Dig Dis Sci (2007) 52:2557–2563 DOI 10.1007/s10620-006-9729-5
ORIGINAL PAPER
Preventing Relapse of Major Depression During Interferon-α Therapy for Hepatitis C—A Pilot Study Ondria C. Gleason · John C. Fucci · William R. Yates · Michelle A. Philipsen
Received: 15 September 2006 / Accepted: 3 December 2006 / Published online: 12 April 2007 C Springer Science+Business Media, LLC 2007
Abstract Depression is common in hepatitis C, exacerbated by interferon, and is a major reason for discontinuing interferon therapy. We aimed to determine (1) whether patients with a history of major depression could complete a course of peginterferon α-2a and ribavirin if pretreated with escitalopram and (2) the relapse rate of depression during the course of therapy in these subjects. Ten patients were enrolled in the study and treated with escitalopram. The Hamilton Depression Rating Scale (Ham-D) and other psychiatric scales were administered throughout the study. There were no statistically significant increases in mean Ham-D scores. No subjects were discontinued from the study due to depression relapse. Nine of 10 subjects maintained remission of depression throughout the study. We conclude that pretreatment with escitalopram in subjects with major depressive disorder in remission may prevent recurrence of major depression during a course of interferon and ribavirin therapy for hepatitis C. Keywords Depression . Hepatitis CI . Interferon . Prevention . Escitalopram
O. C. Gleason · W. R. Yates · M. A. Philipsen () Department of Psychiatry, The University of Oklahoma College of Medicine, Tulsa, 4502 East 41st Street, Tulsa, Oklahoma 74135, USA e-mail:
[email protected] J. C. Fucci Gastroenterology, St. John Health System, 1004 E. Bryan, Sapulpa, Oklahoma 74066
Introduction The prevalence of depression and other psychiatric illness is elevated, ranging from 24% to 49%, among patients with hepatitis C [1, 2]. The most effective treatment for hepatitis C is the combination of pegylated (PEG) interferon-α and ribavirin [3, 4]. Unfortunately, psychiatric adverse reactions are common. Psychiatric adverse reactions were among the most commonly reported adverse effects during clinical trials for the approval of PEG interferon-α-2a and -2b [5, 6]. Psychiatric adverse events occurred in 77% of patients in clinical trials with PEG interferon-α-2b [5]. The most common psychiatric effects were depression (ranging from 25% to 34%) [5], irritability, and insomnia. Suicidal ideation, suicide attempts, and actual suicides occurred in 2% of all patients studied [5]. Furthermore, psychiatric adverse effects were among the most common reasons for therapy discontinuation, along with systemic (e.g., fatigue, headache) and gastrointestinal effects [5, 6]. Previous studies have looked at the treatment of depression in patients with comorbid hepatitis C [7–14]. Others have examined the usefulness of prophylactic treatment of depression in patients undergoing interferon therapy for hepatitis C [15]. Although this approach may be effective, if used widely this would result in unnecessary antidepressant treatment in up to 66% of patients, if up to 34% of patients develop interferon-induced depression. Consideration of prophylactic treatment must take into account not only the potential benefits of such treatment (prevention of depression) but also the potential risks of such treatment (e.g., nausea, vomiting, sexual dysfunction, drug interactions, paradoxical reactions, serotonin syndrome, and withdrawal symptoms upon discontinuation). The safety of using selective serotonin reuptake inhibitors (SSRIs) in patients with hepatitis C has been questioned, particularly with regard to potential Springer
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for increased risk of bleeding and retinopathy [16]. NonSSRI antidepressants present safety concerns as well. Mirtazapine is associated with an increased risk of bone marrow suppression and agranulocytosis [17], potentially placing the interferon-treated patient at increased risk for infection given the potential for bone marrow suppression from interferon. Nefazodone has been shown to induce hepatotoxicity and is contraindicated in patients with liver disease [18]. In fact, all currently available antidepressants are hepatically metabolized. We are aware of one previous small study that examined the prophylactic treatment of interferon-induced depression, using the antidepressant citalopram, in depressed patients [19]. However, this study did not look specifically at major depression or major depression in remission. We are unaware of any studies that have looked at the prophylactic treatment of depression in patients with a history of major depression, currently in remission, and undergoing treatment with combination interferon-α and ribavirin therapy for hepatitis C. The question of whether or not patients with a history of major depression, currently in remission, can safely complete treatment with interferon-α and ribavirin is an important clinical question. The practicing gastroenterologist is often faced with the question of whether a presenting patient with hepatitis C, who reports a history of depression but who is not currently depressed, can be safely treated with interferon. It has been recommended that high-risk patients, those with depression or history of depression, receive a psychiatric assessment prior to initiation of interferon. However, widespread use of practice guidelines outlining such screening is not currently in place [20]. The fear remains that patients with a history of depression may not be offered hepatitis C treatment for fear of depression relapse. This pilot study aimed to determine (1) whether patients with a history of major depression, that is in remission, could complete a course of PEG interferon-α-2a and ribavirin for HCV if first pretreated with escitalopram and (2) the incidence and severity of depression during the course of this treatment. Our hypothesis was that patients with a history of major depression, currently in remission, could complete a course of interferon therapy without recurrence of depression or worsening of quality of life if pretreated with the antidepressant escitalopram.
Methods Subjects Adults aged 18–64 with hepatitis C, and a history of major depression, were recruited by advertisement and from local physicians. Preliminary eligibility of interested subjects was determined by telephone screening. Subjects with Springer
Dig Dis Sci (2007) 52:2557–2563
documented hepatitis C and a history of DSM-IV Major Depressive Disorder, currently in remission, and who were determined to be candidates for combination interferon-α and ribavirin therapy were eligible for study participation after being informed of the potential risks and benefits of study participation and giving informed consent. This study was approved by The University of Oklahoma Health Sciences Center Institutional Review Board.
Study phases and clinical measures The study included two phases. Phase I consisted of the baseline visit to determine study eligibility and 4 weeks of treatment with escitalopram for prophylactic treatment of major depression. The baseline study visit for eligibility included use of the MINI International Neuropsychiatric Interview (MINI) [21], the Hamilton Depression Rating Scale (HamD) [22], and laboratory testing. The MINI was administered to confirm the presence of major depressive disorder and to evaluate for other comorbid psychiatric conditions. Remission of depression was defined as a total Ham-D (17-item) score of ≤8 (throughout phase I) and a Ham-D suicide item score of <2. Study participants were administered a Minimental Status Examination [23] and Trails A and B [24] (a standardized timed dot-to-dot test) at baseline to screen for hepatic encephalopathy or other cognitive impairment. Laboratory testing included a complete blood count, Chem-14, liver enzymes, and uric acid measurements at all clinic visits except for week 2. Upon confirmation of eligibility, study participants not already taking escitalopram were started on escitalopram, 10 mg q day. A telephone visit was conducted 2 weeks later to review progress and tolerability. Hopkins Symptom Checklist-90 (SCL-90) [25], Medical Outcomes Study Short Form Health Survey (SF-36) [26], and Clinical Global Severity (CGS) [27] scales were completed at baseline and at 4 weeks. The HSC-90 was completed by the participant and screened for a broad range of psychological problems and symptoms of psychopathology. The SF-36 was also completed by the participant and screened for limitations and perceptions of an individual’s physical and mental health. The CGS is a clinician-rated scale ranging from 1 to 7 that assesses global severity of symptomatology. Additional test frequencies are noted in the Activities by Visit Schedule (Table 1). Phase II of the study consisted of 24 or 48 weeks of treatment (dependent on genotype) with combination therapy PEG interferon-α-2a and ribavirin. Each study subject was reevaluated at the beginning of phase II for continued remission of major depression using the Hamilton Depression Rating Scale. Subjects with a total Ham-D 17 score of <9 and Ham-D suicide item score of ≤2 were allowed to
Dig Dis Sci (2007) 52:2557–2563 Table 1
2559
Phase I (weeks 0–4) activities by visit Wk 0
Demographics Informed consent Inclusion/exclusion VS/weight Medical & psychiatric history PE, GI/liver exam/ocular exam Adverse events Concurrent illnesses/concomitant medications MINI Ham-D SCL-90 & SF-36 CGI-Severity CGI—Improvement/PCGI—Improvement MMSE/Trails A & B ECG for men > 40 & women > 50 HCV genotype/HCV viral load CBC/liver profile/GGT Urine drug screen (prn) Urine pregnancy test TSH Prothrombin time/INR Amylase/lipase Creatinine/uric acid Apolipoprotein E subtype Telephone visit
Wk 2
X X X X X X
X X X X
Wk 4
Data, excluding identifying information to protect patient confidentiality, were collected in a research chart and then transferred to a computer database. Statistical analysis
X
X X
X X
X X
X X X X
X X X X
X X
X X X X X X
The statistical analysis of this study focused on a descriptive analysis of the study sample measures. Mean Ham-D scores and standard deviations were calculated for each week of the study. Additionally, means and standard deviations were calculated for the escitalopram levels. Each study participant’s highest Ham-D rating throughout the study was identified. Changes in Ham-D rates were calculated from the initial rating to after initiation of escitalopram and from initiation of escitalopram to week 24. A paired t-test was calculated to determine the statistical significance of changes. Additionally, changes in the SF-36 measures were calculated across the same time parameters. A significance level of P < 0.05 was used to indicate a statistically significant finding.
Results X X
continue into phase II of the study. During this phase, study subjects continued to receive escitalopram while combination therapy with PEG interferonα-α-2a and ribavirin was started. Subjects were monitored psychiatrically with office visits every 2 weeks for the first 4 weeks, then every 4 weeks through week 48. The Hamilton Depression Rating Scale and Clinical Global Impression rating scales were administered throughout phase II at weeks 0, 4, 8, 12, 16, 20, 24, 32, 40, and 48. In addition, telephone visits were conducted at weeks 1, 3, 6, 10, and 14 to assess for mood changes, medication changes, and adverse events. During phase II, subjects also received medical evaluation every 4 weeks, including physical examination and laboratory tests. Dose reductions of PEG interferon-α-2a and ribavirin were made as needed for subjects with laboratory parameters indicated in the medications’ package inserts. The protocol allowed for the duration between visits to be shortened, at the discretion of the investigators, for patients who experienced breakthrough of psychiatric symptoms during the study. One participant with multiple somatic complaints received additional study visits. Three study participants who met termination criteria during the study were referred for psychiatric and medical care outside of the study. Table 2 outlines study activities by visit.
Subjects Fifteen subjects consented for study participation. Five were excluded at the baseline visit for the following reasons: one subject was found to have decompensated cirrhosis, another patient’s hepatitis C virus had cleared, another had a significantly abnormal electrocardiogram reading, and two had Ham-D rating scale scores that were above the inclusion level (scores = 20 and 22). The remaining 10 subjects included 6 females and 4 males between 27 and 60 years of age. Hepatitis C viral genotype was determined and liver biopsy information was gathered for each patient. Eight of the 10 subjects were identified as being infected with hepatitis C genotype I virus. One subject had genotype II, and one had genotype III virus. Histological ratings of liver biopsies ranged from grade I to grade III inflammation and stage I to stage III fibrosis. No patient had cirrhosis. All subjects met DSM-IV criteria for Major Depressive Disorder, in remission (baseline Ham-D score range of 1–7.) Six of the 10 subjects met DSM-IV criteria for substance use disorders in remission. One subject had a diagnosed personality disorder (antisocial). Chronic comorbid medical conditions included low back pain in one subject and chronic obstructive lung disease and hypertension in another. There were no other significant comorbid medical conditions. Educational levels of subjects ranged from eighth grade to 1 year of college. The majority of subjects (6 of 10) were Springer
Springer X X X X X X
X
Wk 2
X X
X
X X X X X X X X X X
Wk 8
X
X X X X X X X X X X
Wk 4
X
X
X X X X X X X X X X Xb
Wk 12
X
X
X X X X X X X X X X
Wk 16
X
X
X X X X X X X X X X
Wk 20
X Xc X
X X X X X X X X X X Xc
Wk 24 Xb Xb Xb Xb Xb Xb Xb Xb Xb Xb
Xb Xb
Xb Xb Xb Xb Xb
Xb Xb
Xb Xb
Wk 32
Wk 28
Xb
Xb
Xb Xb
Xb Xb Xb Xb Xb
Wk 36
Xb
Xb
Xb Xb Xb Xb Xb Xb Xb Xb Xb Xb
Wk 40
In addition to final visit of phase I.
For subjects with genotype 1.
For subjects completing the study at 24 weeks.
a
b
c
Note. Telephone visits were conducted at weeks 1, 3, 6, 10, and 14 to record adverse events, concomitant illness, concomitant medications, and CGI scales.
X
X
Wk 0a
Phase II (weeks 0–24) activities by visit
VS/weight PE, GI/liver/ocular exam Adverse events Concurrent illnesses Concomitant medications Ham-D SCL-90/SF-36 CGI scales CBC 8.3.1 Liver profile/GGT HCV viral load Urine drug screen (prn) Urine pregnancy TSH Uric acid
Table 2
Xb
Xb
Xb Xb
Xb Xb Xb Xb Xb
Wk 44
Xb Xb Xb
Xb Xb Xb Xb Xb Xb Xb Xb Xb Xb Xb
Wk 48
2560 Dig Dis Sci (2007) 52:2557–2563
Dig Dis Sci (2007) 52:2557–2563
2561 Rate of relapse of MDD, demonstrated by peak HAM-D scores relapse of depression = 17 or more HAM-D-17 - highest scores 0
10
1 7 4.11
6.4
5.78
6.56
7
3.6
-4
0
6 4.5
4
8
12
16
20
24
32
40
48
Weeks of IFN therapy
unemployed. Nine subjects were self-identified as Caucasian and one was mixed race (Caucasian and American Indian). Viral clearance Viral loads were measured before, during, and after treatment. Nine of 10 patients cleared their virus with treatment, defined as a viral load of <615 IU/ml. The one patient who did not demonstrate viral clearance had a > 2 log decrease in viral load at 12 weeks and had genotype I virus. Depression ratings (Ham-D Scores) Throughout the course of treatment, there were no statistically significant increases in mean Ham-D scores compared to baseline. The mean Ham-D score prior to initiation of any treatment was within the normal nondepressed range, 3.90 (95% CI, 2.12–5.6; P = 0.3874). The highest mean score during treatment was 8.22 (95% CI, 4.3–12.1; P = 0.568), observed at week 16 (Fig. 1). Relapse of major depression was defined as a Ham-D score of ≥ 17. One subject experienced a relapse of depressive symptoms at week 24. Escitalopram was increased from 10 to 15 mg daily in this subject, and Ham-D score was back in remission range at subject’s next scheduled visit. Nine of 10 subjects (90%) maintained Ham-D scores of <17 throughout the study (Fig. 2). Nine of 10 subjects (90%) continued their course of interferonα and ribavirin therapy without significant psychiatric complications.
40
50
14
4
15
5
11 8
6
10
7
13
8 7
17
10
Fig. 2 Rate of relapse of MDD demonstrated by peak Ham-D scores. Relapse of depression, score of ≥ 17
ject was discontinued at week 40 due to medically significant anemia (Hgb = 8.1 g/ml). No subjects had to discontinue therapy due to recurrence of major depression. Subjects who were taking escitalopram at study entry were continued on their current dose (one subject was on 15 mg/day and one was on 20 mg/day); all other subjects were started on 10 mg/daily. Dosage increases, at 5-mg increments, were made throughout the study based on clinical indication (including clinical interview, mental status examination, and Ham-D scores). The highest escitalopram dose was 30 mg/day in one patient. Mean escitalopram doses ranged from 11 mg at week 1 to 15 mg at weeks 40, 44, and 48. The mean escitalopram dosage at endpoint was 15 mg daily. Quality of life Quality of life was evaluated throughout the study using the SF-36. The SF-36 measures eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional health problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Items are scored between 0 and 100, with higher scores indicating
Duration of Interferon/Ribavirin Theraphy Week s in the study 0
4
8 12 16 20 24 28 32 36 40 44 48
1
Completion data
2
Study Participant
Six of 10 patients completed all 24 or 48 weeks of therapy (depending on genotype) (Fig. 3). Treatment had to be discontinued at 24 weeks due to prolonged QT syndrome in one patient with genotype 1. Another genotype I patient completed 36 weeks of therapy and was lost to follow-up. For another patient, the therapy was discontinued due to a relapse of substance abuse after 14 weeks and another sub-
30
6
3
9
Fig. 1 Mean Ham-D-17 scores by week of interferon therapy
20 11
2
8.22
7.8
Study participant
Mean MAM-D scores
Mean HAM-D-17 scores by week of IFN therapy 20 18 16 14 12 10 8 6 4 2 0
3
* (2)
* Genotype 2 and 3 recommended treatment is 24 weeks
4 5 6 7
* (3)
8 9 10
Fig. 3 Duration of interferon/ribavirin therapy Springer
2562 Table 3 Effect of interferon-α/ribavirin and escitalopram on quality of life: mean (SD) SF-36a scores for all subjects (n = 10)
a
Short Form Health Survey 36.
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SF-36 subscale
Baseline
Wk 24
t-test
P value
Emotional well-being Social functioning Pain Energy/fatigue Role limitations due to emotional problems Role limitations due to physical problems General health Physical functioning
87.11 (10.91) 93.22 (12.47) 85.72 (15.22) 60.00 (18.03) 88.89 (33.33)
84.44 (12.07) 79.33 (16.54) 67.39 (24.14) 42.22 (21.52) 81.44 (37.73)
−1.414 −2.178 −2.113 −2.644 −1.000
0.1950 0.0610 0.0675 0.0295 0.3466
86.11 (25.34)
63.89 (45.26)
−1.650
0.1375
67.42 (23.63) 83.89 (22.05)
63.33 (20.31) 66.67 (27.50)
−0.956 −2.338
0.3670 0.0475
a more favorable health state. Mean SF-36 scores obtained at phase 2, week 0 (all subjects were on at least 4 weeks of escitalopram therapy and immediately prior to initiation of interferon/ribavirin therapy), were compared to scores obtained at week 24 (after 24 weeks of interferon/ribavirin therapy). Significant changes in subscores (P < 0.05) were seen in two areas. There was a perceived increase in problems with fatigue (0.03) and a decline in perceived physical functioning (P = 0.04) that would be consistent with the side-effect profile of interferon. Significant changes were not seen in perceived role limitations due to emotional health or emotional well-being. Mean SF-36 subscale scores are outlined in Table 3.
Discussion The treatment of hepatitis C patients with depression can be problematic. Many hepatologists treat these patients reluctantly or defer treatment altogether. Often, patients will have treatment discontinued when they become depressed or they will be started on an antidepressant based on their subjective symptoms. A standard method for prevention of depression in patients with such a history would be preferable; currently there is no such practice guideline available. Although our sample size was small, and there was no control group, our study suggests that pretreatment with escitalopram allowed patients with a history of major depression to complete a course of treatment with PEG interferon-α and ribavirin. Only one subject experienced a clinically significant return of depressive symptoms during the study, and this was adequately treated with an adjustment of the antidepressant dose. Clinical psychiatric evaluation, using standard depression and psychiatric rating scales, allowed appropriate dose adjustments of the antidepressant. Study investigators felt that the overall success of psychiatric symptom management relied heavily on the availability of clinicians via telephone. This availability allowed for prompt interventions as needed. As this was a pilot study, we recommend furSpringer
ther multicenter investigations with larger patient numbers in order to establish specific practice guidelines for these high-risk patients. Acknowledgments This work was supported in part by Forest Pharmaceuticals. The study was investigator initiated. Forest Pharmaceuticals had no involvement in collecting, analyzing, or interpreting the data, or in writing the report. Forest Pharmaceuticals had a minimal role in study design.
References 1. Gohier B, Goeb JL, Rannou-Dubas K, Fouchard I, Cal`es P, Garr´e JB (2003) Hepatitis C, alpha interferon, anxiety and depression disorders: a prospective study of 71 patients. World J Biol Psychiatry 4:115–118 2. El-Serag HB, Kunik M, Richardson P, Rabeneck L (2002) Psychiatic disorders among veterans with hepatitis C infection. Gastroenterology 123:476–482 3. Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, Morand P, Goujard C, Pialoux G, Piroth L, Salmon-C´eron D, Degott C, Cacoub P, Perronne C, ANRS HCO2 RIBAVIC Study Team (2004) Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 292(23):2839–2848 4. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonc¸ales FL, H¨aussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347(13):975–982 5. Complete Product Information and Pegasys Medication Guide (2006) Available at: http:/www.rocheusa.com/products/pegasys/ pi.pdf; retrieved July 12, 2006 6. Peg Intron (2006) Product Information Page. Rev. 02/05. Available at: http://www.spfiles.com/pipeg-intron.pdf; retrieved August 17, 2006 7. Hauser P, Khosla J, Aurora H, Laurin J, Kling MA, Hill J, Gulati M, Thornton AJ, Schultz RL, Valentine AD, Meyers CA, Howell CD (2002) A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 7:942–947 8. Gleason OC, Yates WR (1999) Five cases of interferon-alfainduced depression treated with antidepressant therapy. Psychosomatics 40:510–512 9. Levenson JL, Fallon HJ (1993) Fluoxetine treatment of depression caused by interferon-alfa. Am J Gastroenterol 88:760–761
Dig Dis Sci (2007) 52:2557–2563 10. Schramm TM, Lawford BR, Macdonald GA, Cooksley WG (2000) Sertraline treatment of interferon-alfa-induced depressive disorder. Med J Aust 173:359–361 11. Kraus MR, Sch¨afer A, Faller H, Csef H, Scheurlen M (2002) Paroxetine for the treatment of interferon-alfa-induced depression in chronic hepatitis C. Aliment Pharmacol Ther 16:1091–1099 12. Goldman LS (1994) Successful treatment of interferon alfainduced mood disorder with nortiptyline [letter]. Psychosomatics 35:412–413 13. Gleason OC, Yates WR, Isbell MD, Philipsen MA (2002) An openlabel trial of citalopram for major depression in patients with hepatitis C. J Clin Psychiatry 36:194–198 14. Gleason OC, Yates WR, Philipsen MA (2005) Major depressive disorder in hepatitis C: an open-label trial of escitalopram. Prim Care Compan J Clin Psychiatry 7(5):225–230 15. Loftis JM, Hauser P (2003) Safety of the treatment of interferonalpha-induced depression [letter]. Psychosomatics 44:524–526 16. Hejny C, Sternburg P, Lawson DH, Greiner K, Aaberg Jr TM (2001) Retinopathy associated with high-dose interferon alfa-2b therapy. Am J Opthalmol 131:782–787 17. Ozcanli T, Unsalver B, Ozdemir S, Ozmen M (2005) Sertralineand mirtazapine-induced severe neutropenia [letter]. Am J Psychiatry 162:1386 18. Choi S (2003) Nefazadone (Serzone) withdrawn because of hepatotoxicity. CMAJ 169:1187 19. Schaefer M, Schwaiger M, Garkisch AS, Pich M, Hinzpeter A, Uebelhack R, Heinz A, van Boemmel F, Berg T (2005) Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C. J Hepatol 42(6):793–798
2563 20. Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM (2000) Hepatitis C, interferon alfa, and depression. Hepatology 31:1207–1211 21. Sheehan DV, Lecrubier Y, Harnett-Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview. J. Clin Psychiatry 59(Suppl 20):22–33 22. Hamilton M (1976) Hamilton Depression Scale. In: ECDEU assessment manual for psychopharmacology. Rev. ed. Guy W (ed). U.S. Department of Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health, pp 179–192 23. Folstein MF, Folstein SE, McHugh PR (1975) Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198 24. Berg R, Franzen M, Wedding D (1987) Screening for brain impairment: a manual for mental health practice. Springer, New York 25. Derogatis LR (2000) Symptom Checklist-90-Revised (SCL-90-R) In: Task force for the handbook of psychiatric measures. Handbook of psychiatric measures. American Psychiatric Association, Washington, DC, pp 81–84 26. Ware JE, Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36). 1. Conceptual framework and item selection. Med Care 30:473–483 27. National Institute of Mental Health (1970) CGI: clinical global impressions. In: Manual for the ECDEU assessment battery, 2. Rev ed. Guy W, Bonato RR (eds). Chevy Chase, MD: National Institute of Mental Health, pp 12-1–12-6
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