a single i.v. Aβ injection was reported to induce a depressive phenotype and to inhibit BDNF expression in the prefrontal cortex (Colaianna et al., 2010). Based on these observations, we speculate with caution that the altered plasma Aβ peptide levels of the resistant patients would reflect some brain neurodegenerative and neurotoxic phenomena hindering the BDNF-mediated neurorestorative action induced by ECT. This could explain why in our sample a high Aβ40/Aβ42 ratio seems to be predictive of nonresponse to ECT.
The small sample size is the major bias of the present study. For this reason, the comparisons of biological parameters between remitters and non-remitters are based on a few cases (9 vs. 16 subjects). Further, the fact that all the patients were taking psychotropic drugs during the ECT course may constitute a possible bias, although no influence of psychotropic medications on the plasma Aβ40/Aβ42 ratio was reported (Baba et al., 2012). Moreover, the precise origin of plasma Aβ is not known and results regarding the relationship between peripheral blood and cerebrospinal fluid Aβ levels have been contradictory (Mehta et al., 2001; Kawarabayashi et al., 2001; Giedraitis et al., 2007; Le Bastard et al., 2009). Therefore, a lack of data on cerebrospinal fluid may also be considered a limitation. Lastly, further studies comparing baseline plasma Aβ levels of patients with those of healthy control subjects are needed to clarify whether potential variations of Aβ peptides to ECT could depend on baseline values, and therefore whether or not originally normal or abnormal plasma Aβ peptide levels might influence this response.
CONCLUSIONS
In conclusion, we propose with caution that particular changes in Aβ peptide levels may represent a potential trait marker of a mood disorder subtype characterized by a great severity, a high cognitive impairment, and worse response to treatments. In any case, studies with larger samples of patients suffering from mood disorders are needed to understand whether changes in plasma Aβ peptides may be used as possible predictors of response, are associated with alterations of other biomarkers, such as the BDNF, and might, therefore, represent a trait or state marker of mood disorders. Similarly, it would be extremely useful to explore more thoroughly the possible associations of Aβ peptides with specific symptoms or symptom clusters, irrespective of the diagnosis.
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