Part III, Chapter 1: Depression Case Studies

Martha Pauli, M.Ed., Pharm. D. Drug Eductaion Coordinator, Kaiser Permanente

Profiles

- 1 -

Linda, 48, comes into the pharmacy to pick up her prescription for an antidepressant. She sys her family is not supportive of her taking this medicine. They think she takes too much, and hav e calledit an upper, a crutch, and addicting. She’s trying to take it only when she needs it. She asks, “ Shouldn’t I feel better right away after I take it?”

- 2 -

Joan. 33. comes in to ask your opinion of using St. John’s wort to treat her lack of energy and depressive symptoms. She was previously treated with paroxetine (Paxil TM and felt it helped her depression, but libido difficulties forced her to stop taking it.

- 3 -

Mary, 28, a mother of three, including a new infant, wonders about taking a medicine for depression while breast-feeding. She feels she has no energy, cries a lot, feels overwhelmed, and has a hard time caring for the children.

- 4 -

Susan, 35, has been on prescription diet pills in the past. She comes to the pharmacy with a prescription for fluoxetine (Prozac™) from another doctor. She heard this is one antidepressant that doesn't cause weight gain, and she is eager to try it for that reason.

- 5 -

Jane, 70, .relates that she has many physical complaints, has low energy and just can't seem to concentrate. "I guess that is just what happens with getting older," she says.

What do all these women have in common? They may be experiencing symptoms of depression—an all too common, but treatable illness.

Frequency and Cost of Depression

Millions of adults suffer from depression; it is more common than coronary heart disease or cancer. More women than men are affected, with the ratio of women to men approaching 2:1. Depression is under diagnosed and under treated in the primary care setting. A recent consensus statement in the Journal of the American Medical Association concluded that even though safe, effective, and affordable treatments are available, barriers to treatment remain within the medical community and the general public, leading to under-recognition and under treatment of this condition (see Table 1).

The costs of depression are staggering. Direct costs include treatment with antidepressant drugs, other auxiliary medications, other therapies (e.g., psychotherapy), and increased use of medical services in general. Indirect costs include absence from work and lost productivity, social, physical, and family disabilities, and mortality costs (i.e., suicide). Estimates have placed the total cost of depression at approximately $44 billion a year in the United States.

The Pharmacist's Role in the Treatment of Depression

Pharmacists, as patient advocates, can have a positive impact on a patient's quality of life by monitoring and supporting rational antidepressant drug treatment. Knowledge of the diagnostic criteria for depression and the medical illnesses and drugs that may contribute to depression is important (see Tables 2 and 3).

What should pharmacists consider when responding to the women in the cases described above?

Profile 1: Depression is not caused by a personal weakness or lack of willpower. Antidepressants are not addicting or habit-forming, nor are they uppers in the abusive sense of the word. In fact, depression is one of the most treatable—medication responsive—of all mental illnesses. It usually takes from 4-6 weeks for a full therapeutic trial, although some symptoms begin to resolve sooner (see Table 4).

Profile 2: Various alternative or folk medications are promoted in current magazines and literature. One German medicinal is St. John's wort. This compound is an extract from the plant Hypericum perforatum and appears more effective than placebos in European studies. Long-term studies and comparisons to existing antidepressants are lacking, as is a standardized preparation, but careful use by select patients could be supported, as side effects appear minor. St. John's wort should not be combined with prescription anti-depressants without physician approval.

Antidepressants belonging to the serotonin specific reuptake inhibitors (SSRI) group are the most likely to cause sexual dysfunction in men and women (delayed orgasm or ejaculation, anorgasmia). The reported frequency of this bothersome side effect ranges from 9%-40%. The exact frequency is unknown, since women may be hesitant to discuss sexual problems, and diminished libido is also a symptom of depression. Decreasing the dose or taking a drug holiday—for example from Friday to Sunday—may help minimize sexual dysfunction, especially with paroxetine (Paxil™) or senraline (Zolofr™), two SSRIs with shorter half lives. This treatment regimen is controversial and may result in withdrawal symptoms or noncompliance. Occasionally, yohimbine, buspirone (Buspar™), or amantadine is prescribed. Some clinicians advocate the use of ginkgo biloba, a Chinese botanical medicine, for sexual dysfunction induced by SSRIs. In some cases, a switch to an anudepressant in another drug class may be necessary.

Profile 3: Breast feeding allows transmission of many drugs to the infant, who has an immature metabolic system. Some clinicians advocate the use of sertraline if therapy with an SSRI is necessary, since little or no drug enters the breast milk, and there is no evidence of adverse effects on breast fed infants. Tricyclic antidepressants (TCAs) have a longer history of use in pregnancy and breast feeding. As with any medication used during pregnancy or breast feeding, benefits and risks must be individually assessed. (A recent study in the New England Journal of Medicine found TCAs and fluoxetine to have no effect on global IQ, language development, or behavioral problems in preschool children who had been exposed in utero.)

Each year, 30 percent of all new mothers, or more than 300,000 women, may show symptoms of post-partum depression, generally within four weeks of delivery. However, the occurrence of postpartum depression is probably underestimated.

Clinically diagnosable depression may occur at many different stages of women's lives, including prepartum, postpartum, after miscarriages, during infertility treatment, and at menopause. These are all times of changes in endocrine status. Mood changes and depressive symptoms are influenced by estrogen (and other hormonal) balance. The role of estrogen in women who present with signs and symptoms of depression during these times is not clearly understood and the subject of ongoing study.

Particularly during menopause, some women may be sensitive to low estrogen, or estrogen loss, and may find their mood more stable on estrogen replacement. Estrogen replacement is not an "antidepressant," and each woman must weigh her individual risks and benefits of estrogen replacement therapy with her physician. There is evidence for depressive symptoms, although not full depression, secondary to menopause.

Profile 4: Combining agents that act on the neurotransmitter serotonin and related receptors may cause serotonin syndrome, a drug-induced condition that can be life-threatening. Combining drugs that act on serotonin—such as diet pills, ergotamine, sumatriptan, meperidine, dextromethorphan, or 1-tryptophan—with an SSRI can lead to this drug interaction. Signs and symptoms of serotonin syndrome include excitement, confusion, restlessness, agitation, fever, perspiration, motor weakness (ataxia), tremor, rapid heart rate, and hypertension. These can progress to loss of consciousness, requiring immediate medical assistance.

In recent years the amount of money spent on direct-to-consumer advertising of prescription drugs, including anridepress.mts, has increased dramatically. Whether this marketing strategy empowers or confuses consumers is debatable. This "pill for every ill" emphasis may mislead consumers into thinking a certain medicine is just what they need. Pharmacists are on the frontline here and have both the ability and responsibility to educate patients about their use of antidepressants and identify potential drug interactions, including those with over-the-counter agents.

Profile5: Elderly people with depression generally have more physical symptoms and complaints (headache, chronic pain, constipation) than do younger individuals. Depression in the elderly may be harder to recognize and may accompany chronic diseases. Suicide rates are higher in the elderly. Cognitive symptoms may also be prominent—disorientation, memory loss, or distractibility.

Older people may have the "keep a stiff upper lip" attitude. It is not uncommon for families to consider depression a normal part of aging and its treatment unnecessary or futile. Pharmacists can help ensure that this misconception about depression is not perpetuated! A response to antidepressants in elderly patients may require 9-12 weeks of treatment at therapeutic doses. A patient or his or her family should avoid premature termination. Slower dosage ritrarion may be necessary. However, not all geriatric patients need smaller doses as compared with younger individuals.

Gender and Depression

Women consume greater numbers of psychotropic medications than men, but drug development studies have historically relied on men (almost exclusively) as subjects. Even though the gap in medical research between men and women is starting to close, there is still not equality between the sexes in this area.

Both the National Institutes of Health and the Food and Drug Administration have established guidelines for clinical research to correct under-representation of women in medical and drug studies, but there are no gender-specific recommendations for the treatment of depression. One ongoing observational study, the Nurses Health Study, hopes to look at psychosocial factors such as mood changes, stress, anxiety, and social isolation that may influence women's health and longevity.

There is some general information available on the influence of gender on various pharmacokinetic parameters (see Table 5). Consideration of these factors when assessing the efficacy, toxicity, or dosing of antidepressant drugs in women may improve outcomes and minimize side effects.

A Short Discussion of Antidepressant Drugs: A Heterogeneous Family

Effectiveness

All antidepressants are equally effective in relieving depression—a 60-80% response rate is generally reported. The search for an ideal antidepressant continues (see Table 6). With the introduction of newer drugs, progress has been made towards some ideal characteristics, but greater efficacy has not been achieved. Some antidepressants have utility in other related diseases (see Table 7).

Among the antidepressant drugs, there are tremendous differences in pharmacologic profiles, neurotransmitter effects, side effects, and cost.

Selection

Treatment should be individualized and based on the following patient and drug specific characteristics:

• family history of response (if any)
• prior patient response (if any)
• patient age and lifestyle considerations
• potential for side-effect tolerability
• potential for suicide—likelihood of overdose (see Table 8)
• convenience—once vs. multiple daily dosing
• medical and drug history—potential for drug interactions, disease state interactions
• desire for lab monitoring
• neurotransmitter effects
• cost

Generally, a single antidepressant is chosen, but occasionally, antidepressant combinations are utilized in refractory cases of depression. Combination antidepressant therapies, whether used to counter initial side effects on a short-term basis or as augmentation in long-term therapy. should be prescribed by one knowledgeable clinician.

Mechanism of Action

Antidepressant drugs interact in the brain with a number of neurotransmitters—specifically serotonin, norepinephrine, and dopamine. Our understanding of the mechanism of action of antidepressant drugs continues to evolve. We know that neurotransmitters, the receptors on individual cells or neurons, the enzymes that metabolize neurotransmitters, and even other substances such as peptides and hormones, all play interdependent modulatory roles in causing and alleviating depression. If a patient fails therapy with one antidepressant, it may be reasonable to choose another drug that has a primary action involving different neurotransmitters. The reader is referred to current literature for a thorough discussion of mechanisms of action.

Costs

Drug cost differences (wholesale or acquisition costs) for months of treatment with different anridepressants can range from under twenty dollars to several hundred dollars. With the current emphasis on cost-containment, cost constraints may affect drug selection, whether patients belong to an HMO, have other traditional medical insurance, or have no medical insurance/drug coverage.

Drug selection should take into account more than the acquisition costs of medications. Pharmacoeconomic studies are examining benefits, costs, and outcomes of different treatment strategies. The total cost of care includes both direct (medicine, labs, MD visits) and indirect costs (lost productivity, family upheaval). Additionally, newer research is examining the short- and long-term benefits and quality of life measures. Identifying the most cost-effective therapy is the goal.

There is no general consensus as to the best antidepressant drug, and many agents claim first line status, but SSRIs are the most frequently prescribed antidepressant class of drugs.

Available Drugs

There is an impressive array of choices below for the pharmacological treatment of depression

TCAs - tricyclic antidepressants

There are eight agents in the tricyclic class of antidepressants, an older, chemically-related group that has been extensively used and studied. The tertiary amines consist of amitriptyline (Elavil™), clomipramine (Anafranil™), doxepin (Sinequan™), imipramine (Ton-anil™), and trimipramine (Surmontil™). The secondary amines are more popular and better tolerated due to their lower anricholinergic and orthostatic activity. (Anticholinergic side effects include constipation, blurry vision/dry eyes, urinary hesitancy, and dry mouth.) This group includes desipramine (Norpramin™)—the least anticholinergic TCA, nortriptyline (Pamelor™)—the least orthostatic TCA, and protriptyline (Vivactil™)—the least sedaring TCA.

The ability to monitor therapeutic drug levels with most of the TCAs may be useful in assessing compliance, toxicity, and response. Since women may have higher serum levels than men, lower initial doses and conservative dosage increases should be the rule. TCAs can cause serious toxicity in an overdose: as little as two grams can be fatal. Cardiovascular effects, primarily conduction delay and arrhythmias, pose a risk in the elderly or individuals with heart block. The elderly may also be especially sensitive to anticholinergic side effects, including mental status changes and sedation (which is a contributor to tails/fractures).

Weight gain is common. Tolerance to sedation (which may be beneficial) and anticholinergic effects may occur with continued use. Additive sedative effects occur when a sedating antidepressant is given with another central nervous system (CNS) depressant. A once daily dose (at bedtime) is standard therapy, as is starting at low doses and using small increases to lessen side effects and to improve tolerability.

SSRIs—serotonin specific reuptake inhibitors

There are four agents in this class—fluoxetine (Prozac™), sertraline (Zoloft™), paroxetine (Paxil™), and fluvoxamine (Luvox™). All four drugs are associated with gastrointestinal (GI) complaints, although they are better tolerated than the TCAs. Headache, insomnia, and agitation can also occur. Paroxetine and fluvoxamine are slightly anticholinergic and slightly sedating. All of the SSRIs can cause sexual dysfunction. Weight gain is not usual with these agents (as compared to the TCAs, which frequently cause weight gain). Older patients may be especially sensitive to side effects such as diarrhea, anxiety, or loss of appetite.

The specificity with which these drugs work on the neurotransmitter serotonin (as compared to other classes of antidepressants with broader neurotransmitter effects) has revolutionized antidepressant drug treatment and helped clarify the modulator role serotonin plays in a number of conditions (e.g., sleep and eating disorders, autism, aggression, emesis, and migraines). It has also caused societal reflection and debate on whether, and to what extent, the human condition is biochemical determined.

All SSRIs have the potential to inhibit the liver enzymes responsible for the metabolism of many drugs (see Table 9). These interactions are the subject of ongoing study. There is no evidence that SSRI plasma levels correlate with the dose or the response to therapy.

The dosing of SSRIs is generally simpler than the gradual dose titrations that are used to reach a therapeutic dose with TCAs. Most SSRIs have a small dose range, if any, and therapy is typically initiated with a therapeutic dose in the great majority of patients.

MAOIs—monoamine oxidase inhibitors

There are two agents in this class—phenelzine (Nardil™) and tranyl-cypromine (Pamate™). These drugs are rarely the first choice for the treatment of depression. They are primarily reserved for refractory or atypical cases of depression, where such symptoms as increased sleep and appetite, tension, phobias, or increased depression in the evening are present.

Careful selection of patients and good compliance with MAOI regimens are important in order to minimize toxicity with these agents. Tyramine dietary restrictions are particularly important to avoid a potentially fatal interaction with MAOIs. Daily divided doses are usually necessary, rather than a single daily dose as is used with TCAs and SSRIs. Drug interactions with meperidine, sympathomimetics, or serotonergic agents can lead to serious toxicity

Miscellaneous older (second generation) agents

This group of antidepressants includes amoxepine (Ascendin™), maprotiline (Ludiomil™), trazodone (Desyrel™), and bupropion (Wellbutrin™). Amoxepine and maprotiline have very limited usefulness due to renal and neurologic toxicity (amoxepine), the potential for overdose toxicity (maprotiline), and the potential for seizures (maprotiline and amoxepine).

Trazodone is less likely than the TCA group of drugs to impair cardiac conduction and does not have anticholinergic side effects. The sedative effect of trazodone is sometimes used during initial SSRI treatment if insomnia is a problem. A rare side effect of trazodone is priapism. Trazodone usually requires multiple daily dosing.

Bupropion has low cardiovascular, anticholinergic, and sedative effects. It may have stimulant effects. There is little or no evidence for drug interactions with bupropion, and it causes little sexual dysfunction. Bupropion is associated with an increased risk of seizures, particularly with higher doses. It has recently been given FDA approval (under the brand name Zyban™) as a smoking cessation aid.

Miscellaneous newer agents

Nefazodone (Serzone™), venlafaxine (Effexor™), and mirtazapine (Remeron™) are newer antidepressants that do not fit into the antidepressant classes discussed above. Nefazodone is structurally related to trazodone, requires twice daily dosing, and may cause dizziness, nausea, and hypertension. Its sedative quality may be an advantage for patients with anxiety or insomnia. Nefazodone causes little or no sexual dysfunction.

Venlafaxine has little cardiovascular toxicity, low toxicity following an overdose, and may be beneficial in resistant cases of depression. Multiple daily dosing is required. The major side effects of venlafaxine include GI complaints, dizziness, sedation, sweating, tremor, hypertension, and sexual dysfunction. It does not appear to cause weight gain.

Mirtazapine is the newest agent available and may have antianxiety as well as antidepressant activity. This agent causes sedation, tremor, weight gain, and increased liver enzyme and lipid levels.

Length of Drug Treatment

Drug treatment generally continues for 6-9 months after a posit: response has occurred. The dose that achieved remission is usually considered the maintenance dose, although lower doses have been used. About 50% of patients with depression have a recurrence sometime during their life. Therefore, some individuals may need ongoing maintenance treatment, especially those with risk factors for recurrence (see Table 10).

When drug therapy is discontinued, a slow dose taper should be utilized to minimize the risk of recurrence and withdrawal effects. TCAs should be tapered over 3-4 weeks (at the very minimum), and SSRIs should be tapered over 1-2 weeks. A withdrawal syndrome, which may last a week or more, occurs in a number of patients when TCAs, MAOIs, or SSRIs are discontinued. The reported incidence of withdrawal syndrome varies from 20% to more than 80% and depends, to some extent, on the length and type of antidepressant therapy, speed of dosage taper, and provider awareness. It is important for health care providers to recognize, prevent, and manage antidepressant withdrawal symptoms which may include flu-like malaise, subtle mental symptoms, GI effects, changes in sleep and dreaming, sensations such as burning or tingling, and cholinergic symptoms.

Other Treatments for Depression

Nondrug therapies — Psychotherapy is an important component in the treatment of depression, and it may be used alone or in combination with antidepressants. Many forms of psychotherapy are used; short-term therapy is common and usually lasts 10-20 weeks. Most health care organizations offer an array of educational classes in such subjects as relaxation, mood management, depression, and mind/body medicine. Light therapy has been used in cases of seasonal depression. Electroconvulsive therapy (ECT) is usually reserved for refractory or geriatric depression, although response rates are high and the risks are low with modern administration methods.

Supplemental medications — Psychotropics such as lithium, carba-mazepine, or valproic acid may be used with antidepressants in bipolar mood disorders. Antidepressants may actually precipitate mania in individuals who have bipolar illness. Thyroid hormone has been combined with antidepressants to enhance the antidepressant effect. Stimulants such as dextroamphetamine or methylphenidate (which has less cardiovascular effect than dextroamphetamine) are used primarily in elderly, apathetic, or medically ill individuals. Antipsychotics are used in conjunction with antidepressants in cases of depression with psychotic features.

Conclusion

Whether in a retail, clinic, or hospital setting, the pharmacist has an important role in the treatment of depression that can directly impact the patient's quality of life. Pharmacists can help ensure that depression is recognized and treated early, appropriately, and successfully in both females and males. An important aspect of providing pharmaceutical care to patients with depression is encouraging patients to seek help and follow through on therapy for this highly treatable condition. Pharmacists should work collaboratively with other health care professionals and:

• understand the diagnosis of depression and recognize the symptom?
  
  
• contribute to an appropriate individualized drug choice;
  
  
• help ensure an adequate drug trial—assess the drug, dose and duration of therapy;
  
  
• promote patient compliance;
  
  
• provide patient and family education regarding expectations and therapeutic goals;
  
  
• monitor for effectiveness, side effects and drug interactions;
  
  
• be aware of and learn about new research and new drugs; and
  
  
• document their impact on the delivery of health care in these areas: patient-focused care, optimal drug therapy, continuity of care, and positive patient outcomes.

Further Reading

1. Linde K, et al. "St John's wort for depression—an overview and meta-analysis of randomized clinical trials." BMJ, 1996: 313: 253-8.
   
   
2. Kramer PD, Listening to Prozac, Viking Penguin Books USA, 1993.
   
   
3. Hirschfeld R, et al. The National Depressive and Manic-Depressive Association Consensus Statement on the Undertreatment of Depression. JAMA, January 22/29: Vol 227, no 4, 1997.
   
   
4. Nulman I, et al. "Neurodevelopment of Children Exposed In Utero to Antidepressant Drugs." NEJM; Vol 336, no. 4, January 23, 1997.
   
   
5. "Practice Guideline for Major Depressive Disorder in Adults." AM J Psychiatry: 150:4, Apr 1993 Supplement.
   
   
6. Aldrich AP, et al. "Retrospective Review of Selective Serotonin Reuptake Inhibitor-Induced Libido Disturbance in Women." Clin Drug Invest: 11(6) 1996.
   
   
7. Depression Guideline Panel. "Depression in Primary Care: Detection, Diagnosis, and Treatment." Quid; Reference Guide for Clinicians: no. 5, Rockville MD. US Department of Health and Human Services, Public Health Service, Agency for Hearth Care Policy and Research. AHCPR Publication no. 93-0552, Apr 1993.
   
   
8. Floren LC, Ravnan M. "Pharmaceutical Care, Pharmacoeconomics, and the Future of Pharmacy." CJHP, 1995: 7(6): 5.