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ORIGINAL ARTICLE
Year : 2016  |  Volume : 25  |  Issue : 1  |  Page : 93-100  Table of Contents     

Accelerated antidepressant response to lithium augmentation of imipramine


1 Department of Psychiatry, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Psychiatry, Peoples Medical College and Hospital, Bhopal, Madhya Pradesh, India
3 Department of Psychiatry, Pravara Institute of Medical Sciences (Deemed University), Rural Medical College, Loni, Maharashtra, India

Date of Web Publication19-Dec-2016

Correspondence Address:
Suprakash Chaudhury
Department of Psychiatry, Pravara Institute of Medical Sciences (Deemed University), Rural Medical College, Loni, Ahmednagar - 413 736, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-6748.196057

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   Abstract 

Background: Treatment of depressive episode often poses a challenge. Although there are numerous medicines available for its treatment but they all have a lag period of 2–3 weeks before they start showing their result. Aim: The aim of the present study was to test the hypothesis that an initial lithium-tricyclic antidepressant (TCA) combination has a quicker and better antidepressant effect than standard TCA treatment in unipolar depression. Materials and Methods: Twenty unipolar depressed inpatients under lithium-TCA treatment were compared with twenty patients with similar diagnosis treated with TCA-placebo combination. The duration of the study was 4 weeks under double-blind conditions. Results: Initial lithium-TCA treatment reduced depressive symptoms significantly more than TCA alone. The difference was evident from 1st week onward and persisted at 4 weeks. Conclusion: Lithium augmentation of TCA at the outset offers a strategy to reduce the lag period of antidepressant action. The choice can be made for those patients who are likely to benefit from long-term prophylaxis.

Keywords: Lithium, lithium combination, treatment of depression, tricyclic antidepressant


How to cite this article:
Saini R, Raju M, Chaudhury S, Srivastava K. Accelerated antidepressant response to lithium augmentation of imipramine. Ind Psychiatry J 2016;25:93-100

How to cite this URL:
Saini R, Raju M, Chaudhury S, Srivastava K. Accelerated antidepressant response to lithium augmentation of imipramine. Ind Psychiatry J [serial online] 2016 [cited 2017 Nov 24];25:93-100. Available from: http://www.industrialpsychiatry.org/text.asp?2016/25/1/93/196057

Major depressive disorder is the second leading cause of disability worldwide, and a major contributor to the burden of suicide and ischemic heart disease.[1] The recent epidemiological survey indicates lifetime prevalence of depression in the range of 10%–15%.[2] Its burden on the economy of a nation can be judged from the fact that unipolar major depression ranks second highest in terms of causes of disability. It accounts for 10.7% of total disability for a nation and higher treatment cost.[3],[4],[5] Moreover, the sociooccupational distress and the misery caused to depressed patient cannot be quantified in monetary terms. Untreated depression is a leading cause of suicide.[6] It is, therefore, no surprise that references of depressive illness figure prominently in medical literature.

There were no definitive modalities available to counter depression until the serendipitous discovery of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors in the 1950s that proved to be of seminal importance.[7] First, they demonstrated that major depression was amenable to medical intervention just like other medical conditions such as hypertension and diabetes. Second, they served as roadmaps to improve our understanding of the mechanisms of action. The latter was critical to the era of rational drug development. The approach to pharmacotherapy for depression has remained unchanged over the last several decades; after diagnosis, the clinician initiates his choice of antidepressant agent and then titrates the drug dose over time until symptoms resolve. However, the goal of achieving accelerated antidepressant response has largely remained elusive. There is a delay of 2–3 weeks in the onset of action of all the available antidepressants.[8] Many patients, who do respond to antidepressant therapy, may lose that response after several months of treatment.[9] Augmentation of antidepressant response with lithium brought the much-needed relief to the harried clinician.[10] Its efficacy in the treatment of bipolar mood disorder and refractory depression sparked further interest in its role in amelioration of many other psychiatric disorders [11],[12],[13],[14] and confirmed that it does have those properties though mechanism of action is different.[15]

Attempts at ensuring faster antidepressant response from the outset have been far and few. Combination therapy is often used to improve efficacy, speed response and to attenuate an adverse effect of initial pharmacotherapy.[16],[17],[18] With advances in psychopharmacology, the emphasis has shifted to focus on receptor-symptom complexes and accordingly newer antidepressants and combinations are being tailor-made to meet the specific requirements. With this information in the background, we attempted to analyze the effect of combining imipramine and lithium from the outset in the treatment of unipolar nonrefractory depression. The study tried to ascertain the efficacy of combined approach toward achieving earlier remission and comparing it with monotherapy alone. A positive response to lithium augmentation at the outset and the correlation of such a response to clinical variables would help in chalking out effective strategies to counter depression.


   Materials and Methods Top


The study was carried out in a large multispecialty, tertiary care teaching hospital. The project was approved by the Institutional Ethical Committee. Forty consecutive patients conforming to the diagnosis of unipolar depression constituted the study group. The diagnosis was established as per the International Classification of Diseases-10 Diagnostic Criteria for Research criteria.[19] Patients with underlying or comorbid medical condition, psychotic depression, and those who were already on psychotropic medicines were excluded from the study. Cases having contraindication for imipramine and/or lithium treatment were also excluded from the study. The aim of the study and the method adopted was explained to each patient and his/her cooperation was solicited. Written Informed consent was obtained from every patient. Findings of physical examination, mental status evaluation, sociodemographic data were recorded on a specially designed pro forma. All baseline investigations including electrocardiogram and thyroid function were carried out as per standard guidelines. All patients were randomly assigned to one of the two groups: Group A patients were given tablet imipramine and placebo. Group B patients were administered tablet imipramine and tablet lithium carbonate as per schedule given below. The assessment of psychopathology was done by structured interview of the Hamilton Depression/Melancholia Scale designed by Williams.[20] The instrument ensured a high inter-rater reliability. The serial readings were made at 4 weekly intervals starting at day 1.

Administration of tricyclic antidepressant and lithium

Imipramine hydrochloride was used for all the patients. The investigator had reviewed the records maintained at this center and found that clinical response was recorded in almost all cases at the dose range of 100–150 mg. Barring unforeseen developments, each patient was to be brought up to dose of 150 mg by day 14. The dose was maintained at that level during the study period. Lithium carbonate was administered in such a way as to achieve a serum lithium concentration in the range of 0.6–0.8 mEq/L by day 7. This range was subject to revision in case of unforeseen circumstances. It was arrived at taking in to consideration the findings of earlier studies.[21],[22],[23] Lithium concentration was measured by atomic absorption spectrophotometry. The nursing staff who administered the drugs was blind to the nature of regimen given to the patients. A professional colleague's help was taken to maintain the double-blind format.

Statistical analysis

Students t-test was utilized to test the significance of the difference of means of scores at weekly intervals while categorical data were put to Chi-square test, using the Statistical Package for Social Sciences - Version 16.0 (SPSS 16.0. IBM).


   Results Top


Demographic and clinical details of depressed patients in both groups did not show any significant differences [Table 1]. The two groups did not differ in duration for their current depressive episode [Table 2]. Most of the patients in both the groups complained of multiple somatic complaints. The patients did not differ in terms of frequency a particular symptom [Table 3]. Depression scores of Group “A” and Group “B” patients at baseline and percentage reduction of scores at weekly intervals is shown in [Table 4] and [Table 5], respectively. Comparison of two Groups in depression ratings at baseline and at weekly intervals [Table 6]. There is no difference between the two groups at baseline, but the difference is significant at the end of 1st week, 2nd week, 3rd week, and 4th week.
Table 1: Demographic and clinical details of depressed patients

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Table 2: Duration of index episode at outset

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Table 3: Most common symptoms at the time of initial assessment

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Table 4: Depression scores of Group A patients at Baseline and at weekly intervals

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Table 5: Depression scores of Group B patients at Baseline and at weekly intervals

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Table 6: Comparison of two Groups in depression ratings at baseline and at weekly intervals (unpaired t-test)

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Mean percentage reductions in depression ratings at weekly intervals for both the groups revealed a larger reduction in depression ratings for Group “B” as compared to Group “A” at end of 1st, 2nd, 3rd, and 4th week [Figure 1]. Difference between the baseline scores and at scores at weekly intervals for Groups A and B is shown in [Table 7]. There are significant reductions in depression ratings for both groups at 1 week, 2 week, 3 week, and at 4 week intervals. However, the decline in scores is more for Group B as compared to Group A. The mean serum lithium level for the Group achieved was 0.555 (standard deviation: 0.186). The plasma serum levels of lithium correlated with the clinical response positively at 1 week but had no correlation at 4 weeks [Table 8].
Figure 1: Mean percentage reductions in depression ratings at weekly intervals for both the groups revealed a larger reduction in depression ratings for Group B as compared to Group A at the end of 1st, 2nd, 3rd, and 4th week

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Table 7: Difference between the baseline scores and at scores at weekly intervals for Groups A and B (Student's paired t-test)

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Table 8: Mean serum lithium levels and percentage response at 1 week and at 4 weeks for Group B patients

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Majority (65%) of patients of Group B showed at least 25% improvement in depression ratings by the end of the 1st week. Although the sample size in nonresponder group (i.e., <25% by 1 week) is small, but the trend shows a positive correlation of response with female gender, married status of the patient, absence of an enduring psychosocial problem, and a positive family history for a mood disorder [Table 9].
Table 9: Difference in variables associated with response at 1 week within Group B between partial responders (i.e., having response >25% and) and nonresponders (i.e., having response <25%)

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The most common side effect for Group A was dry mouth whereas it was digital tremor for the Group B patients. Other side effects encountered were constipation, postural hypotension, foul taste, blurred vision, urinary problems, palpitations, and impotence. Manic switch for 2 patients in Group A and dysarthria and arrhythmia in one patient each for Group B were exclusively group specific [Table 10].
Table 10: Common side effects for both the groups

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   Discussion Top


The last century was often termed as the century of anxiety. In contrast, 21st century can perhaps be described as the age of depression as evidenced by the fact that it is one of the most common scourges causing distress and disability. Although remarkable advances in somatic and psychological interventions have brought in salutary change, but patients are still obliged to endure the anathema at least for a few weeks until the administered drugs start to take effect. Ongoing research holds promise of rationalizing and optimizing drug therapies so as to provide maximum benefit to the patient. The current study was a step in this direction wherein an attempt was made to curtail the lag period of TCA response by the addition of lithium from the outset and comparing it with the same TCA monotherapy in a double-blinded randomized controlled study.

The mean age of the sample is around 37 years [Table 1]. The means are comparable to a similar study [24] where mean age was about 39 years (39.5 for imipramine and 38.5 for imipramine + lithium group). A total of five patients in Group A and 1 patient of Group B [Table 1] shared a positive family of a mood disorder. A total of 6 patients of Group A and 5 patients of Group B [Table 1] had a history of mental or neurological illness. However, none of the patients had a concurrent medical or surgical illness and were not on any psychotropic medications (exclusion criteria). The trial was extended to include unipolar, recurrent depression as well as dysthymic patients [Table 1] against an earlier study [24] where they restricted the sample to only bipolar depressed with melancholic features. Duration of the index depressive episode was identical for both the groups [Table 2]. The symptom profile for patients of both the groups at baseline [Table 3] is in agreement with a similar study,[25] which suggests higher prevalence of somatic rather than cognitive symptoms in depressed subjects of this country.

In the current study, patients receiving lithium and imipramine combination responded more rapidly and completely than the imipramine-placebo groups [Tables 4], [Table 5] and [Figure 1]. The differences in response between the two groups at the end of 1st week, 2nd week, 3rd week, and 4th weeks were both statistically significant and clinically meaningful. The mean percentage change in depression ratings [Figure 1] after 1 week (38.37%) for the lithium + imipramine group was higher than the imipramine + placebo group (14.97%). Although the difference between the two groups [Table 6] was not significant at baseline (t = 0.5891, P > 0.05), but it was significant at week 1 (t = 3.8747, P < 0.01), week 2 (t = 3.6895, P < 0.01), week 3 (t = 2.8153, P < 0.01), and at week 4 (t = 2.2682, P < 0.05). The important clinical relevance in the finding is that the combination proves its superiority over monotherapy in that it brought a faster onset of action which persisted during the duration of the study. The mean percentage reduction at 4 weeks [Figure 1] of depression ratings was higher (96.2%) for Group B (imipramine + lithium combination) than that of 60.5% for Group A (imipramine + placebo combination) implying that the combination brought a more complete remission. The findings are supported by a similar study [24] who found better efficacy at 6 weeks rather than at 4 weeks.

The principal hypothesized mechanism of action of imipramine is its ability to inhibit reuptake of both serotonin and noradrenaline. The exact mechanism of action of lithium remains a mystery though recent research points toward its salubrious effect in stabilizing ionic and molecular transmission.[15],[26] Lithium is also known to produce striking enhancements in some aspects of serotonergic functions, which is also caused by Imipramine. Although the exact pharmacodynamics and pharmacokinetics were not the principal foci of this study, it appears that the superior response to the combination may have been obtained because of two separate actions concomitantly by imipramine (in monoamine enhancement at the synaptic cleft) and lithium (in altering intra-neuronal signal pathways) at molecular level.

The strategy is not new to medical profession and is an accepted norm in the treatment of malignancies and chronic infections such as tuberculosis and HIV. Lithium is not known to interfere with pharmacokinetics of imipramine, and the combination has been described to be a safe and effective one.[27] At the outset, it was not known as to what degree patients would be tolerating the combination, and the emergence of side effects (in the form of coarse digital tremor) at the predefined serum levels of 0.6–0.9 mEq/L was underestimated. Emergence of this side effect in the combination group warranted a more cautious approach and serum lithium targets were revised from 0.6–0.9 mEq/L to 0.4–0.8 mEq/L. The strategy helped in restricting the tremor to only a mild form, which was acceptable to the patients. The use of other antitremor agents such as clonazepam or propranol was of course considered but was not required as tremors reached acceptable levels by just lowering the mean serum lithium levels. That the therapeutic effect was obtained with this much concentration is supported by earlier studies, which suggest that lower concentrations may be as effective as higher concentration for augmentation purpose.[28],[29],[30] Moreover, correlation studies at 1 week and at 4 weeks [Table 8] suggest a mildly significant positive correlation at 1 week and an insignificant correlation at 4 weeks. This study did not address whether augmentation should be continued beyond 4 weeks. Lithium was administered for 4 weeks because the intent was to augment imipramine and interest was in early response. How far is the combination likely to be beneficial beyond 4 weeks is subject to further evaluation. However, existing research supports its use, and it may be an alternative in difficult cases.[31]

On further analysis, it is seen that 14 out of 20 patients in Group B (i.e. 70%) showed a higher than 25% response in depression ratings by the end of 1st week [Table 9]. A search was made to study the variables associated with difference in response of more than 25% and that of <25%. The variables of age, occupation, educational status, interpersonal relations, past history of mental or neurological illness, depression typology, or duration of index depressive episode did not significantly influence the outcome though the variables of gender (of being females), married status, absence of enduring psychosocial problem, and a positive family history for a mood disorder predicted a better response. It appears fairly reasonable to presume at this stage that the response to lithium plus imipramine combination was quicker and superior than tricyclic monotherapy alone and it was seen across majority of depressed subjects. The limiting factor of the study was small sample size and a narrow spectrum of depressive disorders which were studied. However, more research in this direction with larger sample is suggested.


   Conclusions Top


Concurrent administration of lithium and imipramine from the outset produced quicker antidepressant response in unipolar depression and the effect was evident in 70% of the patients by the end of the 1st week. However, larger sample and more studies are needed to confirm these findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Ferrari AJ, Somerville AJ, Baxter AJ, Norman R, Patten SB, Vos T, et al. Global variation in the prevalence and incidence of major depressive disorder: A systematic review of the epidemiological literature. Psychol Med 2013;43:471-81.  Back to cited text no. 1
    
2.
Lépine JP, Briley M. The increasing burden of depression. Neuropsychiatr Dis Treat 2011;7 Suppl 1:3-7.  Back to cited text no. 2
    
3.
Henk HJ, Katzelnick DJ, Kobak KA, Greist JH, Jefferson JW. Medical costs attributed to depression among patients with a history of high medical expenses in a health maintenance organization. Arch Gen Psychiatry 1996;53:899-904.  Back to cited text no. 3
    
4.
Katzelnick DJ, Kobak KA, Greist JH, Jefferson JW, Henk HJ. Effect of primary care treatment of depression on service use by patients with high medical expenditures. Psychiatr Serv 1997;48:59-64.  Back to cited text no. 4
    
5.
Broadhead WE, Blazer DG, George LK, Tse CK. Depression, disability days, and days lost from work in a prospective epidemiologic survey. JAMA 1990;264:2524-8.  Back to cited text no. 5
    
6.
Isacsson G, Reutfors J, Papadopoulos FC, Ösby U, Ahlner J. Antidepressant medication prevents suicide in depression. Acta Psychiatr Scand 2010;122:454-60.  Back to cited text no. 6
    
7.
Ban TA. The role of serendipity in drug discovery. Dialogues Clin Neurosci 2006;8:335-44.  Back to cited text no. 7
    
8.
Stassen HH, Angst J, Delini-Stula A. Onset of action under antidepressant treatment. Eur Psychiatry 1997;12:163-5.  Back to cited text no. 8
    
9.
Judd LL, Paulus MJ, Schettler PJ, Akiskal HS, Endicott J, Leon AC, et al. Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness? Am J Psychiatry 2000;157:1501-4.  Back to cited text no. 9
    
10.
Lingjaerde O, Edlund AH, Gormsen CA, Gottfries CG, Haugstad A, Hermann IL, et al. The effects of lithium carbonate in combination with tricyclic antidepressants in endogenous depression. A double-blind, multicenter trial. Acta Psychiatr Scand 1974;50:233-42.  Back to cited text no. 10
    
11.
Cole N, Parker G. Cade's identification of lithium for manic-depressive illness – The prospector who found a gold nugget. J Nerv Ment Dis 2012;200:1101-4.  Back to cited text no. 11
    
12.
Goodwin FK, Ghaemi SN. The impact of the discovery of lithium on psychiatric thought and practice in the USA and Europe. Aust N Z Psychiatry 1999;33Suppl:S54-64.  Back to cited text no. 12
    
13.
Johnson G. Antidepressant effect of lithium. Compr Psychiatry 1974;15:43-7.  Back to cited text no. 13
    
14.
Doyal LE, Morton WA Jr. The clinical usefulness of lithium as an antidepressant. Hosp Community Psychiatry 1984;35:685-91.  Back to cited text no. 14
    
15.
Chiu CT, Chuang DM. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther 2010;128:281-304.  Back to cited text no. 15
    
16.
Blier P, Gobbi G, Turcotte JE, de Montigny C, Boucher N, Hébert C, et al. Mirtazapine and paroxetine in major depression: A comparison of monotherapy versus their combination from treatment initiation. Eur Neuropsychopharmacol 2009;19:457-65.  Back to cited text no. 16
    
17.
Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: A double-blind randomized study. Am J Psychiatry 2010;167:281-8.  Back to cited text no. 17
    
18.
Cappiello A, McDougle CJ, Delgado PL, Malison RT, Jatlow P, Charney DS, et al. Lithium and desipramine versus desipramine alone in the treatment of severe major depression: A preliminary study. Int Clin Psychopharmacol 1998;13:191-8.  Back to cited text no. 18
    
19.
World Health Organization. International Classification of Diseases-10: Diagnostic Criteria for Research. Geneva: World Health Organization; 1993.  Back to cited text no. 19
    
20.
Williams JB. Structured interview guide for Hamilton Rating Scale. In: Bech P, Coppen A editors. The Hamilton Scale. Berlin: Springer; 1990. p. 48-63.  Back to cited text no. 20
    
21.
Katona CL, Abou-Saleh MT, Harrison DA, Nairac BA, Edwards DR, Lock T, et al. Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine. Br J Psychiatry 1995;166:80-6.  Back to cited text no. 21
    
22.
de Montigny C, Cournoyer G, Morissette R, Langlois R, Caillé G. Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry 1983;40:1327-34.  Back to cited text no. 22
    
23.
Cipriani A, Smith K, Burgess S, Carney S, Goodwin G, Geddes J. Lithium versus antidepressants in the long-term treatment of unipolar affective disorder. Cochrane Database Syst Rev 2006;18:CD003492.  Back to cited text no. 23
    
24.
de Montigny C, Cournoyer G, Morissette R, Langlois R, Caillé G. Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry 1983;40:1327-34.  Back to cited text no. 24
    
25.
Ebert D, Jaspert A, Murata H, Kaschka WP. Initial lithium augmentation improves the antidepressant effects of standard TCA treatment in non-resistant depressed patients. Psychopharmacology (Berl) 1995;118:223-5.  Back to cited text no. 25
    
26.
Grover S, Avasthi A, Kalita K, Dalal PK, Rao GP, Chadda RK, et al. IPS multicentric study: Functional somatic symptoms in depression. Indian J Psychiatry 2013;55:31-40.  Back to cited text no. 26
[PUBMED]  Medknow Journal  
27.
Bschor T, Bauer M. Efficacy and mechanisms of action of lithium augmentation in refractory major depression. Curr Pharm Des 2006;12:2985-92.  Back to cited text no. 27
    
28.
Taylor D, Payton D, Kapur K. The Maudsley Prescribing Guidelines. 10th ed. New Jersey, USA: Informa Healthcare; 2010.  Back to cited text no. 28
    
29.
Stein G, Bernadt M. Lithium augmentation therapy in tricyclic-resistant depression. A controlled trial using lithium in low and normal doses. Br J Psychiatry 1993;162:634-40.  Back to cited text no. 29
    
30.
Kantor D, McNevin S, Leichner P, Harper D. The benefit of lithium carbonate adjunct in refractory depresssion- fact or fiction? Can J Psychiatry 1996;31:416-8.  Back to cited text no. 30
    
31.
Alevizos B, Alevizos E, Leonardou A, Zervas I. Low dosage lithium augmentation in venlafaxine resistant depression: An open-label study. Psychiatriki 2012;23:143-8.  Back to cited text no. 31
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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