Treating Depression
in Adults with Cystic Fibrosis

INTRODUCTION
Since the emergence of safer and more tolerable antidepressant medications, the treatment options have increased for individuals with cystic fibrosis (CF). Due to the lack of studies or reviews on the use of pharmacological treatment for depression and anxiety in individuals with CF, I researched the area and presented this work at last year's North American Cystic Fibrosis Conference [1]. This has stimulated much interest amongst colleagues and patients with a request from the IACFA editorial staff to publish a review. The following article will focus on the treatment of uncomplicated depression. Since the paper presentation was specific to psychotropics more coverage will be provided on pharmacological treatments.

"I believe therapy is essential in treating depression…"

A section on psychosocial treatments was included in the article, as I believe therapy is essential in treating depression but often underutilized due to specialist availability or patient preference. There are other treatments (e.g., electroconvulsive therapy (ECT), additional medication classes such as stimulant medications, alternative therapies) that were also neglected due to space considerations. The purpose of the article is to provide a general review of the most commonly used psychosocial and pharmacological treatments. Special considerations for the use of these treatments in individuals with CF will be provided.

BACKGROUND
Much attention has been paid over the years to the psychological functioning of individuals with chronic illness. Early studies of adolescents and young adults with cystic fibrosis showed rates of depression to be higher than those seen in individuals without chronic illness [2, 3]. These older studies were filled with methodological problems including small numbers of participants and higher proportions of individuals with advanced disease.

To increase our understanding of adjustment in adults with CF, Anderson and her colleagues [4] conducted a study of 34 adults with CF (aged 18 to 49). The participants in the study completed psychological self-report measures including instruments specific to depression. These researchers concluded that individuals with CF had levels of depression similar to the population of adults without chronic illness. While this study may not generalize to the whole population of adults with CF due to the limited number of participants, restricted geographic region, and use of self-report methodology, the results are promising and consistent with several other small studies of young adults [5, 6, 7, 8, 9, 10].

DIAGNOSIS OF DEPRESSIVE DISORDERS
Despite these positive findings, both clinicians and adults with cystic fibrosis are well aware that many individuals with CF experience depression. These difficulties may be mild, temporary bouts of depressive feelings in response to changes in illness or non-illness life events. On the other hand, symptoms may be severely debilitating and chronic.

Depression is diagnosed through an interview with a psychologist, psychiatrist, or clinical social worker. Other health care specialists may also be trained to diagnose depression. A major depressive episode, according to the Diagnostic and Statistical Manual-Fourth Edition-Text Revision (DSM-IV-TR) [11], entails a depressed mood or loss of interest in pleasurable activities for most of the time over a two week period or longer.

"…a change in normal functioning…"

Differentiating the physical symptoms of depression (e.g., fatigue, appetite change) from physical illness change can be difficult. To overcome these difficulties, diagnosis should not rely on only the physical symptoms of depression, albeit with the understanding that bodily symptoms will also be part of depression in individuals with chronic illness. Additionally, more useful than symptom identification is to review the impact of all psychological, social, and physical factors on the quality of life of the individual. That is, if this experience is not a temporary reaction to adjusting to life changes, then one should look at how the experience of these symptoms impacts school or work performance, socialization with peers, family relations, motivation towards treatment, and daily coping with chronic illness.

TREATMENT STRATEGIES

"…this may be perceived as not being strong in the face of illness."

In my work with adults with cystic fibrosis, I usually get several different reactions to the suggestion of initiating counseling or a medication consultation to treat depression. Some individuals are relieved that there are viable treatments that may end their suffering. Other individuals are more reluctant to begin treatment as this may be perceived as not being strong in the face of illness. Many people also have preconceived notions about the type of person who receives psychological care. Our task then is to uncover the individual's beliefs about depression and treatment and clarify misconceptions.

Depression affects individuals across all social classes, ethnic and racial backgrounds, and geographic regions. Depression is not a weakness or a lack of good character. There is evidence of a strong genetic component that renders some individuals more vulnerable to mood disorders [12]. The cause of depression has not been determined and is most likely due to a combination of psychosocial and biological factors [13].

Psychotherapeutic Strategies

"…counseling should be an initial consideration in treatment."

Ideally, the CF team includes a psychosocial provider (i.e., social worker, psychologist, psychiatrist, family therapist, nurse practitioner) who is skilled in evaluation and treatment of depressive disorders. More typically, CF physicians initially evaluate depressive symptoms and then refer to psychiatric colleagues outside of the team as needed. Regardless of which approach is used, a comprehensive evaluation is necessary and psychotherapy or counseling should be an initial consideration in treatment.

"…understanding the impact of CF treatment on a patient's daily life…"

Treatment of depression in individuals with chronic illness should not significantly differ from treatment of individuals without chronic illness. Certain considerations are important, however. The clinician should be skilled in treating depression and also understand cystic fibrosis and issues related to adjustment to chronic illness. Since depressive symptoms and physical functioning interact, progress will need to be monitored for both processes. Additionally, understanding the impact of CF treatment on a patient's daily life will be essential.

Psychological treatments differ in relation to the assumed theories behind the treatment. Cognitive-behavioral therapies focus on the influence of negative thinking patterns and behavior on mood. Psychodynamic therapy focuses on resolving internal conflicts that often emanate from early and ongoing relationships. Difficulties involving relationships and/or loss is the focus of interpersonal psychotherapy. Family therapies attempt to alter negative interactions within the family system, which may contribute to and maintain depression in the identified patient. Many therapists do not adhere to a single theory but employ different perspectives and techniques tailored to the suspected causes of an individual's depressive state.

There is well-established literature supporting the efficacy of cognitive-behavioral therapy in the treatment of depression [14]. There have also been promising results for interpersonal psychotherapy [15, 16, 17, 18]. Psychodynamic therapies and family therapies, to date, have been inadequately tested in controlled studies; thus, comparisons are difficult.

In the largest multicenter study of depression in the United States, the National Institute of Mental Health's Treatment of Depression Collaborative Research Program (TDCRP), the following treatments were compared: cognitive therapy (CT) [19], interpersonal psychotherapy (IPT), the standard tricyclic antidepressant imipramine, and a no treatment placebo control condition. Overall, there were no differences among the 3 treatment groups in the patients' overall functioning and level of depressive symptoms at the end of treatment [20]. Those in the medication group responded faster than the two therapy groups but these differences diminished when the patients were reassessed at 16 weeks [21]. Re-analysis of the data indicated that of those patients who were more severely depressed at the beginning of treatment, IPT and imipramine were superior to CT and placebo. When there was severe depression and excessive difficulties in daily life functioning, treatment with imipramine produced the best results [22].

Psychopharmacological Strategies
Biological treatments for depression have advanced quite remarkably in the past decade. Early biological models suggested a deficiency of neurotransmitters (the chemicals that modify or result in the transmission of nerves in the brain) i.e., serotonin and norepinephrine, led to the development of depression [23]. Although current research also implicates serotonin and norepinephrine systems in the pathophysiology of depression, their role is most likely not direct but due to a cascade of influences [24]. Healy and McMonagle [25] proposed a theory relating various domains of functioning affected by serotonin, norepinephrine, and dopamine. The authors contended that medications affecting norepinephrine influence levels of energy and interest, those that affect serotonin influence impulse control, and those that affect dopamine influence drive. There is also overlap in the domains affected (i.e., all 3 are implicated in mood, emotion, and cognitive function while serotonin and norepinephrine are both implicated in anxiety and irritability). The overlap in the effect of neurotransmitters across domains of functioning may explain why antidepressant medications have untoward side effects, such as sleep difficulty.

"…earlier antidepressant agents had adverse effects on CF physical status…"

The emergence of medications known as serotonin re-uptake inhibitors (SSRI's; e.g., fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram) has dramatically increased the treatment of depression in CF as the earlier antidepressant agents had adverse effects on CF physical status or CF-specific treatment [1]. One of the older classes of medications, the tricyclic antidepressants (TCA's; see Table 1), were problematic because of their high propensity for anticholinergic effects (mainly drying up of secretions). Secretions in the lungs could be even harder to clear and problems with constipation could lead to intestinal complications. Aside from these side effects, the use of tricyclics has decreased in the general population because of their potential for inducing heart irregularities.

Table 1: Less Favorable Antidepressant Options for Individuals with CF
(Information obtained from Ison, 2000)

Another class of older agents, the monoamine oxidase inhibitors (MAOI's, see Table 1), were problematic for patients with CF because of restrictive dietary and medication guidelines secondary to the potential for dangerous changes in blood pressure. Currently being used in European countries and under FDA application in the US are reversible inhibitors of monamine oxidase A (RIMA's; e.g., moclobemide). These medications do not require the same level of dietary restrictions but may not have the same level of efficacy for atypical or treatment-refractory depression [26].

Since the SSRI's ("Prozac-like drugs") were developed, new antidepressants have been devised that target both the serotonergic and noradrenergic systems (e.g., mirtazapine, nefazadone, venlafaxine). More domains of functioning (e.g., arousal and motivation) can theoretically be affected due to this property. There have also been medications designed that are selective for the noradrenergic system (e.g., reboxetine, a drug used throughout Europe and the United Kingdom but declined for approval by the FDA in the United States). An antidepressant dissimilar to the other antidepressants, bupropion, affects the dopaminergic and noradrenergic systems. Due to the domains affected by bupropion, the medication is thought to be "drive-enhancing." The newer antidepressants are promising in that they target the same neurotransmitters as the older agents but without the same concerning side effects [27, 28].

No studies of the clinical effectiveness of antidepressant medications in patients with CF have been published. However, a review of studies of patients with a range of other physical illnesses (e.g., chronic obstructive pulmonary disease, diabetes) concluded that patients prescribed antidepressant medication were more likely to improve than those patients prescribed placebo pills or no treatment [29]. The majority of studies of persons in the general population have not shown significant differences in the clinical efficacy of the available antidepressants [30].

Since there has not been much demonstrated difference in efficacy among the choices of antidepressants for CF patients, the choice of medication is often determined by the profile of psychological and behavioral symptoms, potential adverse events of the medications, past psychotropic medication response, drug cost, and considerations of treatment adherence.

For example, if a patient is depressed and anxious with sleep onset difficulties, a medication that is less stimulating may be warranted. In this situation, an adverse event (i.e., sedation) could be used therapeutically. A nighttime dose of a sedating antidepressant (e.g., trazadone, mirtazapine) could be provided in addition to a non-stimulating antidepressant (e.g., paroxetine, citalopram). Because individuals with similar symptom profiles may respond differently to the same medication, physicians may switch medications or add an additional medication to find the most effective treatment regimen for a particular patient.

An appropriate trial of the medication (generally 4 weeks) is necessary because these medications may take 2 or more weeks to demonstrate an effect on depressive symptoms [32]. If the patient and/or physician decide to discontinue a medication after this time, slowly tapering the medication down over several weeks is the preferred practice as suddenly stopping a medication may lead to adverse effects [33]. Additionally, a condition termed "serotonin syndrome" can occur if MAOI's are administered while there are levels of serotonergic or noradrenergic agents still present.

This potentially fatal reaction may include fever, muscular rigidity, hypotension, convulsions, and coma [23]. A 2 - 6 week washout period (depending on the drug) is required before beginning an MAOI after stopping one of these agents or before initiating a serotonergic or noradrenergic agent after discontinuing an MAOI [26].
"Antidepressant medications may cause unpleasant side effects…"
Antidepressant medications may cause unpleasant side effects such as nausea or restlessness (see Table 2), many of which disappear or lessen with time [34].
Side effects can often be addressed by treatment methods such as decreasing the dose, changing the time of administration, switching to another antidepressant, adding a medication, or using behavioral strategies [35]. Because antidepressants may interact with other medications [32] and CF treatments can be changed quite frequently, CF physicians need to be aware of concurrent use of psychotropics. Consistent follow-up to monitor the effects of the medication is important. Many individuals initiated on antidepressants soon stop their medication in the early weeks of treatment because of unpleasant effects, no perceived benefit from the treatment, or perceived improvement in symptoms [36]. Communication with the treating physician at this time is important to sort through these issues.
"…concerned about adding one more medication…"
The adults with whom I work are often concerned about adding one more medication to their already intensive treatment regimen. This concern should be balanced against the impact of the depression on overall psychological and physical functioning. Patients also worry that antidepressants may lead to physical or psychological dependence ("addiction"). Antidepressants differ from a class of medications used to treat anxiety, the benzodiazepines (e.g., alprazolam, clonazapam), which can lead to dependency in some patients [37]. For persons concerned about using benzodiazepines, the good news is that many antidepressants are also effective in treating anxiety [38].

Table 2: Adverse Events of Commonly Prescribed Antidepressants for Patients with CF
(Information obtained from Gumnick & Nemeroff, 2000)

Patients often wonder how long the treatment will be necessary. For some patients, the depression is chronic or recurring, which leads to lifetime treatment with antidepressant medication. Others may be able to attempt a trial without medication 4 - 5 months after a response is shown to the medication [32]. This issue and other concerns should be discussed with the treating physician.

CONCLUSIONS

"…depression may be a normal response to living with chronic illness."