Incidence and clinical course of major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy: a prospective study

1. Introduction 

Interferon (IFN) is frequently used to treat a wide variety of illnesses, including viral hepatitis, several types of malignancy and multiple sclerosis. Psychiatric symptoms, especially depression, are one of the most significant complications of IFN therapy [1], [2]. These symptoms cause considerable distress to patients, and often necessitate discontinuation of the therapy [1], [2]. In extreme cases, such depression may lead to suicide or attempted suicide [3], [4], [5]. There have been some prospective follow-up studies assessing IFN-associated psychiatric symptoms [6], [7], [8], [9], [10], [11], [12], [13]. However, many of these have only used self-rating depression or anxiety scales. Although some previous studies have been based on psychiatric interviews [10], [12], [13], they often have methodological flaws, such as bias in patient selection [13] or a low frequency of follow-up examinations [10], [12], [13]. As a result, there is insufficient information about the clinical characteristics of these patients. For this reason we have carried out a prospective study on a large number of patients with chronic hepatitis type C undergoing IFN-alpha therapy, and investigated the incidence of depression during the treatment period, its clinical course and the risk factors for depression.

2. Materials and methods 

3. Results 

No patients satisfied the criteria for major depression before IFN therapy, although depressive mood and/or anhedonia defined in the DSM-IV were seen in 8 (8.1%). Twenty-three patients (23.2%) were diagnosed as having major depression at least once during the 24-week treatment period. No manic episode, schizophrenic disorder, other psychotic disorders, or delirium occurred during the treatment period. In addition, no patients were diagnosed as having current substance-related disorders, although 4 had a history of psychiatric treatment for alcohol dependence.

The numbers of patients diagnosed as having major depression for the first time were 6, 11, 2, 2 and 2 at 4, 8, 12, 16 and 20 weeks after the start of IFN therapy, respectively (Fig. 1). The mean total HAMD scores (SD) for these patients were 17.5 (4.2), 14.7 (3.7), 16.0 (1.4), 15.5 (0.7) and 16.5 (2.1) at 4, 8, 12, 16 and 20 weeks of the therapy, respectively. In 17 (73.9%) of these 23 patients, depression occurred during the first 8 weeks of therapy.

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Fig. 1. Numbers of patients diagnosed as having major depression for the first time.

In one patient, IFN therapy was discontinued 9 weeks after the start of therapy because of severe depression. Of the other 22 patients, 13 (59.1%) achieved remission during the treatment period. The duration of depression in these patients ranged from 4 to 20 weeks with a mean (SD) of 11.6 (5.5) weeks. Although the other 9 (40.9%) were not in remission at the end of therapy, they achieved remission by 4 (3 patients), 8 (2 patients), and 12 (4 patients) weeks after the end of therapy.

Sulpiride (150 mg/day) was prescribed po for 17 of the 22 patients with depression who completed the IFN therapy, and no psychotropic drugs were used for the remaining 5. The remission rate during the treatment period was higher in patients given sulpiride (11 of 17, 64.7%) than in those without medication (2 of 5, 40.0%), but the difference was not significant (χ2=0.98, df=1, P=.32).

Table 1 shows the sociodemographic and medical characteristics of the 23 patients with depression and the 76 without. The mean age of patients with depression (53.9 years) was significantly higher than that of patients without depression (47.1 years) (t=2.38, df=97, P=.02). No significant differences in other sociodemographic and medical characteristics were noted between patients with and without depression.

Table 1. Sociodemographic and medical characteristics of hepatitis patients with or without major depression

		Patients With Major Depression (N = 23)		Patients Without Major Depression (N = 76)		Analysis
		Mean	SD	Mean	SD	t	df	p
	Age at beginning of IFN therapy (years)	53.9	11.4	47.1	12.3	2.38	97	0.02
	Education (years)	12.3	2.1	13.0	2.4	−1.27	97	0.21
	Duration of hepatitis (years)*	1.3	1.5	2.0	4.1	−1.36	94.7	0.18
	GOT before IFN therapy (IU/l)*	58.2	28.0	70.2	55.8	−1.38	75.1	0.17
	GPT before IFN therapy (IU/l)*	85.5	54.8	109.0	89.7	−1.52	60.8	0.13
	Score for HAMD before IFN therapy**	4.3	3.6	4.1	3.4	0.24	97	0.81
	Score for SDS before IFN therapy†	36.0	6.8	33.9	7.6	1.14	95	0.26
	Score for MAS before IFN therapy‡	14.7	7.9	13.3	8.1	0.71	93	0.48
		N	%	N	%	χ2	df	p
	Sex
	Male	10	43.5	44	57.9	1.48	1	0.22
	Female	13	56.5	32	42.1
	Marital status
	Married	21	91.3	63	82.9	2.77	4	0.60
	Widowed/divorced	1	4.3	7	9.2
	Never married	1	4.3	6	7.9
	Central nervous system complications§
	Present	1	4.3	5	6.6	0.31	1	0.86
	Absent	22	95.7	71	93.4
	History of prior psychiatric treatment¶
	Present	4	17.4	6	7.9	1.75	1	0.19
	Absent	19	82.6	70	92.1
	Type of IFN-alpha
	Natural IFN-alpha	11	47.8	34	44.7	0.07	1	0.79
	Recombinant IFN-alpha-2b	12	52.2	42	55.3
	Dose of IFN
	6 million IU/day	2	8.7	5	6.6	0.12	1	0.73
	10 million IU/day	21	91.3	71	93.4

* Two-tailed unpaired t test with Welch’s correctrion. ** HAMD = Hamilton Depression Scale for Depression. † SDS = Zung Self-rating Depression Scale. N = 74 for patients without major depression. ‡ MAS = Taylor Manifest Anxiety Scale. N = 21 for patients with major depression, and N = 74 for patients without major depression. § Central nervous complications include microcephaly, arterio-venous malformation, a history of cerebral infarction (2 patients), a history of subarachnoid hemorrhage, and a history of severe diffuse brain injury. ¶ Mental disorders include some depressive disorders (5 patients), panic disorder (1 patient) and alcohol dependence (4 patients).

4. Discussion 

The present study showed that the incidence of major depression in patients with chronic hepatitis type C undergoing IFN-alpha therapy was 23.2%. Some authors [10], [12] have previously reported a high incidence of depression during IFN therapy. Pariante [12] examined 50 patients with hepatitis type B or C treated with IFN-alpha for 12 months, and found that the incidence of DSM-III-R-defined major depression was 24.1%, excluding patients who had to discontinue IFN therapy because of physical complications. Miyaoka [10] has reported that the incidence of DSM-III-R-defined major depression was 43.9% in 66 patients with hepatitis type C treated with IFN-alpha for 24 weeks. However, Renault [13] has reported that DSM-III-defined organic affective syndrome was seen in only 5.2% of 58 patients with some types of viral hepatitis undergoing IFN-alpha therapy for 4 to 12 months. This low incidence may be related to the fact that they did not examine all of the patients: only those who were believed by hepatologists to have psychiatric complications requiring intervention. Thus it can be postulated that patients with milder depressive symptoms were eliminated. In addition, this author found that 5.2% of patients showed evidence of delirium, but this condition was not found in any of the patients in our present study. The reason of this difference is unclear, since the patients characteristics and IFN therapy methods were similar.

In the present study, no patients were diagnosed as having major depression before the start of IFN therapy, although depressive symptoms are reported to be frequent among patients with hepatitis type C in the United States [19]. This distinction may be related to the difference in the common route of hepatitis transmission. It is known that iv drug use is the most common route and currently accounts for the majority of new cases in the United States [20], and that the incidence of depression is especially high among these drug users with hepatitis type C [21]. However, there are fewer iv drug users in Japan and the route of hepatitis transmission has been via medical procedures such as blood transfusion in the majority of patients [22]. In fact, no iv drug users were included among the patients examined in the present study.

There was a tendency for major depression to occur more frequently in the earlier stage of treatment; 73.9% of patients developed depression during the first 8 weeks of the 24-week treatment period.

The incidence of patients who achieved remission by the end of therapy was 59.1%. Although the other 40.1% were not in remission at that time, they achieved remission within 12 weeks thereafter. The remission rate may depend on the effectiveness of treatment for depression. We used low doses of sulpiride, because sulpiride has been reported to be effective for the depressive symptoms [23], [24], [25], [26] and irritability [25] that is also frequently found during IFN therapy [3], [13], [27], [28]. In addition, in general sulpiride has only minor adverse effects at low dosage [24], [25], [26]. However, in the present study no significant relationships were found between the remission rate and the use of sulpiride. Tricyclic antidepressants were not used since it is possible that these can cause cognitive disturbances associated with their anticholinergic effect [29]. In addition, there were no selective serotonin reuptake inhibitors (SSRIs) being marketed in Japan at the time when this study was done.

The effectiveness of psychotropic drugs for treatment of IFN-associated depressive symptoms is one of the most important problems. According to some case reports [30], [31], [32], [33], imipramine, nortriptyline, fluoxetine, paroxetine and sertraline are effective in treating these depressive symptoms. A recent prospective controlled study [34] has shown that paroxetine is useful in preventing depression in hepatitis patients undergoing IFN therapy. Antidepressants, especially the SSRIs, are considered to be effective in the treatment of IFN-associated depressive symptoms. Further prospective controlled studies with large number of patients are needed to assess this.

The only apparent risk factor for major depression was advanced age, as reported previously for cancer patients treated with IFN [35]. Although organic brain damage [36] and higher HAMD or MAS scores before IFN therapy [10], [37] are reported to be risk factors for psychiatric complications, these were not confirmed in the present study. Also, a history of prior psychiatric treatment was not a risk factor for major depression. This finding is similar to that of previous studies [12], [38], [39], where a history of mental disorders has not been found to be a risk factor of those for patients undergoing IFN therapy. In addition, we confirmed the results of previous studies showing that the type and dose of IFN-alpha [40], and values of GOT and GPT before therapy [13] were not risk factors for depression.

This present study has some limitations. One of these is the lack of iv drug users among the study subjects. In view of this, it may not be possible to generalize our findings to groups of patients with hepatitis that include a significant percentage of iv drug users. In addition, we can not draw any clear conclusions about the effectiveness of psychotropic drug therapy for treating IFN-associated depressive symptoms. Not only was the sulpiride treatment in this present study open-labeled, but there was also a patient-selection bias since sulpiride was only used in patients who agreed to have psychopharmacotherapeutic intervention. In addition, neuropsychiatric symptoms other than depression, such as anxiety, irritability, cognitive disturbance, parkinsonism and akathisia, were not assessed. These symptoms can occur during IFN therapy and cause considerable distress to patients [1], [2], [13], [41]. Further research is needed to clarify the clinical features of IFN-associated neuropsychiatric symptoms and the most appropriate treatment methods.

5. Conclusions 

We have confirmed that major depression is a frequent occurrence among patients with hepatitis type C undergoing IFN-alpha therapy. Such patients require careful observation, and psychiatrists should be sufficiently aware of the incidence of depression, its clinical course, and associated risk factors.