Role of baseline depressive symptoms in the development of depressive episode in patients receiving antiviral therapy for Hepatitis C infection Sudhir Mahajan, Ajit Avasthi, Sandeep Grover, Yogesh Chawla PII: DOI: Reference:
S0022-3999(14)00220-7 doi: 10.1016/j.jpsychores.2014.05.008 PSR 8819
To appear in:
Journal of Psychosomatic Research
Received date: Revised date: Accepted date:
3 March 2014 21 May 2014 23 May 2014
Please cite this article as: Mahajan Sudhir, Avasthi Ajit, Grover Sandeep, Chawla Yogesh, Role of baseline depressive symptoms in the development of depressive episode in patients receiving antiviral therapy for Hepatitis C infection, Journal of Psychosomatic Research (2014), doi: 10.1016/j.jpsychores.2014.05.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Role of baseline depressive symptoms in the development of depressive episode in patients receiving antiviral therapy for Hepatitis C infection
RI
PT
Running title: Depression associated with antiviral therapy for HCV
SC
Authors: Sudhir Mahajan, MD, Senior Resident1
NU
Ajit Avasthi, MD, Professor1 Sandeep Grover, MD, Assistant Professor1
D
MA
Yogesh Chawla, MD, Professor and Head2
TE
1-Department of Psychiatry; 2- Department of Hepatology
AC CE P
Post Graduate Institute of Medical Education and Research, Chandigarh
Corresponding Author: Dr Sandeep Grover Assistant Professor Department of Psychiatry Postgraduate Institute of Medical Education & Research Chandigarh 160012, India Phone: 0091-172-2756807 (O)
Fax: +91-172-2744401; 2745078 (Dr. Sandeep Grover, Psychiatry) Email: [email protected] Funding: None
ACCEPTED MANUSCRIPT Abstract: Objective: This study aimed to study the symptom profile and the role of baseline
PT
depressive symptoms in the development of depressive episode in patients receiving a
RI
combination of pegylated IFN-alpha and ribavirin. Methods: 82 consecutive patients
SC
with HCV infection in whom combination of pegylated interferon-α 2a/2b and ribavirin was prescribed were assessed at baseline and thereafter at 2, 4, 8 and 12 weeks. At the
NU
baseline, patients were assessed on Patient Health Questionnaire (PHQ-9), Mini
MA
International Neuropsychiatric Interview (MINI) and Beck Depression Inventory (BDIII). Thereafter patients were assessed on PHQ-9 and when ever found to have Major
D
Depressive Disorder as per PHQ-9, they were assessed on MINI. Those found to have
TE
Major Depressive Episode (MDE) on MINI were rated on BDI-II for phenomenology and severity of depression. Results: Common symptoms of pegylated IFN-alpha and
AC CE P
ribavirin induced MDE include sadness, irritability, work inhibition, sleep disturbance, fatigability and loss of appetite. Presence of certain depressive symptoms i.e., presence of little interest or pleasure in doing things, feeling tired or having little energy, poor appetite, social withdrawal and work inhibition at the baseline were associated with development of depression during the course of pegylated IFN-alpha plus Ribavirin therapy. Conclusion:Depressive symptoms in patients with pegylated IFN-alpha and ribavirin induced MDE are influenced by the symptoms of depression prior to starting of pegylated IFN-alpha and ribavirin combination. A short screening questionnaire may be constructed which will include the symptoms which predict of development of depression to screen patients at high risk for development of depression. Key words: Interferon, depression, symptom profile
ACCEPTED MANUSCRIPT Introduction Many studies have evaluated the incidence of depression associated with Interferon-
PT
alpha (IFN-α) in patients with Hepatitis C Virus (HCV) infection and have shown
RI
induction of depression in 5-82%of patients [1-15].A recent meta-analysis [16], reported cumulative incidence of major depressive episode (MDD) during IFN treatment to be
SC
25% by 24 weeks after initiation and 28% after 48 weeks in patients who had no history
NU
of depression before starting treatment.
Some of the studies which have studied the incidence of IFN induced depression in
MA
patients with HCV infection have also tried to evaluate the various predictors of depression and the results are not conclusive [16]. Among the various clinical factors,
TE
D
subclinical depressive symptoms at baseline are an important predictor of interferonassociated depression during the therapy. This association was also confirmed by the
AC CE P
metanalysis [16] which has evaluated the relationship of depression with interferon. The metanalysis concluded that higher scores on depression scales before starting antiviral treatment predicted subsequent development of depression. The metanalysis also showed that personal history of major depressive disorder (MDD) was associated with development of interferon-induced depression. However, the literature is very silent about specific depressive symptoms which when present at baseline can predict incident depression associated with IFN. Further only occasional studies [17,18] have described the symptom profile of depression in patients with IFN-α induced depression. One recent study evaluated the depressive symptoms associated with IFN-α in HCV using the two-factor model (i.e., CognitiveAffective and Somatic factors) and reported that IFN-α therapy was associated with
ACCEPTED MANUSCRIPT significant increase in ‘somatic factor’, whereas there was minimal change in the ‘cognitive-affective’ factor score following IFN-α therapy [19]. However, the sample size
PT
of this study was small and few patients had BDI-II scores above the cutoff values at the
RI
baseline itself. These limitations underscore the need for further research in this area. Understanding the role of sub-syndromal baseline symptoms can help in patients who are
SC
at high risk of developing incidence depression with IFN-α.
NU
Therefore, the present study aimed to study the symptom profile and the role of baseline sub-syndromal depressive symptoms in the development of depressive episode in patients
MA
receiving the combination of pegylated IFN-α and ribavirin. Additionally an attempt was made to study the symptom profile of depression in patients receiving a combination of
Methodology:
TE
D
pegylated IFN-alpha and ribavirin for treatment of hepatitis C virus infection.
AC CE P
This prospective follow-up study was conducted in the Department of Hepatology of a tertiary care teaching hospital in North-west India. The study was approved by the Institute Ethics Review Committee and all the patients were recruited after obtaining proper written informed consent. All the patients aged 18-65 years found to be positive for any of the genotypes of HCV in whom combination of peg-IFN-α 2a/2b plus ribavirin was prescribed were eligible for the study. Those with hepatitis B virus (i.e., IgM Anti HBV +ve) or HIV (i.e., ELISA + ve) co-infection were excluded. Patients diagnosed during the life time to have MDD, anxiety disorder, psychosis, dementia, organic brain syndrome (except for short lasting delirium) were also excluded. Those patients using alcohol/opioids on regular basis and currently not abstinent (in last 4 weeks) and those on any antidepressant or antipsychotic
ACCEPTED MANUSCRIPT medication were excluded. Also those with history of autoimmune disorders like, systemic lupus erythematous, drug induced lupus, autoimmune thyroiditis were not
PT
included. Those on investigation, found to have abnormal thyroid function tests, anaemia
RI
(i.e., haemoglobin: < 11 gm% for males; < 10 gm% for females) and positive for autoimmune markers - anti-mitochondrial antibody, smooth muscle antibody, Liver-
SC
kidney microsomal antibody and antinuclear antibody prior to starting therapy were not
NU
considered for the study. Those patients with comorbid coronary artery disease, Parkinson's disease, diabetes mellitus, hypothyroidism or malignancy were not
MA
considered because these illnesses are known to have high prevalence of depression. Those with past history of IFN-α therapy, cirrhosis of liver and pregnancy were excluded
TE
D
too.
Consenting patients were initially evaluated on Mini International Neuropsychiatric
AC CE P
Interview (MINI) [20] for the presence of psychiatric illness (past and present). Patients found positive for a life time psychiatric illness (except substance dependence) were excluded from the study. Those patients who were free from lifetime psychiatric illness were assessed on PHQ-9 [21] and Beck Depression Inventory (BDI-II) [22] at baseline, i.e., prior to starting of pegylated IFN-α and ribavirin therapy. These subjects were serially followed at 2, 4, 8 and 12 weeks and were assessed on PHQ-9 in person or over phone. Those found to have MDD as per PHQ-9 (i.e., positive for 5 or more items on PHQ-9 including a score of 2 on either of the first 2 items of PHQ-9) at any time during the follow-up, were assessed in detail by using MINI by a psychiatrist to confirm the diagnosis of depression. Those found to have major depressive episode (MDE) on MINI
ACCEPTED MANUSCRIPT were again rated on BDI-II for phenomenology and severity of depression. All those not found to have MDE as per MINI were rated on BDI-II at 12 weeks.
PT
Whenever a patient was detected to have MDE as per MINI, the primary treating
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Hepatologist was informed about the same and the patient was offered psychiatric treatment. Similarly, when the sub-syndromal symptoms threatened the life of patient or
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others, it was reported to the primary treating Hepatologist for possible change in therapy
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as per the clinical assessment and liaison with treating Psychiatrist. The data of incidence of depression with pegylated IFN-α and ribavirin arising out of this study is already
MA
published [23].
Additionally the patients were evaluated for anemia and thyroid dysfunction at the
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D
baseline. During the follow-up haemogram was done once weekly and the thyroid function tests were done at the 12 weeks or when the patient was detected to have
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depression. A person was defined to have anemia if the haemoglobin levels were found to be below 11 gm% for males and 10 gm% for females. A person was considered to have thyroid dysfunction if the thyroid parameters were out of the normal range [i.e., T3 - 0.82.0 (ng/ml); T4- 4.8-12.7 (µg/dl) and TSH- 0.27- 4.2(µIU/ml)]. Statistical analysis
Descriptive analysis was carried out using mean and standard deviation with range for continuous variables. Frequency and percentages were calculated for discontinuous variables. Comparisons were done by using t-test, Mann-Whitney U test, Chi-square test and Fisher exact test. Comparisons of continuous variables assessed at 2 time points were done by using paired t-test or Wilcoxon signed ranked test.To examine the association between the severity of depressive symptoms (as assessed on PHQ-9 and BDI score) and
ACCEPTED MANUSCRIPT various sociodemographic and clinical variables (viral load, dose of medications etc.), Pearson’s product moment correlation coefficients or Spearman’s rank correlation
PT
coefficients were used.
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Results
One hundred and nine (N=109) consecutive patients diagnosed with HCV infection and
SC
recommended to receive pegIFN-α2a/2b and ribavirin by their treating Hepatologist were
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approached. Of the 109 patients, 24% (N=27) of patients were excluded because of presence of physical or psychiatric comorbidity.
MA
The final study sample comprised of 82 patients. The mean age of the study sample was 41.76 (SD-11.6; range-21-64) years. About two-third of the participants were male
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(67.1%). Most common genotype of HCV infection in the study group was type-3 (70.7%) and this was followed by type-1 genotype (28%). Only 1 patient had type-4
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genotype infection. Few patients had history of alcohol dependence in the past (12.2%) and family history of depression (12.2%). Nearly one-tenth of the patients were currently smoking tobacco. None of the patients had history of intravenous illicit drug use. In most (78%) of the cases exact route of HCV infection could not be ascertained. None of the study participants had low haemoglobin level or abnormality in the thyroid function test at the baseline. The mean Hepatitis C- viral load at baseline was 1,638,700 (SD: 2592700) international units (IU) per millilitre (ml).
One half of the study sample (50%) received pegylated IFN-α 2a and the other half received pegylated IFN alpha 2b. The cumulative dose of pegylated IFN alpha 2a during the study period was 2160 microgram and the cumulative dose of pegylated IFN-α 2b
ACCEPTED MANUSCRIPT was 1179 (SD-257.93) microgram. The cumulative dose of ribavirin for the 12 weeks was 82,190 milligram.
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Incidence of depression
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During the study period 28% (N=23) of patients developed MDE as per the MINI. Another one patient met the criteria of MDD on PHQ-9 (but did not meet the diagnosis of
SC
MDE as per assessment of the psychiatrist) and 14 patients met the criteria of other
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depressive disorder (i.e., patients scored positive for 2-4 PHQ-9 items at any time during follow up) as per PHQ-9 during the study period. In 8 of these 14 patients, other
MA
depressive disorder seen at a particular assessment was not confirmed in subsequent assessment.
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Most of the patients who developed depressive symptoms did so during the initial 4 weeks. Further, most of the patients developed MDD (as per PHQ-9) and MDE (as per
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MINI) by 4 weeks of therapy.
Phenomenology of depression: As shown in Table-1, as per PHQ-9, at the baseline assessment 68.3% reported ‘feeling tired or having little energy’ and 12.2% (N=10) reported presence of ‘little interest or pleasure in doing things’. Few patients also reported the presence of ‘feeling down, depressed or hopeless’ (N=6; 7.31%) and about 10% (N=8) reported the presence of ‘trouble falling or staying asleep, or sleeping too much’. None of the participants in study group met the criteria for MDD or other depressive disorder as per PHQ-9 at the baseline. Among the PHQ-9 items ‘feeling tired or having little energy’ was the most common item rated as positive on at least one occasion during the study period. This was followed by ‘little interest or pleasure in doing things’, ‘poor appetite or overeating’ and ‘trouble
ACCEPTED MANUSCRIPT falling or staying asleep, or sleeping too much’. Table-2 shows severity scores on PHQ-9 at various assessments.
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Tables-3 and 4 show the baseline symptoms as per BDI in the whole study sample and
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those who developed MDE. The commonly seen symptoms at baseline were: fatigue (69.5%), work inhibition (30.5%), irritability (17.1%), loss of appetite (12.2%), social
SC
withdrawal (8.5%), sadness (8.5%), sleep disturbance (8.5%), and somatic preoccupation
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(8.5%). In the whole study group (shown in table-2) and in those diagnosed to have MDE as per MINI (shown in table-3), compared to baseline, there was significant increase in
MA
the frequency and severity of each symptom assessed on BDI. On BDI-II equal percentage of patients (15.85%) with MDE as per MINI, had mild mood
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disturbance (i.e., BDI: 10-16) and moderate depression (i.e., BDI: 21-30) while 5 patients (6.1%) were rated to have borderline clinical depression (BDI: 17-20) and another 3
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patients (3.66%) had severe depression (BDI: 31-40). As shown in Table-5, the mean baseline PHQ-9 and BDI-II scores were significantly higher in those who developed MDE during the therapy.
ACCEPTED MANUSCRIPT
Table-1: Frequency of Depressive symptoms (PHQ-9) during various assessments 4 weeks N=82
8 weeks N=66
12 weeks N=59
Positive atleast once during the study period N=82 1 Frequency of participants found to have depressive symptoms 10 (12.2%) 37 (45.1%) 44 (53.7%) 33 (50.0%) 29 (49.2%) 58 (70.7%) 6 (7.3%) 23 (28.0%) 28 (34.1%) 14 (21.2%) 9 (15.3%) 38 (46.3%) 8 (9.8%) 32 (39.0%) 35 (42.7%) 19 (28.8%) 14 (23.7%) 47 (57.3%) 56 (68.3%) 72 (87.8%) 73 (89.0%) 56 (84.8%) 47 (79.7%) 78 (95.1%) 8 (9.8%) 30 (36.6%) 33 (40.2%) 22 (33.3%) 17 (28.8%) 51 (62.2%) 0 7 (8.5%) 16 (19.5%) 6 (7.3%) 1 (1.7%) 22 (26.8%)
AC
CE
MA
PT ED
Little interest or pleasure in doing things Feeling down, depressed, or hopeless Trouble falling or staying asleep, or sleeping too much Feeling tired or having little energy Poor appetite or overeating Feeling bad about yourself—or that you are a failure or have let yourself or your family down Trouble concentrating on things, such as reading the newspaper or watching television Moving or speaking so slowly that other people could have noticed. Or the opposite—being so fidgety or restless that you have been moving around a lot more than usual Thoughts that you would be better off dead, or of hurting yourself in some way PHQ-9 (> 2 symptoms)2 Symptoms resolved (i.e., those who had at least 2 symptoms as per PHQ-9 at the prior assessment, but found not to have the same in subsequent assessment) 2 PHQ-9 Major Depressive Disorder 2
NU
SC
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PHQ-9 questions
2 weeks N=82
PT
Baseline N=82
0
16 (19.5%)
24 (29.3%)
10 (15.2%)
8 (13.6%)
33 (40.2%)
0
5 (6.1%)
15 (18.3%)
4 (6.1%)
1 (1.7%)
17 (20.7%)
0
4 (4.9%)
7 (8.5%)
3 (4.5%)
1 (1.7%)
11 (13.4%)
0 0
19 (23.2%) 0
27 (32.9%) 2 (2.4%)
15 (22.7%) 3 (4.5%)
7 (11.9%) 3 (5.1%)
38 (46.3%) 8 (9.8%)
0
6 (7.3%)
19 (23.2%)
8 (12.1%)
0
24 (29.3%)
1- For determining the frequency count any item on PHQ-9 rated as 1 or more was counted as present 2- For considering Major Depressive Disorder as per PHQ -9, item was considered to be present when the participants scored 2 or 3 on item 1-8 and 1-3 on item 9 of PHQ-9
ACCEPTED MANUSCRIPT
0.00
0.24
0.56
0.23
0.15
0.00
0.09
0.27
0.08
0.02
0.00
0.07
0.10
0.06
0.02
PT ED
Trouble concentrating on things, such as reading the newspaper or watching television
MA
NU
SC
RI
PT
Table-2: Severity of depressive symptoms (PHQ-9) during various assessments Baseline 2 weeks 4 weeks 8 weeks 12 weeks N=82 N=82 N=82 N=66 N=59 PHQ-9 questions Mean of severity of depressive symptoms as per PHQ-9 Little interest or pleasure in doing things 0.12 0.60 0.96 0.71 0.58 Feeling down, depressed, or hopeless 0.09 0.40 0.68 0.30 0.17 Trouble falling or staying asleep, or sleeping too much 0.11 0.55 0.74 0.47 0.32 Feeling tired or having little energy 0.76 1.43 1.79 1.71 1.71 Poor appetite or overeating 0.10 0.52 0.78 0.55 0.41 Feeling bad about yourself—or that you are a failure or have let 0.00 0.09 0.32 0.14 0.02 yourself or your family down
AC
CE
Moving or speaking so slowly that other people could have noticed. Or the opposite—being so fidgety or restless that you have been moving around a lot more than usual Thoughts that you would be better off dead, or of hurting yourself in some way
ACCEPTED MANUSCRIPT
AC
CE
PT ED
MA
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SC
RI
PT
Table-3: Frequency and severity of depressive symptoms as per Beck Depression Inventory in the Study group (N=82) Frequency of symptoms Severity of symptoms Present at Present at 12 week Chi-square Severity at Severity at 12 week Paired tbaseline or when-ever found test baseline or when-ever found test positive for positive for BDI items depression on MINI depression on MINI Sadness 7 (8.5%) 37 (45.1%) 27.96*** 0.09 (0.28) 0.68 (0.83) 6.54*** Pessimism 0 16 (19.5%) 15.58@ *** 0.00 (0.00) 0.23 (0.50) 4.16*** @ Sense of failure 0 17 (20.7%) 16.80 *** 0.00 (0.00) 0.26 (0.54) 4.29*** Lack of satisfaction 0 30 (36.6%) 34.31@*** 0.00 (0.00) 0.5 (0.72) 6.25*** @ Guilt feeling 1 (1.2%) 24 (29.3%) 22.84 *** 0.01(0.11) 0.32 (0.52) 5.14*** @ Sense of punishment 0 16 (19.5%) 15.58 *** 0.00 (0.00) 0.21 (0.44) 4.30*** Self-hate 2 (2.4%) 17 (20.7%) 11.67@ *** 0.02 (0.16) 0.22 (0.45) 3.87*** @ Self-accusations 0 9 (11.0%) 7.52 ** 0.00 (0.00) 0.13 (0.44) 2.78** Self-punitive wishes 0 9 (11.0%) 7.52@ ** 0.00 (0.00) 0.16 (0.48) 2.97** @ Crying spells 0 9 (11.0%) 7.52 ** 0.00 (0.00) 0.11 (0.31) 3.16** Irritability 14 (17.1%) 52 (63.4%) 36.61*** 0.17 (0.38) 0.91 (0.8) 8.28*** Social withdrawal 7 (8.5%) 49 (59.8%) 47.83*** 0.09 (0.28) 0.83 (0.78) 8.98*** @ Indecisiveness 1 (1.2%) 23 (28.0%) 21.53 *** 0.01 (0.11) 0.32 (0.56) 5.37*** Body image 0 6 (7.3%) 4.33@* 0.00 (0.00) 0.10 (0.37) 2.37* Work inhibition 25 (30.5%) 68 (82.9%) 45.92 *** 0.32 (0.49) 1.46 (0.82) 12.93*** Sleep disturbance 7 (8.5%) 36 (43.9%) 26.51*** 0.10 (0.34) 0.85 (1.12) 6.32*** Fatigability 57 (69.5%) 73 (89.0%) 9.50** 0.82 (0.63) 2.00 (0.98) 10.76*** Loss of appetite 10 (12.2%) 41 (50.0%) 27.35*** 0.12 (0.33) 0.74 (0.89) 6.37*** Weight loss 0 6 (7.3%) 4.33@* 0.00 (0.00) 0.09 (0.32) 2.40* Somatic preoccupation 7 (8.5%) 47 (57.3%) 44.18*** 0.09 (0.28) 0.59 (0.52) 7.92*** Loss of libido 1 (1.2%) 34 (41.5%) 37.20@ *** 0.01 (0.11) 0.46 (0.59) 6.91*** 1- For determining the frequency count any item on BDI rated as 1 or more was counted as present
* p value
S0022-3999(14)00220-7 doi: 10.1016/j.jpsychores.2014.05.008 PSR 8819
To appear in:
Journal of Psychosomatic Research
Received date: Revised date: Accepted date:
3 March 2014 21 May 2014 23 May 2014
Please cite this article as: Mahajan Sudhir, Avasthi Ajit, Grover Sandeep, Chawla Yogesh, Role of baseline depressive symptoms in the development of depressive episode in patients receiving antiviral therapy for Hepatitis C infection, Journal of Psychosomatic Research (2014), doi: 10.1016/j.jpsychores.2014.05.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Role of baseline depressive symptoms in the development of depressive episode in patients receiving antiviral therapy for Hepatitis C infection
RI
PT
Running title: Depression associated with antiviral therapy for HCV
SC
Authors: Sudhir Mahajan, MD, Senior Resident1
NU
Ajit Avasthi, MD, Professor1 Sandeep Grover, MD, Assistant Professor1
D
MA
Yogesh Chawla, MD, Professor and Head2
TE
1-Department of Psychiatry; 2- Department of Hepatology
AC CE P
Post Graduate Institute of Medical Education and Research, Chandigarh
Corresponding Author: Dr Sandeep Grover Assistant Professor Department of Psychiatry Postgraduate Institute of Medical Education & Research Chandigarh 160012, India Phone: 0091-172-2756807 (O)
Fax: +91-172-2744401; 2745078 (Dr. Sandeep Grover, Psychiatry) Email: [email protected] Funding: None
ACCEPTED MANUSCRIPT Abstract: Objective: This study aimed to study the symptom profile and the role of baseline
PT
depressive symptoms in the development of depressive episode in patients receiving a
RI
combination of pegylated IFN-alpha and ribavirin. Methods: 82 consecutive patients
SC
with HCV infection in whom combination of pegylated interferon-α 2a/2b and ribavirin was prescribed were assessed at baseline and thereafter at 2, 4, 8 and 12 weeks. At the
NU
baseline, patients were assessed on Patient Health Questionnaire (PHQ-9), Mini
MA
International Neuropsychiatric Interview (MINI) and Beck Depression Inventory (BDIII). Thereafter patients were assessed on PHQ-9 and when ever found to have Major
D
Depressive Disorder as per PHQ-9, they were assessed on MINI. Those found to have
TE
Major Depressive Episode (MDE) on MINI were rated on BDI-II for phenomenology and severity of depression. Results: Common symptoms of pegylated IFN-alpha and
AC CE P
ribavirin induced MDE include sadness, irritability, work inhibition, sleep disturbance, fatigability and loss of appetite. Presence of certain depressive symptoms i.e., presence of little interest or pleasure in doing things, feeling tired or having little energy, poor appetite, social withdrawal and work inhibition at the baseline were associated with development of depression during the course of pegylated IFN-alpha plus Ribavirin therapy. Conclusion:Depressive symptoms in patients with pegylated IFN-alpha and ribavirin induced MDE are influenced by the symptoms of depression prior to starting of pegylated IFN-alpha and ribavirin combination. A short screening questionnaire may be constructed which will include the symptoms which predict of development of depression to screen patients at high risk for development of depression. Key words: Interferon, depression, symptom profile
ACCEPTED MANUSCRIPT Introduction Many studies have evaluated the incidence of depression associated with Interferon-
PT
alpha (IFN-α) in patients with Hepatitis C Virus (HCV) infection and have shown
RI
induction of depression in 5-82%of patients [1-15].A recent meta-analysis [16], reported cumulative incidence of major depressive episode (MDD) during IFN treatment to be
SC
25% by 24 weeks after initiation and 28% after 48 weeks in patients who had no history
NU
of depression before starting treatment.
Some of the studies which have studied the incidence of IFN induced depression in
MA
patients with HCV infection have also tried to evaluate the various predictors of depression and the results are not conclusive [16]. Among the various clinical factors,
TE
D
subclinical depressive symptoms at baseline are an important predictor of interferonassociated depression during the therapy. This association was also confirmed by the
AC CE P
metanalysis [16] which has evaluated the relationship of depression with interferon. The metanalysis concluded that higher scores on depression scales before starting antiviral treatment predicted subsequent development of depression. The metanalysis also showed that personal history of major depressive disorder (MDD) was associated with development of interferon-induced depression. However, the literature is very silent about specific depressive symptoms which when present at baseline can predict incident depression associated with IFN. Further only occasional studies [17,18] have described the symptom profile of depression in patients with IFN-α induced depression. One recent study evaluated the depressive symptoms associated with IFN-α in HCV using the two-factor model (i.e., CognitiveAffective and Somatic factors) and reported that IFN-α therapy was associated with
ACCEPTED MANUSCRIPT significant increase in ‘somatic factor’, whereas there was minimal change in the ‘cognitive-affective’ factor score following IFN-α therapy [19]. However, the sample size
PT
of this study was small and few patients had BDI-II scores above the cutoff values at the
RI
baseline itself. These limitations underscore the need for further research in this area. Understanding the role of sub-syndromal baseline symptoms can help in patients who are
SC
at high risk of developing incidence depression with IFN-α.
NU
Therefore, the present study aimed to study the symptom profile and the role of baseline sub-syndromal depressive symptoms in the development of depressive episode in patients
MA
receiving the combination of pegylated IFN-α and ribavirin. Additionally an attempt was made to study the symptom profile of depression in patients receiving a combination of
Methodology:
TE
D
pegylated IFN-alpha and ribavirin for treatment of hepatitis C virus infection.
AC CE P
This prospective follow-up study was conducted in the Department of Hepatology of a tertiary care teaching hospital in North-west India. The study was approved by the Institute Ethics Review Committee and all the patients were recruited after obtaining proper written informed consent. All the patients aged 18-65 years found to be positive for any of the genotypes of HCV in whom combination of peg-IFN-α 2a/2b plus ribavirin was prescribed were eligible for the study. Those with hepatitis B virus (i.e., IgM Anti HBV +ve) or HIV (i.e., ELISA + ve) co-infection were excluded. Patients diagnosed during the life time to have MDD, anxiety disorder, psychosis, dementia, organic brain syndrome (except for short lasting delirium) were also excluded. Those patients using alcohol/opioids on regular basis and currently not abstinent (in last 4 weeks) and those on any antidepressant or antipsychotic
ACCEPTED MANUSCRIPT medication were excluded. Also those with history of autoimmune disorders like, systemic lupus erythematous, drug induced lupus, autoimmune thyroiditis were not
PT
included. Those on investigation, found to have abnormal thyroid function tests, anaemia
RI
(i.e., haemoglobin: < 11 gm% for males; < 10 gm% for females) and positive for autoimmune markers - anti-mitochondrial antibody, smooth muscle antibody, Liver-
SC
kidney microsomal antibody and antinuclear antibody prior to starting therapy were not
NU
considered for the study. Those patients with comorbid coronary artery disease, Parkinson's disease, diabetes mellitus, hypothyroidism or malignancy were not
MA
considered because these illnesses are known to have high prevalence of depression. Those with past history of IFN-α therapy, cirrhosis of liver and pregnancy were excluded
TE
D
too.
Consenting patients were initially evaluated on Mini International Neuropsychiatric
AC CE P
Interview (MINI) [20] for the presence of psychiatric illness (past and present). Patients found positive for a life time psychiatric illness (except substance dependence) were excluded from the study. Those patients who were free from lifetime psychiatric illness were assessed on PHQ-9 [21] and Beck Depression Inventory (BDI-II) [22] at baseline, i.e., prior to starting of pegylated IFN-α and ribavirin therapy. These subjects were serially followed at 2, 4, 8 and 12 weeks and were assessed on PHQ-9 in person or over phone. Those found to have MDD as per PHQ-9 (i.e., positive for 5 or more items on PHQ-9 including a score of 2 on either of the first 2 items of PHQ-9) at any time during the follow-up, were assessed in detail by using MINI by a psychiatrist to confirm the diagnosis of depression. Those found to have major depressive episode (MDE) on MINI
ACCEPTED MANUSCRIPT were again rated on BDI-II for phenomenology and severity of depression. All those not found to have MDE as per MINI were rated on BDI-II at 12 weeks.
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Whenever a patient was detected to have MDE as per MINI, the primary treating
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Hepatologist was informed about the same and the patient was offered psychiatric treatment. Similarly, when the sub-syndromal symptoms threatened the life of patient or
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others, it was reported to the primary treating Hepatologist for possible change in therapy
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as per the clinical assessment and liaison with treating Psychiatrist. The data of incidence of depression with pegylated IFN-α and ribavirin arising out of this study is already
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published [23].
Additionally the patients were evaluated for anemia and thyroid dysfunction at the
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baseline. During the follow-up haemogram was done once weekly and the thyroid function tests were done at the 12 weeks or when the patient was detected to have
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depression. A person was defined to have anemia if the haemoglobin levels were found to be below 11 gm% for males and 10 gm% for females. A person was considered to have thyroid dysfunction if the thyroid parameters were out of the normal range [i.e., T3 - 0.82.0 (ng/ml); T4- 4.8-12.7 (µg/dl) and TSH- 0.27- 4.2(µIU/ml)]. Statistical analysis
Descriptive analysis was carried out using mean and standard deviation with range for continuous variables. Frequency and percentages were calculated for discontinuous variables. Comparisons were done by using t-test, Mann-Whitney U test, Chi-square test and Fisher exact test. Comparisons of continuous variables assessed at 2 time points were done by using paired t-test or Wilcoxon signed ranked test.To examine the association between the severity of depressive symptoms (as assessed on PHQ-9 and BDI score) and
ACCEPTED MANUSCRIPT various sociodemographic and clinical variables (viral load, dose of medications etc.), Pearson’s product moment correlation coefficients or Spearman’s rank correlation
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coefficients were used.
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Results
One hundred and nine (N=109) consecutive patients diagnosed with HCV infection and
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recommended to receive pegIFN-α2a/2b and ribavirin by their treating Hepatologist were
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approached. Of the 109 patients, 24% (N=27) of patients were excluded because of presence of physical or psychiatric comorbidity.
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The final study sample comprised of 82 patients. The mean age of the study sample was 41.76 (SD-11.6; range-21-64) years. About two-third of the participants were male
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(67.1%). Most common genotype of HCV infection in the study group was type-3 (70.7%) and this was followed by type-1 genotype (28%). Only 1 patient had type-4
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genotype infection. Few patients had history of alcohol dependence in the past (12.2%) and family history of depression (12.2%). Nearly one-tenth of the patients were currently smoking tobacco. None of the patients had history of intravenous illicit drug use. In most (78%) of the cases exact route of HCV infection could not be ascertained. None of the study participants had low haemoglobin level or abnormality in the thyroid function test at the baseline. The mean Hepatitis C- viral load at baseline was 1,638,700 (SD: 2592700) international units (IU) per millilitre (ml).
One half of the study sample (50%) received pegylated IFN-α 2a and the other half received pegylated IFN alpha 2b. The cumulative dose of pegylated IFN alpha 2a during the study period was 2160 microgram and the cumulative dose of pegylated IFN-α 2b
ACCEPTED MANUSCRIPT was 1179 (SD-257.93) microgram. The cumulative dose of ribavirin for the 12 weeks was 82,190 milligram.
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Incidence of depression
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During the study period 28% (N=23) of patients developed MDE as per the MINI. Another one patient met the criteria of MDD on PHQ-9 (but did not meet the diagnosis of
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MDE as per assessment of the psychiatrist) and 14 patients met the criteria of other
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depressive disorder (i.e., patients scored positive for 2-4 PHQ-9 items at any time during follow up) as per PHQ-9 during the study period. In 8 of these 14 patients, other
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depressive disorder seen at a particular assessment was not confirmed in subsequent assessment.
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Most of the patients who developed depressive symptoms did so during the initial 4 weeks. Further, most of the patients developed MDD (as per PHQ-9) and MDE (as per
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MINI) by 4 weeks of therapy.
Phenomenology of depression: As shown in Table-1, as per PHQ-9, at the baseline assessment 68.3% reported ‘feeling tired or having little energy’ and 12.2% (N=10) reported presence of ‘little interest or pleasure in doing things’. Few patients also reported the presence of ‘feeling down, depressed or hopeless’ (N=6; 7.31%) and about 10% (N=8) reported the presence of ‘trouble falling or staying asleep, or sleeping too much’. None of the participants in study group met the criteria for MDD or other depressive disorder as per PHQ-9 at the baseline. Among the PHQ-9 items ‘feeling tired or having little energy’ was the most common item rated as positive on at least one occasion during the study period. This was followed by ‘little interest or pleasure in doing things’, ‘poor appetite or overeating’ and ‘trouble
ACCEPTED MANUSCRIPT falling or staying asleep, or sleeping too much’. Table-2 shows severity scores on PHQ-9 at various assessments.
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Tables-3 and 4 show the baseline symptoms as per BDI in the whole study sample and
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those who developed MDE. The commonly seen symptoms at baseline were: fatigue (69.5%), work inhibition (30.5%), irritability (17.1%), loss of appetite (12.2%), social
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withdrawal (8.5%), sadness (8.5%), sleep disturbance (8.5%), and somatic preoccupation
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(8.5%). In the whole study group (shown in table-2) and in those diagnosed to have MDE as per MINI (shown in table-3), compared to baseline, there was significant increase in
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the frequency and severity of each symptom assessed on BDI. On BDI-II equal percentage of patients (15.85%) with MDE as per MINI, had mild mood
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disturbance (i.e., BDI: 10-16) and moderate depression (i.e., BDI: 21-30) while 5 patients (6.1%) were rated to have borderline clinical depression (BDI: 17-20) and another 3
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patients (3.66%) had severe depression (BDI: 31-40). As shown in Table-5, the mean baseline PHQ-9 and BDI-II scores were significantly higher in those who developed MDE during the therapy.
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Table-1: Frequency of Depressive symptoms (PHQ-9) during various assessments 4 weeks N=82
8 weeks N=66
12 weeks N=59
Positive atleast once during the study period N=82 1 Frequency of participants found to have depressive symptoms 10 (12.2%) 37 (45.1%) 44 (53.7%) 33 (50.0%) 29 (49.2%) 58 (70.7%) 6 (7.3%) 23 (28.0%) 28 (34.1%) 14 (21.2%) 9 (15.3%) 38 (46.3%) 8 (9.8%) 32 (39.0%) 35 (42.7%) 19 (28.8%) 14 (23.7%) 47 (57.3%) 56 (68.3%) 72 (87.8%) 73 (89.0%) 56 (84.8%) 47 (79.7%) 78 (95.1%) 8 (9.8%) 30 (36.6%) 33 (40.2%) 22 (33.3%) 17 (28.8%) 51 (62.2%) 0 7 (8.5%) 16 (19.5%) 6 (7.3%) 1 (1.7%) 22 (26.8%)
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Little interest or pleasure in doing things Feeling down, depressed, or hopeless Trouble falling or staying asleep, or sleeping too much Feeling tired or having little energy Poor appetite or overeating Feeling bad about yourself—or that you are a failure or have let yourself or your family down Trouble concentrating on things, such as reading the newspaper or watching television Moving or speaking so slowly that other people could have noticed. Or the opposite—being so fidgety or restless that you have been moving around a lot more than usual Thoughts that you would be better off dead, or of hurting yourself in some way PHQ-9 (> 2 symptoms)2 Symptoms resolved (i.e., those who had at least 2 symptoms as per PHQ-9 at the prior assessment, but found not to have the same in subsequent assessment) 2 PHQ-9 Major Depressive Disorder 2
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PHQ-9 questions
2 weeks N=82
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Baseline N=82
0
16 (19.5%)
24 (29.3%)
10 (15.2%)
8 (13.6%)
33 (40.2%)
0
5 (6.1%)
15 (18.3%)
4 (6.1%)
1 (1.7%)
17 (20.7%)
0
4 (4.9%)
7 (8.5%)
3 (4.5%)
1 (1.7%)
11 (13.4%)
0 0
19 (23.2%) 0
27 (32.9%) 2 (2.4%)
15 (22.7%) 3 (4.5%)
7 (11.9%) 3 (5.1%)
38 (46.3%) 8 (9.8%)
0
6 (7.3%)
19 (23.2%)
8 (12.1%)
0
24 (29.3%)
1- For determining the frequency count any item on PHQ-9 rated as 1 or more was counted as present 2- For considering Major Depressive Disorder as per PHQ -9, item was considered to be present when the participants scored 2 or 3 on item 1-8 and 1-3 on item 9 of PHQ-9
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0.00
0.24
0.56
0.23
0.15
0.00
0.09
0.27
0.08
0.02
0.00
0.07
0.10
0.06
0.02
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Trouble concentrating on things, such as reading the newspaper or watching television
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Table-2: Severity of depressive symptoms (PHQ-9) during various assessments Baseline 2 weeks 4 weeks 8 weeks 12 weeks N=82 N=82 N=82 N=66 N=59 PHQ-9 questions Mean of severity of depressive symptoms as per PHQ-9 Little interest or pleasure in doing things 0.12 0.60 0.96 0.71 0.58 Feeling down, depressed, or hopeless 0.09 0.40 0.68 0.30 0.17 Trouble falling or staying asleep, or sleeping too much 0.11 0.55 0.74 0.47 0.32 Feeling tired or having little energy 0.76 1.43 1.79 1.71 1.71 Poor appetite or overeating 0.10 0.52 0.78 0.55 0.41 Feeling bad about yourself—or that you are a failure or have let 0.00 0.09 0.32 0.14 0.02 yourself or your family down
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Moving or speaking so slowly that other people could have noticed. Or the opposite—being so fidgety or restless that you have been moving around a lot more than usual Thoughts that you would be better off dead, or of hurting yourself in some way
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Table-3: Frequency and severity of depressive symptoms as per Beck Depression Inventory in the Study group (N=82) Frequency of symptoms Severity of symptoms Present at Present at 12 week Chi-square Severity at Severity at 12 week Paired tbaseline or when-ever found test baseline or when-ever found test positive for positive for BDI items depression on MINI depression on MINI Sadness 7 (8.5%) 37 (45.1%) 27.96*** 0.09 (0.28) 0.68 (0.83) 6.54*** Pessimism 0 16 (19.5%) 15.58@ *** 0.00 (0.00) 0.23 (0.50) 4.16*** @ Sense of failure 0 17 (20.7%) 16.80 *** 0.00 (0.00) 0.26 (0.54) 4.29*** Lack of satisfaction 0 30 (36.6%) 34.31@*** 0.00 (0.00) 0.5 (0.72) 6.25*** @ Guilt feeling 1 (1.2%) 24 (29.3%) 22.84 *** 0.01(0.11) 0.32 (0.52) 5.14*** @ Sense of punishment 0 16 (19.5%) 15.58 *** 0.00 (0.00) 0.21 (0.44) 4.30*** Self-hate 2 (2.4%) 17 (20.7%) 11.67@ *** 0.02 (0.16) 0.22 (0.45) 3.87*** @ Self-accusations 0 9 (11.0%) 7.52 ** 0.00 (0.00) 0.13 (0.44) 2.78** Self-punitive wishes 0 9 (11.0%) 7.52@ ** 0.00 (0.00) 0.16 (0.48) 2.97** @ Crying spells 0 9 (11.0%) 7.52 ** 0.00 (0.00) 0.11 (0.31) 3.16** Irritability 14 (17.1%) 52 (63.4%) 36.61*** 0.17 (0.38) 0.91 (0.8) 8.28*** Social withdrawal 7 (8.5%) 49 (59.8%) 47.83*** 0.09 (0.28) 0.83 (0.78) 8.98*** @ Indecisiveness 1 (1.2%) 23 (28.0%) 21.53 *** 0.01 (0.11) 0.32 (0.56) 5.37*** Body image 0 6 (7.3%) 4.33@* 0.00 (0.00) 0.10 (0.37) 2.37* Work inhibition 25 (30.5%) 68 (82.9%) 45.92 *** 0.32 (0.49) 1.46 (0.82) 12.93*** Sleep disturbance 7 (8.5%) 36 (43.9%) 26.51*** 0.10 (0.34) 0.85 (1.12) 6.32*** Fatigability 57 (69.5%) 73 (89.0%) 9.50** 0.82 (0.63) 2.00 (0.98) 10.76*** Loss of appetite 10 (12.2%) 41 (50.0%) 27.35*** 0.12 (0.33) 0.74 (0.89) 6.37*** Weight loss 0 6 (7.3%) 4.33@* 0.00 (0.00) 0.09 (0.32) 2.40* Somatic preoccupation 7 (8.5%) 47 (57.3%) 44.18*** 0.09 (0.28) 0.59 (0.52) 7.92*** Loss of libido 1 (1.2%) 34 (41.5%) 37.20@ *** 0.01 (0.11) 0.46 (0.59) 6.91*** 1- For determining the frequency count any item on BDI rated as 1 or more was counted as present
* p value
