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* Syndromes Secondary to General Medical Disorders
Psychosomatics 45:49-57, February 2004
© 2004 The Academy of Psychosomatic Medicine

Association Between Apolipoprotein E {epsilon}4 and Neuropsychiatric Symptoms During Interferon {alpha} Treatment for Chronic Hepatitis C

Peter A. Gochee, Elizabeth E. Powell, David M. Purdie, Nirmala Pandeya, Livia Kelemen, Claudia Shorthouse, Julie R. Jonsson, and Brian Kelly

Received July 26, 2002; revision received April 15, 2003; accepted April 28, 2003. From the Departments of Surgery and Psychiatry, The University of Queensland, Brisbane, Australia; and the Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Population and Clinical Sciences Division, the Queensland Institute of Medical Research, Brisbane, Australia. Address reprint requests to Dr. Kelly, Associate Professor of Psychiatry and Director of Mental Health, St. Vincent's Hospital, Darlinghurst Rd., Darlinghurst, NSW 2010 Australia; briankelly{at}stvincents.com.au (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Neuropsychiatric complications are common in patients with chronic hepatitis C undergoing treatment with interferon {alpha}. These side effects include alterations of mood, cognition, and neuroendocrine function and are unpredictable. In a number of neurological disorders characterized by neuropsychiatric symptoms and cognitive dysfunction, inheritance of an apolipoprotein E (APOE) {epsilon}4 allele is associated with adverse neuropsychiatric outcomes. The authors present evidence that the APOE genotype may influence a patient's neuropsychiatric response to interferon {alpha} treatment. The inheritance of APOE genotypes was examined in 110 patients with chronic hepatitis C treated with interferon {alpha}. A retrospective investigation was conducted by assessing the rates of psychiatric referral and neuropsychiatric symptoms experienced during treatment along with other complaints indicating psychological distress. A highly statistically significant association was seen between APOE genotypes and interferon-induced neuropsychiatric symptoms. Patients with an {epsilon}4 allele were more likely to be referred to a psychiatrist and had more neuropsychiatric symptoms during antiviral treatment than those without an {epsilon}4 allele. Additionally, patients with an {epsilon}4 allele were more likely to experience irritability or anger and anxiety or other mood symptoms. These data demonstrate that an individual's APOE genotype may influence the neuropsychiatric response to antiviral therapy with interferon {alpha}. Prospective studies evaluating the importance of APOE in susceptibility to interferon {alpha}-induced neuropsychiatric complications are needed. Moreover, pathways involving APOE should be considered in understanding the pathophysiology of interferon {alpha}-induced neuropsychiatric complications.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatitis C is a major cause of chronic liver disease worldwide, affecting an estimated 170 million people, approximately 3% of the world's population.1 Progression to cirrhosis may occur in up to 20% of chronically infected individuals, predisposing to the development of hepatocellular carcinoma. In many Western countries, hepatitis C is the leading indication for orthotopic liver transplantation.

Interferon {alpha}, a cytokine with pleiotropic properties, is the recommended treatment for hepatitis C, alone or in combination with other antivirals such as ribavirin.2–4 However, the efficacy of interferon {alpha} therapy is limited, and treatment is associated with a number of side effects.5 Particularly troublesome are the neuropsychiatric complications, which may be observed in more than 30% of treated patients and are largely unpredictable.5 These side effects include alterations of mood, cognition, and neuroendocrine function and can often necessitate psychiatric consultation because of their severity during interferon {alpha} treatment.6 Interferon {alpha}-induced neuropsychiatric side effects are not unique to hepatitis C and have been reported during treatment of other diseases such as hepatitis B, metastatic melanoma, and hematologic malignancies, with incidence rates approaching 50%.7

The mechanism by which interferon {alpha} induces neuropsychiatric side effects remains unknown. The cognitive side effects of interferon {alpha} such as memory loss and generalized slowing, along with depression and lack of initiative, are consistent with a mild frontal subcortical impairment.7 Cognitive deficits and mood disorders may occur independently, or depressive symptoms may occur secondary to cognitive impairment. The adverse effects of interferon {alpha} therapy may be contributed to by the activation of a complex cascade of secondary cytokines both in the peripheral and central nervous system.6

In a variety of neurological disorders characterized by neuropsychiatric symptoms and cognitive dysfunction, inheritance of certain apolipoprotein E (APOE) alleles is associated with particular neuropsychiatric outcomes.8–14 APOE is the major protein involved in transport of cholesterol esters and lipids in the brain and is markedly increased in human astrocytes following injury.15,16 There are three common isoforms of APOE: E2, E3, and E4, which are encoded by the different alleles {epsilon}2, {epsilon}3, and {epsilon}4, respectively. Differences between the APOE isoforms have been noted in their ability to stimulate the branching of growing neurons16 and prevent neuronal death in conditions of oxidative stress.17 In most studies, the APOE {epsilon}4 allele has a detrimental effect when compared to the APOE {epsilon}3 allele.14

In view of the complex role of APOE in the response to both acute and chronic brain injury, we postulated that inheritance of an APOE {epsilon}4 allele may predispose patients to interferon {alpha}-associated neurotoxicity. In order to investigate this hypothesis, we determined the APOE genotypes of patients who underwent interferon {alpha} treatment for chronic hepatitis C and examined the association of APOE alleles with neuropsychiatric side effects necessitating psychiatric consultation during antiviral therapy.


  METHOD

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
One hundred seventy-three patients with chronic hepatitis C commenced antiviral treatment with interferon {alpha} at the Princess Alexandra Hospital in Brisbane, Australia, between February 1995 and August 2000. Genomic DNA was available for 110 patients (106 Caucasians and four individuals of Southeast Asian decent), and this group constituted the study population. The remaining 63 patients were unable to be contacted or were unavailable for follow-up evaluation. Informed consent was obtained from each patient, and the Princess Alexandra Hospital Research Ethics Committee approved the study protocol. Diagnosis of chronic hepatitis C was based on standard serological assays and abnormal serum aminotransferase levels (>=1.5x upper limit of normal) for at least 6 months. All patients were positive for hepatitis C antibody according to a second-generation enzyme-linked immunosorbent assay (Abbott Laboratories, North Chicago, Ill.), with infection confirmed by detection of circulating hepatitis C RNA by polymerase chain reaction with the Amplicor hepatitis C assay (Roche, Nutley, N.J.). Patients were negative for HBsAg or antibodies to human immunodeficiency virus. Viral genotyping was performed with the Inno-Lipa hepatitis C II assay (Innogenetics, Zwijnaarde, Belgium). Patients with chronic liver diseases from other causes were excluded from the analysis.

Information regarding past average alcohol intake (g/day) and source of hepatitis C infection was obtained at initial assessment. Alcohol consumption during antiviral treatment was recorded at each patient encounter during treatment. All patients were required to limit alcohol consumption to less than 70 g/week and cease intravenous drug use for a period of at least 6 months before initiation of interferon {alpha} treatment. Liver biopsies were performed before treatment with antiviral therapy. Specimens were fixed in buffered formalin, embedded in paraffin, and the degree of inflammation and fibrosis was assessed and graded according to the method of Scheuer.18

Antiviral Treatment
Patients received treatment with interferon {alpha} at a dose of 3 million units three times weekly or an elevated induction dose of 3–10 million units/day for the first month of treatment followed by 3 or 5 million units three times weekly. Patients received interferon {alpha} either alone or in combination with ribavirin. Differences in induction doses were due to ongoing clinical trials performed during the study period. Patients were seen weekly for the first month and monthly thereafter. Patients were classified as nonresponsive to interferon {alpha} if they had viremia and elevated liver function test results after 12 weeks of therapy. Those classified as responsive to interferon {alpha} had normal serum ALT levels and loss of hepatitis C RNA after 12 weeks of therapy. Patients were seen in the hepatitis management clinic by the hepatitis nurse manager (C.S.) and one of three hepatologists at each visit. All patients were followed serially during therapy by the same clinician.

Psychological Data Collection
All data were abstracted retrospectively from patients' medical records by an independent observer who was blind to patients' APOE genotypes. Psychiatric history, psychotropic medications, and contributing medical conditions were detailed by the treating hepatologist both before and after commencing treatment. Psychiatric consultation during antiviral therapy and psychological and somatic symptoms of depression, irritability, and other mood symptoms that occurred after commencement of interferon {alpha} treatment were noted along with the date of occurrence. Any documented details of ongoing distress, work- or family-related difficulties, and continuing ethanol or illicit drug use (determined by interview) were also noted. Only symptoms that occurred for the first time or increased in severity after initiation of antiviral therapy, but within 6 months of its cessation, were considered interferon-induced and included in the analysis.

Psychiatric referral during antiviral treatment was initiated by the hepatologist if the neuropsychiatric side effects were deemed to require further assessment or treatment in their own right or were impacting on the patient's ability to complete antiviral therapy. Neither the clinicians nor patients were aware of APOE genotypes during treatment or subsequent follow-up.

Polymorphism Genotyping
Genomic DNA was extracted from peripheral blood mononuclear cells by using the DNAzol Reagent (Life Technologies, Melbourne, Australia). Genomic APOE sequences were amplified by polymerase chain reaction using an MJ Research PTC-100 Thermal Cycler, Qiagen HotStar Taq polymerase (Qiagen Pty Ltd, Clifton Hill, Australia) and the oligonucleotide primers 5'-TCCAAGGAGCTGCAGGCGGCGCA-3' and 5'-ACAGAATTCGCCCCGGCCTGGTACACTGCCA-3' as described by Wenham et al.19 Once amplification was complete, 4 U of endonuclease cfo 1 (Roche Molecular Biochemicals, Castle Hill, Australia) was added to each reaction mixture followed by incubation for 3 hours at 37°C.20 The resulting restriction fragments were resolved by electrophoresis using a 15% nondenaturing polyacrylamide gel. The DNA was stained with ethidium bromide before ultraviolet visualization and photography.

Statistical Analysis
The prevalence of neuropsychiatric symptoms was compared between patient groups by using chi-square tests. The degree of association between various patient characteristics and neuropsychiatric outcomes was measured by using the odds ratio along with a 95% confidence interval. Mean age of patients, time receiving interferon {alpha}, and number of neuropsychiatric symptoms (which were all approximately normally distributed) were compared between groups by using Student's t tests. Multiple logistic regression analysis was used to calculate odds ratios (and 95% confidence intervals) between patient characteristics and neuropsychiatric outcomes after adjustment for potential confounding factors. A significance level of p<0.05 was used for all analyses.

As follow-up was limited for some patients, a survival analysis was conducted to compare the time until a treatment-related neuropsychiatric event (psychiatric referral or cessation of interferon {alpha} treatment because of neuropsychiatric side effects) between APOE allele patient groups. Survival curves, survival probabilities, and estimated mean survival times were generated according to the Kaplan-Meier method. Differences in the survival curves between APOE allele groups were evaluated by using the log-rank test. The characteristics of patients with and without treatment-related neuropsychiatric events were compared, and any variables on which differences were found, and could thus be considered as potential confounders (as well as age and sex), were adjusted for in a subsequent Cox regression analysis.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
The age of the patients (68.2% of whom were male) ranged from 22 to 64 years, with a mean age of 39.2 years (SD=6.85). The source of hepatitis was previous intravenous drug use (57.3%, N=63), posttransfusion (11.8%, N=13), and other risk factors or unknown (30.9%, N=34). Alcohol intake in the past and in the 12 months preceding antiviral treatment ranged from none to very heavy (>360 g/day). No patients were identified as having used intravenous drugs during antiviral therapy. Two patients were drinking >10 g alcohol/day during antiviral therapy, and three patients were smoking marijuana on a daily or weekly basis. Liver fibrosis was stage 0 in 16 patients, stage 1 in 44, stage 2 in 25, stage 3 in 12, stage 4 in nine, and unavailable in four. No patients had decompensated liver disease. The demographic information for the 63 individuals excluded from the study did not differ significantly from the study population (data not shown).

Antiviral Treatment
The majority of patients (75.5%, N=83) received interferon {alpha} at a dose of 3x106 U three times weekly. The remaining patients (24.5%, N=27) received a higher dose of interferon {alpha} (3x106 U/day, 5x106 U/day, or 10x106 U/day) for the first month of treatment. Antiviral treatment was interferon {alpha} alone in 59 subjects, interferon {alpha} combined with ribavirin therapy in 43 subjects, and unknown in eight subjects because of ongoing blinded clinical trials. The mean duration of treatment was 35.4 weeks (range=4–104).

Sixty-one patients completed antiviral treatment and had been followed for at least 6 months. Forty-five patients continued to receive treatment or had not been followed for at least 6 months. Four patients stopped antiviral treatment prematurely because of side effects (three because of neuropsychiatric side effects). Forty-six patients (41.8%) were nonresponsive.

Apolipoprotein E Genotypes
The frequencies of the APOE genotypes in this patient cohort are summarized in Table 1. The genotype frequencies are very similar to those reported previously in subjects with chronic hepatitis C and in population control groups.21–23 There was no significant association between the number or proportion of patients with specific APOE alleles and treating hepatologist.


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TABLE 1. Apolipoprotein E Genotype Frequencies in 110 Patients With Chronic Hepatitis C Treated With Interferon {alpha}



Neuropsychiatric Symptoms
Psychiatric history before antiviral therapy. Twenty-four patients (21.8%) had a history of prior psychiatric disorders or a prior referral to a psychiatrist. All pretreatment psychiatric referrals indicated no contraindication to interferon {alpha} treatment. A history of prior antidepressant use was noted in seven patients (6.4%).

Interferon-induced neuropsychiatric symptoms. Psychiatric consultation for neuropsychiatric complications during interferon {alpha} therapy was observed in 18 patients (16.4%). A significantly greater proportion of APOE {epsilon}4 carriers necessitated psychiatric consultation versus APOE {epsilon}4 noncarriers (Table 2).


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TABLE 2. Association of Apolipoprotein E {epsilon}4 Allele Status With Neuropsychiatric Outcomes in 110 Patients With Chronic Hepatitis C Treated With Interferon {alpha}



Individual neuropsychiatric symptoms occurring during interferon {alpha} therapy are listed in Table 3. Individuals with an APOE {epsilon}4 allele had more neuropsychiatric symptoms observed during interferon {alpha} treatment than those individuals without an APOE {epsilon}4 allele. APOE {epsilon}4 carriers experienced a mean of 5.3 neuropsychiatric symptoms during interferon {alpha} treatment compared with 4.1 neuropsychiatric symptoms for APOE {epsilon}4 noncarriers (t=2.45, df=108, p<0.05). The specific neuropsychiatric symptoms most significantly associated with the APOE {epsilon}4 allele were anger, irritability, or short temper and anxiety, emotional lability, or other nondepressive mood symptoms (Table 2). The positive association found between APOE {epsilon}4 and a previous history of psychiatric disorders or psychiatric referral before treatment was not statistically significant. There was no significant relationship between the number of neuropsychiatric symptoms and mode of acquisition of hepatitis C, alcohol consumption, treatment dose of interferon {alpha}, use of ribavirin during treatment, or response to treatment. Moreover, no difference was observed between treating clinician and the number of patients referred to a psychiatrist or the mean number of neuropsychiatric events experienced among patients (data not shown).


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TABLE 3. Neuropsychiatric Symptoms Observed in 110 Patients With Chronic Hepatitis C During Treatment With Interferon {alpha}



A Kaplan-Meier analysis was conducted to compare time until psychiatric referral or cessation of antiviral therapy due to side effects between individuals with and without the APOE {epsilon}4 allele (Figure 1). This analysis revealed that patients with the APOE {epsilon}4 allele were more likely to experience a neuropsychiatric event sooner than those patients without an APOE {epsilon}4 allele. This difference between groups was significant in a Cox regression analysis that adjusted for age, sex, response to interferon {alpha} treatment, viral genotype, and prior psychiatric history ({chi}2=8.02, df=1, p=0.005). The trend was observed early and was consistent throughout treatment.



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FIGURE 1.  Time Until a Neuropsychiatric Eventa in 110 Patients With Chronic Hepatitis C Treated With Interferon {alpha}, by Apolipoprotein E {epsilon}4 Allele Status

aPsychiatric referral during interferon {alpha} treatment or cessation of antiviral therapy because of neuropsychiatric side effects.



  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
REFERENCES
 
The findings from this study suggest that genetic factors may contribute to the susceptibility to, and variability in, neuropsychiatric symptoms that occur during interferon {alpha} treatment of patients with chronic hepatitis C. We have shown a significant association between the APOE {epsilon}4 allele and psychiatric referral for neuropsychiatric symptoms during interferon {alpha} treatment. Moreover, individuals with an APOE {epsilon}4 allele were more likely to experience neuropsychiatric symptoms, particularly irritability and anxiety, compared with individuals without this apolipoprotein allele.

A persistent depressed mood was reported by 35.5% of our patients. Similar rates of psychiatric side effects have been reported in other studies despite the lack of uniformity in the various methods used for assessment.5,24 Symptoms of anxiety, emotional lability, and irritability have been reported in up to 18%, 11%, and 32% of treated individuals,4 respectively, and these proportions are consistent with our data. Some studies have shown that patients with a prior history of psychiatric distress may have an increased susceptibility to interferon {alpha}-induced depression. However, this remains controversial,25–29 and in our patient population this association did not reach statistical significance. In addition, no significant association was seen between side effects and history of intravenous drug use, alcoholism, viral genotype, induction dose of interferon {alpha}, response to treatment, or age or sex of the patient.

Interferon {alpha} has been postulated to affect neuroendocrine, neurotransmitter, and cytokine pathways both in the CNS and the peripheral nervous system.24 Exogenously administered interferon {alpha} is associated with cognitive changes, even with doses as small as 1.5 million units.30 These changes include inability to concentrate, decreased attention span, impaired short-term memory, and indecisiveness, all of which have been reported to become more pronounced with increased duration of interferon {alpha} treatment. With high-dose interferon {alpha}, hallucinations have been observed. Periods of vacant staring mid-sentence, prolonged silence, and progression to dementia have also been reported.31,32 While the side effects of interferon {alpha} are generally mitigated with decreased dosage, the persistence of neuropsychiatric changes has been observed for up to 2 years.28

The mechanisms of interferon {alpha}-induced neurotoxicity are not well defined. Interferon {alpha} is a pleiotropic cytokine that promotes the production of other cytokines, including interleukin-1, interleukin-2, interleukin-6, and tumor necrosis factor {alpha}.33 In response to interleukin-1, interleukin-2, and tumor necrosis factor {alpha}, the level of cyclooxygenase-2 mRNA rises rapidly and is associated with increased generation of reactive oxygen radicals, which can damage lipids, protein, and DNA.34,35 It is possible that interferon {alpha} exerts many of its adverse events by modifying the secretion and activity of these other molecules. While the blood-brain barrier is impermeable to interferon {alpha} and many of the cytokines it modulates, access to the CNS can occur in areas that lack a blood-brain barrier (e.g., the area postrema, median eminence, and infundibular recess)6,24 or in areas where the blood-brain barrier is slightly permeable (e.g., the pons and hypothalamus).36 Many cell types within the CNS, including microglial cells, astrocytes, and neurons, express cytokine receptors, including interferon {alpha} receptors, and are sensitive to the effects of these cytokines.36,37 Moreover, although staining for interferon {alpha} is seen in normal human brain, intense staining for interferon {alpha} and its receptor is observed in microglia around amyloid plaques in Alzheimer's disease and in brain tissue from cerebral infarcts,37,38 indicating a role for interferon {alpha} in inflammatory processes within the CNS. Interferon {alpha} is structurally similar to endogenous opiates, and it has been shown to alter the hypothalamic-pituitary-adrenocortical axis.7,24,36 Additionally, interferon {alpha} has recently been demonstrated to increase transcription of the serotonin transporter.39 The successful clinical use of selective serotonin reuptake inhibitors40–43 and opioid antagonists44 in the prevention and treatment of interferon {alpha}-induced neurotoxicity supports a complex and multifaceted role for interferon {alpha} within the CNS and suggests that multiple pathways are involved in the pathogenesis of neuropsychiatric symptoms during interferon {alpha} treatment.

The pathogenic mechanism whereby APOE {epsilon}4 increases the vulnerability of the brain to interferon {alpha}-induced side effects remains to be determined. APOE is the major lipoprotein in the brain and is a key protein in the transport of cholesterol esters and lipids. Following neuronal tissue damage, the synthesis of APOE is up-regulated in reactive astrocytes and has an important role in neuronal repair mechanisms.8 APOE isoforms vary in their neuroprotective properties, with APOE {epsilon}3 being more effective in enhancing neuronal growth than APOE {epsilon}4.16 The resistance of neural cell cultures16,17 and in vivo models45,46 to oxidative stress is influenced by APOE in an allele-specific manner, with the {epsilon}4 allele being less protective and the {epsilon}2 allele being more protective.14,17 Transgenic mice with the APOE {epsilon}3/3 genotype have a better neurological outcome and survival rate after ischemic stress than mice with the APOE {epsilon}4/4 genotype.47 The APOE {epsilon}4 allele is a major risk factor for Alzheimer's disease and worsens neurological outcome after traumatic brain damage.8,48 In Wilson's disease, the onset of neurological symptoms is significantly delayed in patients with the APOE {epsilon}3/3 genotype compared with the APOE {epsilon}3/4 genotype.49

The association of specific APOE genotypes with depression remains controversial. In most studies, the association of APOE with depression is secondary to cognitive decline in predisposed {epsilon}4 allele carriers. Nondepressive symptoms, such as irritability and anxiety, have been seen in APOE {epsilon}4 carriers with dementia, although this remains inconclusive.50,51 Recently, in a study examining the relationship between stress and mood disturbance, carriers of the {epsilon}4 allele responded differently to psychological stress than individuals without the {epsilon}4 allele.52

The influence of specific APOE alleles on outcomes following acute and chronic brain injury and cerebrovascular disease appears to be related to ethnicity.53 Although the {epsilon}4 allele is associated with an increased risk of Alzheimer's disease in Caucasians, this association is not observed in African Americans or Hispanics.54 Recent evidence suggests that geographic and ethnic differences exist in the haplotype distribution within APOE alleles, and that this may account for the variation observed between ethnic groups and the adverse outcomes of specific APOE genotypes.53 Our patient cohort was predominantly Caucasian, and further studies are needed to determine the effect of specific APOE alleles on interferon-induced neuropsychiatric symptoms in other ethnic populations.

Although statistical significance was not achieved, our data show that prior psychiatric illness tended to be associated with the presence of the APOE {epsilon}4 allele. This may be important, since a recent study that used magnetic resonance spectroscopy (MRS) demonstrated that patients with histologically mild chronic hepatitis C infection have altered cerebral metabolism.55 These cerebral MRS abnormalities are seen in conditions associated with cellular proliferation or inflammation and may reflect infection of cerebral tissue by hepatitis C or a central effect of peripherally derived cytokines. Infection with hepatitis C has been shown to increase oxidative stress through the formation of reactive oxygen species56 and induce transcription of oxidative stress response genes such as NF-{kappa} B57 and superoxide dismutase.58 In view of the role of specific APOE genotypes in neurological conditions associated with oxidative stress, it is possible that {epsilon}4 allele carriers may be predisposed to develop neuropsychiatric symptoms as a result of hepatitis C infection alone. Further studies are required to determine whether hepatitis C-infected subjects with an APOE {epsilon}4 allele have more neuropsychiatric symptoms than those with other APOE alleles.

Although the association between APOE {epsilon}4 and interferon {alpha}-induced neuropsychiatric symptoms does not prove causality, it supports the involvement of pathways influenced by the neuroprotective properties of APOE in the pathogenesis of interferon {alpha}-induced neurotoxicity. These findings are preliminary but raise the importance of prospectively conducted studies addressing this association using structured clinical assessment tools. Important limitations of the study include the retrospective data collection and the reliance on clinical records. Aspects of clinical practice such as underreporting of psychological symptoms by clinicians are another caveat, but this limitation would apply across all patients attending the clinic. Since the neuropsychiatric symptoms may have arisen or been noted at varying time points during treatment and were not subject to standardized structured clinical assessment for diagnostic purposes, it was not possible to apply psychiatric diagnostic groupings to these symptoms. This limits the conclusions regarding the clinical severity of the symptoms, the diagnostic profile, or the potential association between genotype and the presence of specific psychiatric disorders such as major depression. Nevertheless, the findings are based on an independent assessment of the routine clinical records, blind to the patient's genotype.

In this study we found a highly significant association between referral to a psychiatrist during interferon {alpha} treatment, neuropsychiatric side effects, and common genetic variation in the APOE gene. Knowledge of a patient's APOE genotype may have important therapeutic implications in the management of patients with chronic hepatitis C and may lead to a better understanding of the pathogenesis of interferon {alpha}-induced neuropsychiatric distress. However, prospective research is required to investigate the role of APOE genotypes in predicting treatment response and toxicity and the role of other treatments (such as selective serotonin reuptake inhibitors) in the prevention of neurotoxic effects in individuals with this genotype. The findings are insufficient at this stage to support pretreatment screening in clinical practice to select for such preventive treatments and strategies.


  ACKNOWLEDGMENTS

 
Supported by the Queensland Liver Transplant Trust Fund and the Princess Alexandra Hospital Foundation. Dr. Gochee is a J. William Fulbright Fellow in Medicine to Australia.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 

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