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Continuing Education
Depression and Current Treatment

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This program (# 032-000-03-062-H01) is approved for 2 hours (0.2 CEU) of continuing pharmaceutical education credit.  A score of 70% on the examination is required to receive CE credit.

This lesson is no longer valid for CE credit after 12/31/2005
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 Depression and Current Treatment

Melanie Hammill Bishop, PharmD
King’s Daughters Medical Center
Brookhaven , Mississippi

Needs Statement:  Depression is a common and disabling disorder that is receiving increase recognition as a significant health problem.   Pharmacists must be ready to recommended treatment options to health professionals.  They must also be able to educate patients on current antidepressants.

Intended Audience:  Pharmacists

Goal:  To provide the pharmacist with an overview of depression with a focus on treatment.

Objectives:  Upon successful completion of this lesson, the participant should be able to:
1.  Discuss the signs and symptoms of depression
2.  Identify the medical conditions and medications that may cause or worsen depression
3. Compare and contrast the treatment options
4.  Explain the role of the CYP450 enzymes in prevention of drug interactions

Introduction
    Clinical depression affects some 26% of women and 13% of men in the United States.  In addition, the incidence is 2 to 3 times higher in first-degree relatives of depressed persons.  Although depression can occur at any age, adults 25 to 44 years of age experience the highest rates.  Patients with depression frequently develop other psychiatric illnesses, such as anxiety disorders and alcoholism.  Depression is the eighth leading cause of death in the United States.  Suicide attempts by patients with major depression are severalfold higher in comparison with the general population.
    Suicide by the depressed patient is not the only concern regarding mortality in depressed patients.  Many studies suggest that depressed patients with medical problems have higher morbidity and mortality.  Results of one study showed a 5-fold increased risk of death in depressed patients over the 6 months following a myocardial infarction (MI), and found that the impact of depression was at least equivalent to that of left ventricular dysfunction and a history of previous MI.  Outcomes are also poor for poststroke patients with depression, as shown by a study conducted in a consecutive series of 103 patients who were assessed for major depression or dysthymia 2 weeks following a stoke.  During the study’s 10-year follow-up period, depressed patients were found to be 3.4 times as likely to die than those without depressive symptoms.

Clinical Presentation/Diagnosis
    When a patient presents with depressive symptoms, it is necessary to investigate the possibility of a medical, psychiatric, and/or drug induced cause (Table 1).   All depressed patients should have a complete physical examination, mental status examination, and basic laboratory workup. To identify any potential medical problems, lab test should include a complete blood count with differential, thyroid function tests, and electrolyte determinations.
     Even though depression can be treated safely and effectively, it remains underdiagnosed and undertreated.  Major Depression can present as a single episode, but is often recurrent and chronic.  It is characterized by one or more major episodes consisting of a period of at least 2 weeks in which the patient exhibits five or more specific symptoms.  These symptoms cause significant distress or impairment in social or occupational functioning (Table 2).  Symptoms must not be due to the direct physiological effects of a substance or a general medical condition, and they cannot be better accounted for by bereavement. Severe depression can be accompanied by psychotic symptoms.   A simple way to remember the criteria for major depression is: The prescription (SIG) for major depression is energy (E) capsules (CAPS) - or SIG E CAPS.
     Depressed patients must be assessed for suicidal thoughts.  Factors that increase the risk of suicide include living alone, substance abuse, family history of suicide, presence of a serious medical condition, increasing age, unemployment, divorce, death of a spouse, and prior attempts.  The presence of a very detailed plan with the intention and ability to carry it out indicates a high risk of suicide.

Pathogenesis
    Many theories attempt to explain the pathophysiology of depression.   It is likely that several different factors work together to cause the illness.  Treatment that involves alterations in brain neurotransmitters can improve symptoms and have provided clues to the pathophysiology of depression.  Primarily, serotonin and norepinephrine neurotransmitter systems appear to play the greatest role in depression.  The most widely accepted theory is that reduced levels of these neurotransmitters lead to depression.  One other theory states that decreased levels of serotonin may allow for the expression of the mood disorder, but the level of norepinephrine determines the type of disorder displayed.   Another possible etiology is receptor upregulation, which results from a decreased amount of neurotransmitter chronically.  There are many other theories of cause including abnormal neurokinins, decreased neurogenesis caused by heightened glucocorticoid release, and structural and functional brain changes.

General Overview of Treatment
    Therapeutic options used in the treatment of depression are psychotherapy, pharmacotherapy, and electroconvulsive therapy (ECT).  The combination of psychotherapy and pharmacotherapy is the optimal approach for most patients.  The difficulty with psychotherapy is the fact that it is often difficult to obtain, or not covered by third parties.
    Electroconvulsive therapy (ECT) is very effective in treating refractory depression.  Contrary to popular belief resulting from hearsay and movies such as One Flew Over the Cuckoo’s Nest, ECT is safe and humane.  The patient is anesthetized and paralyzed and a nonconvulsive seizure is induced for about 30 seconds.  The entire process takes about 1 to 2 hours in an outpatient setting and the patient usually goes home after treatment.  A course of ECT generally consists of 6 to 12 treatments administered either unilaterally or bilaterally two to three times weekly.  Contraindications to ECT include intracranial pressure, cerebral lesions, recent myocardial infarction, recent intracerebral hemorrhage, or bleeding.  The most common side effect of ECT is short-term memory loss that tends to improve with time.  Memory loss is less pronounced with unilateral ECT.
    Recent advancement in the development of new and effective antidepressants has been astounding.   Studies comparing the efficacy of antidepressants have found that they are of equivalent efficacy when administered in comparable doses.  Factors that often influence the choice of an antidepressant include the patient’s past history of response, familial antidepressant response, the potential for drug-drug interactions, adverse effects, and ability to target particular depressive symptoms (i.e. insomnia).  One would also want to avoid tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) in patients who are impulsive and at high risk for overdose.  Cost is also a consideration in many patients; however, older medications which are cheaper, have more side effects. The mechanism of action of antidepressants is not clear.  It is believed that adaptive changes in neurotransmission in the brain occur with antidepressant administration.  This process takes time to occur, and we generally inform patients it will take 6 weeks to see antidepressant effect.  Anxiolytic properties of antidepressants are manifested sooner.  Initially, benzodiazepines are sometimes added for their benefit in treatment of anxiety and insomnia.  If depression is accompanied by psychosis, low dose antipsychotic therapy is added to the antidepressant until those symptoms resolve.
     Although definitive research is lacking, TCAs and SSRIs are used in the treatment of childhood depression.  The risk and benefits of antidepressant therapy in pregnancy must be weighed, and concerns about the risks of untreated depression during pregnancy should be considered.  No major teratogenic effects have been identified with the SSRIs or TCAs.  Further evaluation of antidepressants is needed to fully understand the risk associated with their use.
     Antidepressants will be placed into four basic categories for discussion.  These are: tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants.

Tricyclic Antidepressants (TCAs)
    TCAs were among the first antidepressants available.  Although effective, TCAs are considered as second or third-line treatment due to their unfavorable side effect profile and lethality potential when taken in overdose.  These agents act by blocking the reuptake of serotonin and norepinephrine.  The tertiary amines are frequently metabolized to secondary amines that are active, and generally more potent for norepinephrine reuptake.  The activity of TCAs at other receptors, including cholinergic, histaminergic, noradrenergic, and dopaminergic receptors, leads to a broad spectrum of efficacy in disorders other than depression, such as enuresis, chronic pain, and migraine prophylaxis.  However, activity at these receptor sites also leads to the unfavorable side effects such as dry mouth, urinary retention, constipation, blurred vision, sedation, weight gain, and sexual dysfunction.  These drugs should be used with extreme caution in patients with cardiac disease or seizure disorders.  Patients at risk for orthostatic hypotension are at increase risk of falls if they use these agents.
    Because TCAs are metabolized in the liver through the cytochrome P450 system, they may interact with other drugs that affect hepatic enzyme activity.  TCAs are involved in pharmacodynamic drug interactions as well.  They may reverse the hypotensive effects of certain antihypertensives such as guanethidine, methyldopa, and clonidine.  TCAs may increase the vasopressor response to phenylephrine and epinephrine.  Fatal reactions may occur when combined with MAOIs.  Monitoring of therapeutic serum concentration is beneficial when using TCAs to confirm that the dose has led to a value within the range for efficacy and to guard against toxic values.  

Monoamine Oxidase Inhibitors (MAOIs)
    MAOIs are effective antidepressants, but use of these agents should be restricted to treatment-refractory depression or atypical depression.  The nonselective MAOIs inhibit type A and type B monoamine oxidases, the enzymes responsible for the breakdown of catecholamines such as norepinephrine, serotonin, and dopamine. This enzyme blockade presumably results in an increase in the concentration of these neurotransmitters in neuronal synapses.  Common side effects include orthostatic hypotension, sedation, dizziness, insomnia, constipation, tachycardia, peripheral edema, sexual dysfunction, and weight gain.  Drug interactions with the MAOIs are significant.  Monoamine oxidases are also responsible for the breakdown of certain amines found in foods, beverages, and OTC sympathomimetics. Thus, combinations with many of these substances can produce dangerous interactions.  If MAOIs are used, thorough patient education and monitoring is required so that patients avoid foods high in tyramine to prevent a hypertensive crisis and subsequent stroke.  Combination with other antidepressants can be problematic as well.  When switching to or from another antidepressant, a washout period is mandatory.  The MAOIs  available in the US are phenelzine and tranylcypromine.

Selective Serotonin Reuptake Inhibitors (SSRIs)
    Because of their comparable efficacy and better-tolerated adverse effects, selective serotonin reuptake inhibitors (SSRIs) have replaced tricyclic antidepressants as the drugs of choice in the treatment of depression.  In addition to depression, the SSRIs have proven efficacy in treating anxiety disorders, including obsessive compulsive disorder (OCD), panic disorder, social phobia, and post traumatic stress disorder (PTSD).  SSRIs block the reuptake of serotonin, therefore enhancing serotonin activity within the synapse.  Although this is the predominant mechanism of action of this class of drugs, each SSRI has a slightly different pharmacological profile that leads to its distinct clinical activity, side effects, and drug interactions. It also appears that some patients may respond to one but not another SSRI.
    The SSRIs have a low affinity for the histaminic, cholinergic, and noradrenergic receptors and are generally well tolerated.  Common side effects of SSRIs include transient nausea, diarrhea, insomnia, somnolence, dizziness, akathisia, and long-term sexual dysfunction.  Because these drugs have such potent serotonergic activity, combinations with other drugs affecting serotonin can lead to serotonin syndrome.  Examples include MAOIs, TCAs, dextromethorphan, and meperidine.  Serotonin syndrome is manifested as confusion, hypomania, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, and diarrhea.  Treatment of serotonin syndrome includes discontinuation of the offending agents as well as supportive measures.  The SSRIs are metabolized by the cytochrome p-450 system, leading to interactions with drugs involved in that system (Table 3).   As with all antidepressants, care must be taken to screen patients for symptoms of bipolar disorder before prescribing SSRIs, to avoid precipitation of a manic episode.
    There are five SSRIs that are approved by the U.S. Food and Drug Administration (FDA) for the treatment of depression, which include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and escitalopram (Lexapro).  Although fluvoxamine (Luvox) is an effective antidepressant, it is only FDA approved for the treatment of OCD.

Fluoxetine (Prozac®):  Fluoxetine was the first SSRI to be FDA-approved for the treatment of depression.  Administration usually begins with 20mg per day, taken in the morning because of its potential for central nervous system activation.  A starting dose of 10mg per day is preferred in the elderly patients.  Fluoxetine may be increased to 40 to 60mg for depression; 80mg per day may be necessary for the treatment of OCD.  Fluoxetine has a half-life of two to four days and its active metabolite, norfluoxetine, has a half-life of seven to nine days.  The long half –life makes fluoxetine beneficial in noncompliant patients.  It may also be an appropriate antidepressant choice in patients with hypersomnia or psychomotor retardation.
     Fluoxetine is now available in a special form taken once-weekly for therapy of depression.  Prozac Weekly is a capsule with pellets containing 90mg of fluoxetine hydrochloride.  The enteric coating prevents dissolution of the pellets until they have passed into the portion of the gastrointestinal tract where the pH exceeds 5.5.  In a study of 500 patients with depression, the percentage of patients relapsing during continuation treatment with a 90mg weekly dose was not significantly different from those taking a 20mg daily dose.  Weekly dosing is recommended to begin seven days after the last daily dose of 20mg.  Fluoxetine (under the trade name Sarafem) is now indicated for the treatment of premenstrual dysphoric disorder (PMDD).  Because of its long half-life, patients should allow at least five weeks between discontinuation of fluoxetine and MAOI therapy.

Sertraline (Zoloft®):  Sertraline is widely used in the treatment of depression. In addition to serotonergic activity, this drug causes some minor blockade of dopamine reuptake, which can lead to extrapyramidal side effects.  It causes minimal anticholinergic, and sexual dysfunction.  Sertraline has been associated with more cases of diarrhea than fluoxetine, but with fewer cases of anxiety and insomnia.  At high doses, sertraline is an inhibitor of the CYP2D6 enzyme, but clinically significant drug interactions are unusual.  The usual starting dose is 50 mg per day and dosage may be titrated to a range of 100 to 200 mg per day in a single or divided daily dose.

Paroxetine (Paxil®):  In the treatment of depression, paroxetine is initiated at a dosage of 20 mg per day.  The upper limit of the dosage range is 40 to 60 mg per day.  The side effect profile of paroxetine is similar to that of the other SSRIs, except that paroxetine tends to be more sedating and anticholinergic.  It should probably be avoided in patients in whom the anticholinergic activity would be undesirable, such as those with Alzheimer’s disease or other cognitive disorders.  The potential for weight gain, drug interactions, and sexual dysfunction tends to be slightly higher with paroxetine than with fluoxetine and sertraline.   Paroxetine has a half-life of twenty hours and no metabolites; thus patients are more prone to have withdrawal symptoms such as headache, nausea, insomnia, and anxiety if doses are missed.
     Recently, Paxil CR was brought to market in an attempt to decrease the gastrointestinal side effects of immediate-release paroxetine.  The recommended initial dosage for the treatment of depression is 25mg per day, with a range of 25 to 62.5mg per day.  Patients should be counseled that the tablets are to be swallowed whole and not crushed or chewed. 

Citalopram (Celexa®):  Citalopram has been associated with low rates of insomnia, anxiety, and other activating side effects.  Nausea is the most common early side effect, but it should be transient.  Citalopram has a relatively long half-life; thus it is less likely to cause a withdrawal syndrome compared with shorter acting SSRIs.  The dose range of citalopram is 20 to 60 mg per day; the higher dose is typically used in the treatment of OCD.  No clinically significant drug interactions have been documented.  This drug may be appropriate in patients who take multiple medications because of its low potential for drug interactions. 

Escitalopram (Lexapro®):   Escitalopram oxalate is the S-enantiomer of citalopram.  Escitalopram is the newest and most selective SSRI approved by the FDA for the treatment of depression, and is also useful in conditions for which other selective serotonin reuptake inhibitors have proven beneficial, such as anxiety disorders and PMDD.  The most notable difference between escitalopram and citalopram is its potency.  Clinical studies suggest that the efficacy of 10mg/day of escitalopram is comparable to 40mg/day of citalopram.  An earlier onset of action of escitalopram relative to citalopram has also been suggested.  The side effect profiles of the two agents are quite similar.  As with citalopram, the potential for drug interactions is low.

Fluvoxamine (Luvox®):  Fluvoxamine is FDA-approved only for the treatment of OCD in patients who are at least eight years of age.  It is also used in the treatment of depression and anxiety disorders.  The initial dosage in adults is 50mg daily, titrating up to 250 mg per day divided into two doses.  Children can be started on a dosage of 25mg at bedtime, increasing every week to a maximum of 200mg per day in divided doses.  The most common side effects are nausea, vomiting, and headache.  Clinically important drug interactions with fluvoxamine are documented.  These drug interactions are due to fluvoxamine’s potent inhibitory action at the cytochrome p-450 system.

Atypical Antidepressants
Venlafaxine (Effexor®):  This agent is a potent serotonin and norepinephrine reuptake inhibitor.  Some people now refer to this class as SNRIs.  Whether or not the “dual action” of venlafaxine makes it more effective than SSRIs is an area of research.  There has been the suggestion in the literature that venlafaxine may be more effective acutely for severely depressed patients compared with SSRIs.  Again, this will require further study.  The side effect profile is comparable to that of the SSRIs and lower than that of the tricyclic antidepressants.  Anticholinergic side effects are significantly less severe than those encountered with other antidepressants.  Sexual side effects are similar to side effects caused by SSRIs.  Venlafaxine can cause elevations in diastolic blood pressure.  However, analyses show that this phenomenon is significant only with a dosage above 300mg daily. 
    Venlafaxine was first released in an immediate-release form that is taken two or three times daily.  In 1997, an extended-release form (Effexor XR) was approved by the FDA, allowing for once-daily administration.  The gastrointestinal side effects are less with the extended-release formulation.  The starting dose venlafaxine XR is 37.5 mg to 75 mg per day.  The dosage may be titrated weekly to a maximum recommended dosage of 225mg per day.  Occasionally, patients with refractory depression will be responsive to a dosage of 300mg daily.

Mirtazapine (Remeron®):  Mirtazapine is unique in its action.  Its primary effects appear to be antagonism of presynaptic a 2 autoreceptors and heteroreceptors that prevent release of norepinephrine and serotonin.  The net result is an increase in both norepinephrine and serotonin in the synapse.  In addition to this, the drug blocks 5-HT2A and 5-HT3 receptors. Blockade of these receptors leads to fewer activating side effects, less sexual dysfunction, and fewer gastrointestinal effects compared with other antidepressants.  Mirtazapine has a high affinity for histamine receptors and can thus cause sedation and weight gain.  There is a very small risk of neutropenia and agranulocytosis with mirtazapine.  The recommended starting dosage is 15mg at bedtime, which may be titrated up to 45mg daily, if needed. 

Trazodone (Desyrel®):  This drug is a serotonin reuptake inhibitor that also blocks the 5-HT2A receptors.  It has few anticholinergic side effects, but can cause orthostatic hypotension.  Priapism can occur in men while taking trazodone.  Because of its sedating effect, it is now frequently used in combination with other antidepressants for insomnia treatment. 

Nefazodone (Serzone®):  Nefazodone is a relative of trazodone with  some pharmacological differences.  It too is a 5-HT 2A   antagonist, but also blocks the reuptake of serotonin and norepinephrine.  Unlike trazodone, it causes minimal effects on sexual function, and is less likely to cause orthostatic hypotension.  In January 2002, the FDA and the manufacturer of nefazodone added a black box warning concerning rare cases of liver failure.  Nefazodone therapy should be avoided in patients with active liver disease or elevated serum transaminase levels, and discontinued when transaminase levels are three times the upper limit of normal or more.  Patients taking nefazodone should be counseled on the signs and symptoms of liver failure, including jaundice, anorexia, gastrointestinal problems, and malaise.  Nefazodone use is limited, most likely because of its numerous drug interactions.  It is a potent inhibitor of CYP 3A4, which is the pathway responsible for most drugs metabolized in the liver. 

Bupropion (Wellbutrin®):  This drug is primarily an inhibitor of dopamine and norepinephrine reuptake and has minimal effects on serotonin.  However, its exact mechanism of action remains to be defined.  The drug has a short half-life and must be dosed TID unless the extended-release form is used, which is dosed BID.  The sustained-release product may also cause fewer side effects and has largely replaced the immediate-release tablets.  The most notable side effect of bupropion is increase seizure risk.  This can be minimized by avoiding use in susceptible patients, such as those with epilepsy, and also not giving more than 150mg per dose or 450mg per day (400mg SR).  Slow titration also decreases the risk of seizures.  The most common side effects include nervousness, headache, and insomnia.  Administering the second dose in the afternoon versus the nighttime can prevent insomnia.   Given its potentiation of dopamine, bupropion can  exacerbate psychosis.  Bupropion may actually improve sexual function so it may be useful in treating depression in patients who suffer this side effect with other agents.  Bupropion can also be added to an SSRI to treat sexual dysfunction.  It is used for smoking cessation and marketed under the name of Zyban®.

Duloxetine (Cymbalta®):  Duloxetine is a potent reuptake inhibitor of both serotonin and norepinephrine, which is similar to venlafaxine’s pharmacological activity.  Duloxetine appears to have low affinity for other neurotransmitter systems.   Duloxetine has been approved for the treatment of depression and will be comarketed under the trade name Cymbalta by Eli Lilly and Company.   Duloxetine appears to be generally well tolerated.  Common side effects in clinical trials were nausea, dry mouth, fatigue, somnolence, insomnia, and asthenia.  It may also have minimal effects on sexual function, although effects have not been evaluated in a study designed specifically to assess adverse effects.  Because duloxetine is pharmacologically related to venlafaxine, it will be important for providers to monitor for cardiovascular effects until large-scale data is available.  Research does suggest that duloxetine may moderately inhibit the metabolism of drugs metabolized via CYP2D6 enzyme.  Duloxetine has been administered as a 60mg single daily dose and also as a 40mg twice-daily dose.  Duloxetine is also under investigation for the treatment of stress urinary incontinence in women.  Serotonin and norepinephrine have been implicated in neural control of the lower urinary tract. 

Treatment Resistance: Augmentation Therapy
   
Ten to 30 percent of patients taking antidepressants are partially or totally resistant to the treatment.  Some patients may also experience breakthrough or recurrence of depression while taking the medication.  Antidepressant combinations or augmentation may be beneficial.  Combination therapy with multiple neurotransmitter activity may be used, especially for treatment refractory depression.  Using a second antidepressant may offset a side effect of another, for example, using trazodone to treat SSRI induced insomnia or using bupropion to treat sexual dysfunction associated with SSRIs or venlafaxine.
    Augmentation is a useful strategy in patients with a partial response.  The best-documented options are lithium and levothyroxine.  Lithium is administered in the usual dosages, keeping the lithium blood levels to the lower end of the therapeutic range (0.4 to 0.8 mEq per L).  Lithium may increase serotonin function.  The augmentation dosage of levothyroxine is 25mcg per day.  The effect is not dependent upon thyroid dysfunction.  If levothyroxine is used, cardiac status and thyroid hormone levels must be monitored.
    Case reports and open studies indicate that augmentation with the psychostimulant methylphenidate (Ritalin, in a dose of 5mg to 40mg per day) can be effective.  Caution should be taken when combining methylphenidate or other psychostimulants with antidepressants that are activating. 

Antidepressant-Induced Sexual Dysfunction
    Sexual dysfunction, usually delayed ejaculation or anorgasmia, may occur in both men and women who are taking SSRIs, venlafaxine, and others.  There are several options in reducing this occurrence: decreasing the dosage, switching to another agent, or adding another agent to overcome the sexual side effects.  Sexual dysfunction typically reverses within one to three days after discontinuation of the antidepressant and returns on reintroduction.   Due to its longer half-life, the recovery period may be one to three weeks with fluoxetine.  Uncontrolled studies and case reports suggest that the addition of bupropion, cyproheptadine, nefazodone, or mirtazapine may decrease sexual side effects.  In patients with antidepressant-induced erectile dysfunction, sildenafil (Viagra) may be useful if the patient has no history of angina and is not taking nitrates.

Drug Interactions
    The choice of an appropriate antidepressant should include consideration of drug-drug interactions.  These interactions occur when SSRIs and other antidepressants are coadministered with drugs metabolized via the cytochrome P450 system.  Two of the isoenzymes of the cytochrome P450 system, 2D6 and 3A4, are responsible for the metabolism of over 80% of currently marketed drugs.  Table 3 summarizes the cytochrome P450 drug interactions involving antidepressants.

Conclusion
Great strides have been made over the last two decades in the treatment of depression. Today we have antidepressants that effectively treat depression with few side effects.  However, much remains to be understood as to how the antidepressants work in treatment. 

References


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