New SSRI Antidepressants Offer Advantages in Cancer Patients

A 43-year-old married man was referred to Memorial Sloan-KetteringCancer Center in June, 1995, for further management of a malignantbrain tumor. He was asymptomatic until April, 1994, when he suffereda generalized seizure and was admitted to a local hospital. AnMRI revealed a right parietal lobe lesion. The tumor was resectedand found to be a glioblastoma multiforme.

The patient received hyperfractionated radiation therapy to atotal of 7,124 cGy during May and June of 1994, which was followedby chemotherapy (carmustine [BiCNU]) every 6 weeks until January,1995. No active treatment was administered from January to June,but in April the patient was hospitalized for a partial motorseizure, which was associated with hyponatremia and confusion.

In June, after a fall, a second MRI revealed progression witha large contrast-enhancing right parieto-occipital mass invadingthe corpus callosum and the anterior horn of the lateral ventriclewith considerable edema. He was begun on dexamethasone, 4 mg qid,which produced significant improvement.

On initial consultation at Memorial Hospital in June, 1995, thepatient had considerable left-sided weakness, which was associatedwith sensory impairment and difficulty with left peripheral vision.He was unable to walk and required assistance with dressing andbathing. Although he had no recent seizures, he was experiencingfrequent headaches not associated with nausea or vomiting.

In addition to dexamethasone, his drug regimen included phenytoin,200 mg twice a day; phenobarbital, 45 mg twice a day and 60 mgat bedtime; and trimethoprim-sulfamethoxazole, three times a week.Because of the headaches, his dexamethasone dosage was increasedto 8 mg four times a day.

The patient was considered an appropriate candidate for an experimentalprotocol and proceeded with four inpatient treatments of chemotherapyduring July and August. During the fourth cycle of treatment,a psychiatric evaluation was requested for the assessment andmanagement of depression.

Morbid Preoccupations

At the time of the initial psychiatric consultation, the patientwas easily tearful and reported a sense of sadness and apprehensionabout the uncertainty of his future. He was preoccupied with thoughtsof illness and death, and was concerned about both present andanticipated losses. He was distressed about his inability to ambulateand need for assistance in his activities of daily living. Mostpainful were his ruminations of a truncated life with his wifeand fear that he would not see his daughter grow up.

Nonetheless, he remained hopeful for success with his presenttreatment, and he denied anhedonia, feelings of worthlessness,suicidal ideation, and guilty ruminations. More prominent werecomplaints of anxiety, difficulty sleeping, and fear of dying.

The mental status exam revealed slight memory, attention, andconcentration difficulties, as well as intermittent somnolence.He was diagnosed with a mild delirium secondary to steroids andwas given a sedating neuroleptic, thioridazine, 25 mg at bedtime.His mental status improved by the time of discharge.

Disease Progression

At outpatient follow-up, he complained of more frequent morningheadaches associated with nausea and worsening left-sided weakness.When further clinical tests revealed disease progression, he wasremoved from the protocol and started on procarbazine (Matulane).

Over the next few weeks, the patient became more despondent anddepressed, with insomnia, nightmares, and frequent awakenings.He reported difficulty spending time with family and friends,and a preference for spending time alone. He also expressed anxiety,fatigue, and decreased interest and motivation.

He became more withdrawn and preoccupied with a sense of himselfas a burden to his family, and he wondered if they might be betteroff without him. His mood was increasingly depressed and was accompaniedby hopelessness, helplessness, and increased guilt.

At this time, the patient was diagnosed as significantly depressed,and the tricyclic antidepressant amitriptyline was begun. As themedication was titrated upward, the patient became more confused,presumably due to anticholinergic and antihistaminic side effects.Amitriptyline was discontinued, and a trial of paroxetine (Paxil)was initiated.

Within 3 weeks, the patient reported less anxiety, improved sleepwith fewer awakenings, increased interest in spending time withfamily, fewer guilty ruminations with less of a sense of himselfas a burden, and improved cognitive function, ie, greater attentionspan and concentration.

Normal Sadness or a Disorder?

The incidence of depression in cancer patients ranges from 20%to 25% and increases with higher levels of disability and advancedillness.[1]

The diagnosis and treatment of depression in this population arecontroversial and complex.[2] Depressive symptoms are often viewedas appropriate in the context of terminal illness. However, thephysician must distinguish between the patient's normal feelingsof sadness and fear and the symptoms of a depressive disorder.

Furthermore, many depresive symptoms are similar to those of canceritself: Anorexia, insomnia, fatigue, debilitation, and loss oflibido lack specificity for depression in the cancer patient.It is also important to identify organic changes related to cancerand its treatment because these can produce depressive symptoms.

Since depression adversely influences quality of life, adaptivecoping, and compliance with treatment, the diagnosis of depressioncan be most helpful in the cancer patient's care. In the patientdescribed, risk factors for depression include a primary braintumor, brain irradiation, steroids, a chemotherapeutic agent (procarbazine),and an antibiotic (trimethoprim-sulfamethoxazole).

Problems With Tricyclics

Initially, the patient was treated with a sedating tricyclic antidepressant,amitrip-tyline. This choice was made for several reasons. Sedatingtricyclics often are prescribed for anxious, depressed patientswith insomnia. These medications are also useful in pain management.Furthermore, they may stimulate appetite and weight gain in apopulation at risk for anorexia and weight loss.

The side effects of tricyclic antidepressants can be troubling.Anticholinergic side effects include sedation, constipation, drymouth, and urinary retention. Cardiovascular side effects, whichcan be especially dangerous in elderly patients, include orthostatichypotension and cardiac arrhythmias.

Patients receiving tricyclics are particularly susceptible tomild cognitive deficits, which may worsen with the use of drugsthat have anticholinergic and antihistaminic effects.

In our patient, a confusional state developed and worsened onamitriptyline because of these side effects. Treatment with aselective serotonin reuptake inhibitor (SSRI) was then initiatedwith positive results.

Changing Prescription Pattern

In the last few years, SSRIs have replaced tricyclics as the first-linetreatment of depression. In addition to paroxetine, fluoxetine(Prozac) and sertraline (Zo-loft) are commonly used SSRIs.

These agents have become popular because their side effects profilesare less problematic, especially in the medically ill. SSRIs arenot associated with anticholinergic, antihistaminic, or alpha-adrenergic-receptorblocking activity and the resulting side effects of tricyclicantidepressants.

The most common side effects of SSRIs are gastrointestinal reactions(nausea, vomiting, diarrhea), central nervous system activation(insomnia, transient anxiety, tremor), and anorexia. Less frequentside effects are headache, lethargy, and sexual dysfunction, whichseem to be dose related.

In the cancer patient, exacerbation of nausea and anorexia maybe problematic, particularly in cases of gastrointestinal cancer,during chemotherapy treatment, or in situations of weight lossassociated with advanced disease.

Fluoxetine has the longest half-life of the available SSRIs fortreatment of depression, averaging 1 to 4 days, and an activemetabolite, norfluoxetine, with a half-life of 7 to 14 days.

The shorter elimination half-lives of paroxetine (21 hours) andsertraline (26 hours), as well as the lack of an active metabolitefor paroxetine, allow for quicker clearance of these medicationswith faster resolution of noxious side effects and harmful drug-druginteractions.

The wide therapeutic index of SSRIs, compared with that of thetricyclic antidepressants, provides a buffer for toxicity secondaryto slower metabolism as a result of impaired liver or renal function,often seen in cancer patients.

A number of pharmacokinetic interactions of SSRIs should be considered.First, as these medications are highly protein-bound, coadministrationof other highly protein-bound drugs, including warfarin, tricyclicantidepressants, digoxin, and anticonvulsants, unpredictably altersthe blood levels of such drugs.

SSRIs also undergo oxidative metabolism by the liver, by inhibitingthe cytochrome P450 enzymes. Sertraline causes less inhibitionthan fluoxetine or paroxetine.

Drugs likely to increase blood levels of SSRIs include tricyclics,carbamaze-pine, valproic acid, neuroleptics, and type 1C antiarrhythmics.Closer monitoring of blood levels and clinical signs of toxicityis indicated when using such drugs.

Another group of drugs, the monoamine oxidase inhibitors, givenin combination with SSRIs or soon after their discontinuation,can cause a dangerous or fatal hypertensive crisis.

SSRIs Not Lethal in Overdose

Cancer patients, especially in advanced illness, are at increasedrisk for suicide relative to the general population. SSRIs lacklethality with overdose, whereas the tricyclic antidepressantsare the third most common cause of drug-related death. This reassuringfact supplies another advantage in choosing an SSRI.

Depression in cancer patients is treatable, and treatment resultsin decreased distress, improved quality of life, more adaptivecoping, and better compliance with treatment.

Since all antidepressants are thought to be efficacious, selectionshould be based on the current medical status and psychiatrichistory of the patient and the side effects profile and pharmacokineticsof available agents.

In addition, various antidepressants can be used to treat distressingphysical symptoms. Side effects must be considered because theseagents may exacerbate preexisting medical conditions.

SIDEBAR

Potential Advantages of SSRIs Over Tricyclics

• No anticholinergic, antihistaminic, or alpha-adrenergic-receptorblocking activity.
• Wide therapeutic index provides a buffer for toxicity secondaryto slower metabolism as a result of impaired liver or renal function,often seen in cancer patients.
• SSRIs lack lethality with overdos
• SSRIs = selective serotonin reuptake inhibitors.

References:

1. Bukberg J et al: Depression in hospitalized cancer patients.Psychosom Med 43:199-212, 1983.

2. Cunningham LA: Depression in the medically ill. J Clin Psychiatry55(suppl A):90-97, 1994.