Antidepressant Side Effects 2006 (1)

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 4 APRIL 2006 351

ELIAS A. KHAWAM, MDLouis Stokes Cleveland VA Medical Center;

Senior Instructor, Department of Psychiatry,

Case Western Reserve University

GEORGIA LAURENCIC, MDDepartment of Psychiatry and Psychology,

Cleveland Clinic

DONALD A. MALONE JR., MDHead, Section of Adult Primary Services,

Department of Psychiatry and Psychology,

Cleveland Clinic

Side effects of antidepressants:An overview

CURRENT DRUG THERAPY

ABSTRACT

Adverse effects of antidepressant drugs can decrease

compliance and delay recovery. It is therefore crucial toconsider potential side effects when choosing anantidepressant.Although there is no perfectantidepressant that works quickly and is completely freeof adverse reactions, newer antidepressants are safer,better tolerated, and associated with a lower rate ofnoncompliance.

KEY POINTS

Although side effects can be idiosyncratic, most can beexplained by the drugs mechanism of action.

Most antidepressant side effects subside within the firstfew days to weeks of therapy.

Sexual dysfunction is a side effect of all serotoninreuptake inhibitors, venlafaxine, and duloxetine.Bupropion and nefazodone have the lowest risk forsexual side effects.

The risk of suicide may be increased during the firstmonth or so of antidepressant therapy; physicians,

patients, and family members should be vigilant for signsof suicidal thoughts and behavior.

In elderly patients, serotonin reuptake inhibitors seem tobe safer and better tolerated than tricyclicantidepressants. The choice should be made on the basisof side effect profile and drug interactions.

URRENT ANTIDEPRESSANT DRUGS areeffective and generally well tolerated, but

noncompliance remains worrisome. Up to 70%

of patients taking antidepressants are noncom-pliant,1,2 as a result of either missed doses orpremature discontinuation. According to Linet al,1 28% of patients stopped taking antide-pressants in the first month of treatment, and44% discontinued by the third month. Severalreasons were identified for premature discon-tinuation, with side effects the most common.Dropout rates in studies of tricyclic antidepres-sants varied from 7% to 44%; in studies of sero-tonin reuptake inhibitors, the dropout rateswere 7% to 23%.3,4

Physicians should educate and reassuretheir patients about potential side effects.Benign and transient side effects are morecommon than dangerous or irreversibleeffects, especially with the newer antidepres-sants. This knowledge can help in reducingthe rate of medication discontinuation, whichis important because even after a medicationhas produced the desired benefit, it needs tobe continued to prevent relapses.

This article will focus on the adverseeffects of antidepressants, with the goal of

helping physicians to recognize and under-stand them, so that patients can undergoeffective treatment.

SIDE EFFECTS ARE USUALLY PREDICTABLE

Medications are the mainstay of treatment ofmoderate to severe depression, often com-bined with psychotherapy.5 In addition, anti-depressants are used to treat other psychiatricillnesses and even medical illnesses (TABLE 1).

Although some side effects of antidepres-

C

PATIENT INFORMATION

If you need an antidepressant, page 363


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352 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 73 NUMBER 4 APRIL 2006

Serotonin

reuptakeinhibitors are

metabolized

by the P-450

system

ANTIDEPRESSANTS KHAWAM, LAURENCIC, AND MALONE

sant drugs are idiosyncratic, most can beexplained by their effects at the synaptic level(TABLE 2).6,7 Antidepressants typically blockthe reuptake of certain neurotransmitters(norepinephrine, serotonin, and dopamine)back into the nerve ending and block some ofthe other neurotransmitter receptors.710 Themost clinically relevant receptor blockade

occurs at muscarinic (acetylcholine), hista-minic (H1), alpha-1 adrenergic, dopaminer-gic (D2), and possibly serotonergic (5-HT2A) receptors.

Side effects are not always a disadvantage.For example, a patient with insomnia maybenefit from a sedating antidepressant given atbedtime.

SEROTONIN REUPTAKE INHIBITORS

Serotonin reuptake inhibitors have replaced

the tricyclic antidepressants as the first-linetreatment for depression and now account formost prescriptions for antidepressants in theUnited States. Fluoxetine (Prozac) was intro-duced in 1988 and was followed by sertraline(Zoloft), paroxetine (Paxil), fluvoxamine(Luvox), citalopram (Celexa), and escitalo-pram (Lexapro). All but fluvoxamine areapproved by the US Food and DrugAdministration (FDA) for treating depres-sion; fluvoxamine is approved for obsessive-compulsive disorder.

Mechanism of serotonin reuptake inhibitorsSerotonin reuptake inhibitors selectivelyblock serotonin reuptake at the presynapticnerve terminal.

Citalopram and escitalopram have themost selective effect on serotonin reuptake,with little inhibitory effect on norepinephrineand dopamine reuptake and a low affinity foralpha 1 adrenergic receptors, muscariniccholinergic receptors, and histamine H1receptors.11,12

Other serotonin reuptake inhibitors havesimilar profiles, except that paroxetine hassome anticholinergic properties, fluoxetineweakly inhibits norepinephrine reuptake, andsertraline weakly inhibits norepinephrine and

dopamine reuptake.79,11

Pharmacokineticsof serotonin reuptake inhibitorsSerotonin reuptake inhibitors differ in theirpharmacokinetics. Fluoxetine has the longesthalf-life, and its active metabolite (norfluoxe-tine) has a half-life of 7 to 15 days.11 Paroxetineand fluvoxamine have relatively short half-lives(21 and 15 hours, respectively).

All serotonin reuptake inhibitors aremetabolized in the liver by the cytochrome P-

450 system.11 Because they competitivelyinhibit these hepatic enzymes, serotonin reup-take inhibitors can increase the levels of othermedications metabolized by these enzymes,possibly leading to toxic effects. The greaterthe P-450 inhibition, the greater the possibili-ty of drug interactions. For example, givingdesipramine (a tricyclic antidepressant) with aserotonin reuptake inhibitor such as fluoxetinecan lead to as much as a fourfold increase inthe plasma level of desipramine, which couldlead to increased anticholinergic effects, seda-

tion, seizures, and cardiotoxicity. Fluoxetinemight interact with warfarin, with the possibil-ity of an increased anticoagulant effect and anincreased risk of bleeding.

Side effectsof serotonin reuptake inhibitorsSerotonin reuptake inhibitors are generallywell tolerated. However, approximately 15%of patients cannot tolerate certain side effectsand therefore may stop taking the drug.

Sexual dysfunction. Although psychi-

Other indications for antidepressant drugs

Anxiety disorders: phobic disorders, panic disorder,

obsessive-compulsive disorder, generalized anxiety disorder,post-traumatic stress disorder

Attention deficit and disruptive behavior disorders

Eating disorders: anorexia and bulimia

Gastrointestinal disorders: irritable bowel syndrome

Genitourinary disorders: enuresis

Pain syndromes: migraine headache, other chronic pain conditions

Psychotic disorders: schizoaffective disorder

Sleep disorders: insomnia, night terrors, sleep apnea, narcolepsy,

functional enuresis

T A B L E 1


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atric illnesses in themselves can affect sexualdesire and performance, so can the drugs usedto treat the illness. Sexual dysfunction is themost common side effect of all serotonin reup-

take inhibitors. Delayed ejaculation, anorgas-mia, and decreased libido can occur in up to60% of patients,13,14 and the effects continueas long as the drug is taken.

The stimulation of serotonin 5-HT2 and5-HT3 receptors is a proposed mechanism forthe occurrence of sexual dysfunction due toserotonin reuptake inhibitors, so it has beensuggested that adding medications that blockthose receptors might help with this adverseeffect. The most common medications forcounteracting this adverse effect fall into three

groups: alpha-2 adrenergic receptor antago-nists, serotonin 5-HT2 or 5-HT3 receptorantagonists (eg mirtazapine), and dopaminer-gic agents. Other strategies include decreasingthe dose; adding bupropion, sildenafil, cypro-heptadine, or buspirone; or switching toanother antidepressant that has few sexual sideeffects, such as bupropion, mirtazapine, ornefazodone.2,14

Gastrointestinal effects. Sertraline andfluvoxamine may cause more gastrointestinalside effects than other serotonin reuptake

inhibitors. Nausea and diarrhea are dose-relat-ed and usually resolve within the first 2 weeksof treatment. Starting the medication at a lowdose and giving it with food usually alleviatesnausea.

Constipation and dry mouth tend to bemore common with paroxetine because of itsanticholinergic activity.6

Anorexia is most common with fluoxe-tine and occurs early in the treatment.8,14 It isprobably related to activation of 5-HT2Creceptors.8 However, with time this suppres-

sant effect on appetite is lost. Indeed, sero-tonin reuptake inhibitors have the potentialto cause weight gain, possibly due to desensi-tization and down-regulation of the serotoninreceptors associated with appetite control.

Central nervous system side effectsinclude anxiety, insomnia, sedation, night-mares,6,14 and extrapyramidal symptoms.Patients may experience increased anxiety,most commonly early in treatment.

Sleep disturbances, either insomnia orsomnolence, have been reported in about


Adverse effects of antidepressantdrugs, based on mechanism of action

Norepinephrine transporter blockadeAnxietyAugmentation of pressor effects of sympathomimetic aminesDiaphoresisTachycardiaTremor

Serotonin reuptake inhibitionAnorexia early in the treatment and weight gain laterDose-dependent increase or decrease in anxietyEjaculatory disturbances, anorgasmia, and decreased libidoExtrapyramidal side effectsInteraction with monoamine oxidase inhibitors and tryptophan

Nausea, vomiting, and diarrhea.Sedation or insomniaSerotonin syndrome

Dopamine reuptake inhibitionActivation and aggravation of psychosisParkinsonismPsychomotor activation

Alpha-1 adrenergic receptor blockadePostural hypotension and dizzinessPotentiation of the antihypertensive effect of other medicationsReflex tachycardia

Dopamine D2 receptor blockade

Extrapyramidal side effects: akathisia, dystonia, parkinsonism,tardive dyskinesia

Endocrine effects; prolactin elevation

Histamine H1 receptor blockadeDrowsinessFalls in the elderlyOrthostatic hypotensionSedationWeight gain

Muscarinic acetylcholine receptor blockadeBlurred visionCentral effects: memory and cognitive impairment,

delirium in severe casesGastrointestinal effects: decreased salivation, dry mouth,

decreased peristalsis, constipationPrecipitation of narrow-angle glaucomaSinus tachycardiaUrinary hesitancy and retention

ADAPTED FROM RICHELSON E. INTERACTION OF ANTIDEPRESSANTS WITH NEUROTRANSMITTER

TRANSPORTERS AND RECEPTORS AND THEIR CLINICAL RELEVANCE.

J CLIN PSYCHIATRY 2003; 64(SUPPL 13):513;

AND RICHELSON E. PHARMACOLOGY OF ANTIDEPRESSANTS.

MAYO CLIN PROC 2001; 76:511527.

T A B L E 2


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25% of patients taking serotonin reuptakeinhibitors. Fluoxetine is more likely to causeinsomnia than is paroxetine, which is morelikely to cause sedation. Others tend to lead

equally to somnolence or insomnia. Insomniacan be treated with trazodone, benzodi-azepines, or other sedative medications.14

Headache, nightmares, and vivid dreamshave been reported in a minority of patients.These side effects often resolve within a fewweeks and rarely lead to a change in medica-tion.

In rare cases, serotonin reuptake inhibitorscan cause extrapyramidal side effects, includ-ing akathisia (motor restlessness; constantmovement).6 Such adverse effects are not due

to dopamine receptor blockade but rather toincreased serotonin at the synaptic levels,mediating inhibition of the release ofdopamine through one of the presynaptic sero-tonin receptor subtypes. The rate of seizureswith serotonin reuptake inhibitors is 0.1% to0.2%, which is not significantly different fromthat with placebo.15,16

Orthostatic hypotension is unlikely inpatients treated with serotonin reuptakeinhibitors because they do not block alpha-1adrenergic receptors significantly.6,15

These drugs have minimal effects on hist-amine H1 receptors and therefore they are lesssedating than tricyclic antidepressants.

Bleeding. Serotonin reuptake inhibitorsinhibit platelet function and may prolongbleeding. Several reports have indicated anassociation between the use of these drugs andbleeding disorders ranging from bruising andepistaxis to more serious conditions such asgastrointestinal bleeding.17

Hyponatremia has been reported in rarecases.18

Serotonin syndrome is serious.15,19Resulting from hyperstimulation of serotoninreceptors, it is characterized by nausea, diar-rhea, restlessness, extreme agitation, hyper-reflexia, autonomic instability, myoclonus,hyperthermia, rigidity, delirium, seizure, andstatus epilepticus. In severe cases, it canresult in cardiovascular collapse, coma, anddeath.

This syndrome can occur when amonoamine oxidase inhibitor is given with aserotonin reuptake inhibitor, pentazocine, or

L-tryptophan. Therefore, it is mandatory towait at least 2 weeks after stopping a serotoninreuptake inhibitor before starting a mono-amine oxidase inhibitor, and at least 5 weeks if

switching from fluoxetine, in view of thisdrugs long half-life.Discontinuation syndrome can occur if a

serotonin reuptake inhibitor with a short half-life such as paroxetine or fluvoxamine isabruptly stopped.14,15,20 Patients may experi-ence dizziness, nausea, weakness, insomnia,anxiety, irritability, and headache. Thesesymptoms tend to be transient and resolvespontaneously within a week. Slowly taperingserotonin reuptake inhibitors over a couple ofweeks can help prevent this syndrome.

Fluoxetine is less likely to cause this syndromebecause of its long half-life. Indeed, fluoxetinehas been used to treat the discontinuationsyndrome caused by other serotonin reuptakeinhibitors.

VENLAFAXINE

Venlafaxine (Effexor) was first released in animmediate-release form. An extended-releaseform (Effexor XR) was approved by the FDAin 1997.

Venlafaxine inhibits serotonin and norepi-nephrine reuptake and is a weak inhibitor ofdopamine reuptake.8 It is not active at the mus-carinic, nicotinic, histaminergic, or adrenergicreceptors.

The most common side effects are nausea,dizziness, insomnia, somnolence, and drymouth. Gastrointestinal side effects are lesscommon with the XR preparation.

Sexual dysfunction can occur, as withserotonin reuptake inhibitors.13

Discontinuation syndrome, with nau-

sea, somnolence, insomnia, and anxiety, canresult if venlafaxine is abruptly stopped.21

To prevent this syndrome, venlafaxine XRshould be tapered over several days toweeks.

Hypertension can occur with venlafaxineXR,22 especially in higher doses. Physiciansshould be cautious when prescribing this med-ication to patients with preexisting hyperten-sion. Blood pressure should be monitored reg-ularly, especially when using venlafaxine XRat doses of 225 mg or more per day.

Serotonin

reuptakeinhibitors

should be

tapered to

avoid the

discontinuation

syndrome



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MIRTAZAPINE

Mirtazapine (Remeron) is a presynaptic alpha2 adrenergic receptor antagonist and a potent

antagonist of serotonin 5-HT2 and 5-HT3receptors.8,23 It has very little effect on 5-HT1receptors. Therefore, mirtazapine directlyincreases norepinephrine release and, indi-rectly, serotonin release. It also blocks hista-mine receptors and has minimal affinity formuscarinic and alpha-1 adrenergic receptors.

Sedation is the most common side effect.Giving the medication at bedtime can mini-mize sedation. Nighttime sedation could be anadvantage in depressed patients with sleep dis-turbances, but on the other hand, undesirable

daytime sedation could occur.Weight gain. Mirtazapine can increaseappetite and carbohydrate craving.14 Thismay lead to significant weight gain if notmonitored closely. It may also increase choles-terol and triglyceride levels. Patients shouldbe educated and advised to monitor theirweight and to exercise regularly at the time ofprescribing this medication.

Liver function tests, especially alanineaminotransferase, can be mildly elevated.

Neutropenia has developed in rare cases

in patients treated with mirtazapine.15 Thishematologic condition is more likely to occurin patients with other risk factors for neu-tropenia.

Dizziness, dry mouth, constipation,increased appetite, and disturbing dreamshave also been reported.

Mirtazapine does not tend to cause sexualdysfunction.14

BUPROPION

Bupropion (Wellbutrin) is a unique antide-pressant that has few sexual side effects andtends not to cause an increase in appetite orweight gain.2,13,14 Besides depression, it is usedin smoking cessation.

Bupropion is thought to work by inhibit-ing norepinephrine reuptake and dopamineneurotransmission. It also has an activemetabolite that mediates antidepressant effi-cacy by blocking reuptake of norepinephrineand dopamine.8

Insomnia, headache, tremors, and nau-

sea are common side effects of bupropion.Increased irritability and agitation may alsooccur.

Seizures. The extended-release formula-

tion carries a seizure risk of about 0.4% at adose of 400 mg per day. Physicians shouldavoid prescribing this medication to patientswith a history of seizure, epileptiform dis-charges on electroencephalography, heavyalcohol use, or eating disorders; or with ben-zodiazepine withdrawal, head trauma, ororganic brain syndrome.

Bupropion does not cause orthostatichypotension, daytime drowsiness, or anti-cholinergic side effects.

Caution should be used in patients with

renal or liver diseases because these condi-tions could result in elevated plasma levels ofbupropion.

DULOXETINE

Duloxetine (Cymbalta), the newest approvedantidepressant, is an inhibitor of serotoninand norepinephrine reuptake and a lesspotent inhibitor of dopamine reuptake.24 Ithas no significant affinity for adrenergic,cholinergic, or histaminergic receptors.

The most common side effects reported inplacebo-controlled clinical trials were nausea,dry mouth, constipation, fatigue, decreasedappetite, and sweating.24 The overall dropoutrate due to side effects was 10%, with nauseaas the most common adverse event.

Sexual dysfunction was more commonwith duloxetine than with placebo.25

However, the rate appears to be less than withserotonin reuptake inhibitors.

Initial insomnia, irritability, anxiety,nervousness, and restlessness were also

reported.Duloxetine was associated with anincreased risk ofmydriasis and should be usedwith caution in controlled narrow-angle glau-coma.

Treatment with duloxetine was associatedwith increased blood pressure. Therefore,one should measure blood pressure beforestarting duloxetine and periodically monitorit throughout treatment.26

Duloxetine should not be used in combi-nation with monoamine oxidase inhibitors

Nighttime

sedationmay be

desirable in

depressed

patients with

sleep

disturbances


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and can be used only at least 14 days afterstopping one of these drugs.

If duloxetine is stopped, it should betapered gradually to avoid discontinuation

side effects.

TRICYCLIC AND TETRACYCLICANTIDEPRESSANTS

Tricyclic antidepressants were introducedshortly after monoamine oxidase inhibitors.They were the drugs of choice for depressionin the 1980s, but they are not as widely usednow because less toxic and more selectivemedications are available.

These medications block reuptake of nor-

epinephrine and serotonin. They are also com-petitive antagonists at the muscarinic, hista-minergic, and alpha 1 and 2 adrenergic recep-tors, which results in their characteristic sideeffect profile.8 Amitriptyline, imipramine, anddoxepin have the most anticholinergic activi-ty, whereas nortriptyline and desipramine areless anticholinergic.6,15

Anticholinergic side effects include drymouth, constipation, urinary retention,blurred vision, confusion, and delirium.

Narrow-angle glaucoma can be aggravated.

Cardiac effects. Tricyclic antidepressantsmay slow cardiac conduction, causing intra-ventricular conduction delay, atrioventricularblock, flattened T waves, depressed ST seg-ments, and prolonged QT intervals.27 All tri-cyclic antidepressants can cause tachycardia,which is one of the most common reasons forstopping them. Nortriptyline is the least likelyto cause orthostatic hypotension.

Because of cardiotoxicity, an overdose ofas little as 1 weeks worth of medication can befatal.

Sedation is the most common side effect oftricyclic antidepressants and is a result of anti-cholinergic and antihistaminergic effects.28

Doxepin has the highest antihistaminergicactivity among tricyclic antidepressants.

Weight gain and sexual side effects arealso common.14

A discontinuation syndrome28 is mostlyrelated to cholinergic and serotonergicrebound. After prolonged treatment, tricyclicantidepressants should be tapered graduallyover several weeks.

Drug interactions are significant.Serotonin reuptake inhibitors may raise theplasma levels of tricyclic antidepressants.There is a possibility that phenytoin levels

increase with tricyclic coadministration.Valproic acid can increase levels of tricyclics,and carbamazepine may decrease them.

MONOAMINE OXIDASE INHIBITORS

Monoamine oxidase inhibitors are very effec-tive antidepressants, but dietary restrictions andthe risk of hypertensive crises limit their use.

These drugs irreversibly inactivate theenzyme monoamine oxidase in the centralnervous system, platelets, liver, and gastroin-

testinal tract, the last of which may cause anincrease in tyramine absorption.Monoamine oxidase inhibitors were discov-

ered in the early 1950s. The first drug of thisclass was iproniazid, but serious side effects, par-ticularly hypertensive crisis and hepatic necro-sis, prevented its use.15,29 Currently available arephenelzine (Nardil), isocarboxazid (Marplan),tranylcypromine (Parnate), and selegiline(Eldepryl). Reversible monoamine oxidaseinhibitors require few dietary restrictions but arenot available in the United States; these include

moclobemide (Manerix) and befloxatone.Orthostatic hypotension, the most fre-quent side effect, is secondary to alpha-1 adren-ergic blockade. The exact mechanism is notknown but likely involves elevated norepineph-rine at presynaptic alpha-2 receptors. Dizzinessand reflex tachycardia may also occur.

Antihistaminergic activity might lead toweight gain and sedation.

Hypertensive crises are usually inducedby consuming food rich in tyramine or bymedications with sympathomimetic activity.

Headache, stiff neck, sweating, nausea, andvomiting characterize the prodromal phase.This could be followed by autonomic instabil-ity, elevated blood pressure, cardiac arrhyth-mia, coma, and death.

Sexual dysfunction, hepatotoxicity, andpyridoxine deficiency have been reported.

Drug interactions are numerous, includ-ing problems with over-the-counter medica-tions such as pseudoephedrine. Serotonin syn-drome can occur when monoamine oxidaseinhibitors are combined with serotonin reup-

Renal or liver

diseases canelevate

bupropion

levels



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take inhibitors, tricyclic antidepressants, orcarbamazapine. Coadministration with opi-oids, especially meperidine, may lead to auto-nomic instability, delirium, and death.

Caution should be taken when usingmonoamine oxidase inhibitors with antihy-pertensive agents, due to an increased likeli-hood of hypotension.

TRAZODONE

Trazodone is effective in treating depression,but it is not often used for this indicationbecause other antidepressants with a morebenign side effect profile are available.

Trazodone is a weak inhibitor of serotonin

reuptake and a potent antagonist of serotonin5-HT2A and 5-HT2C receptors.8 The sideeffects of trazodone are mostly attributed toantihistaminic and alpha-1 adrenergic block-ade.

Sedation. Trazodone has been often usedfor treating insomnia because it has sedativequalities. However, in a recent review,Mendelson30 found that data are lacking tosupport its use in this way.

Trazodone can cause significant orthosta-tic hypotension, dizziness, and headache. In

rare cases, it can cause priapism in theabsence of sexual stimuli. This serious sideeffect usually occurs during the first 4 weeks oftreatment, and it is not dose-dependent.

ANTIDEPRESSANTS AND SUICIDE RISK

The relationship between antidepressants,especially serotonin reuptake inhibitors, andsuicidal ideation and behavior has receivedconsiderable public attention lately. The useof these drugs in children and adolescents has

been of particular concern.31In October 2004, the FDA issued awarning about the increased risk of suicidalthoughts and behavior in children and ado-lescents being treated with antidepressantmedications. The agency has asked phar-maceutical manufacturers to add a blackbox warning statement to the label for allantidepressant medications to describe therisk and emphasize the need for close mon-itoring of patients started on these medica-tions.

The risk was identified in a combinedanalysis of short-term (lasting up to 4 months),placebo-controlled trials of the serotonin reup-take inhibitors fluoxetine, citalopram, paroxe-

tine, fluvoxamine, and sertraline, as well asbupropion, nefazodone, mirtazapine, and ven-lafaxine XR, in children and adolescents withmajor depressive disorder and other psychiatricdisorders.32 The analysis showed a twofoldgreater risk of suicidal thoughts and behaviorduring the first few months of treatment inthose receiving antidepressantsan average of4%compared with the rate with placebo.

Of note: although this analysis suggeststhat the incidence of suicide may be higher inpatients taking serotonin reuptake inhibitors,

no definitive link has been made. There wereno reported cases of suicide in these studies.32

If there is an increased risk of suicide, apossible explanation is that serotonin reup-take inhibitors and some other antidepres-sants can cause anxiety, agitation, and activa-tion, particularly at the start of treatment. Insomeone with lowered mood, new aversivesymptoms might further worsen mood andincrease the risk of suicide.33

The FDA recognizes that depression andother psychiatric disorders can have signifi-

cant consequences if not appropriately treat-ed. The new warning does not prohibit theuse of antidepressants, but it warns of the riskof suicidal thoughts and behavior and encour-ages clinicians to balance this risk with clini-cal need and to closely monitor patients, espe-cially at the start of treatment. This issueremains a concern and a topic of continuingscientific debate.

Suicide is a significant public health prob-lem. Each year there are approximately 30,000suicides in the United States and 1 million

worldwide.34,35 Suicide is the eighth leadingcause of death in the United States, and majordepression is a factor in about 50% of suicides.36

The suicide rate has actually been declin-ing over the last 10 to 15 years, coincidingwith the introduction of serotonin reuptakeinhibitors and increases in antidepressant pre-scriptions.3739 Furthermore, most of thosewho commit suicide and carry the diagnosis ofmajor depressive disorder at the time of deathare either untreated or receiving subtherapeu-tic doses of antidepressants,37,39 indicating the

Tricyclic

antidepressantscan cause

tachycardia


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REFERENCES1. Lin EH, Von Korff M, Katon W, et al. The role of the primary care physician

in patients adherence to antidepressant therapy. Med Care 1995;

33:6774.

2. Zajecka JM. Clinical issues in long term treatment with antidepressants. J

Clin Psychiatry 2000; 61(suppl l2):2025.

3. Cohen JB, Wilcox C. Comparison of fluoxetine, imipramine and placebo in

patients with major depressive disorder. J Clin Psychiatry 1985; 46:2631.

4. Dunbar G, Cohen JB, Fabre LF, et al. A comparison of paroxetine,

imipramine and placebo in depressed outpatients. Br J Psychiatry 1991;

159:394398.

5. American Psychiatric Association. Practice guidelines for the treatment of

patients with major depression disorder (Revision). Am J Psychiatry 2000;

157(suppl 4):145.

6. Richelson E. Pharmacology of antidepressants. Mayo Clin Proc 2001;

76:511527.

7. Richelson E. Interaction of antidepressants with neurotransmitter trans-

porters and receptors and their clinical relevance. J Clin Psychiatry 2003;

64(suppl 13):513.

8. Stahl SM. Essential Psychopharmacology. Neuroscientific Basis and Practical

Application. New York, NY: Cambridge University Press. Second edition;

2000.

9. Stahl SM. Basic psychopharmacology of antidepressants, pt 1: antidepres-

sants have seven distinct mechanisms of action. J Clin Psychiatry 1998;

59(suppl):514.

10. Nierenberg AA. The medical consequences of selection of an antidepres-sant. J Clin Psychiatry 1992; 9(suppl):1924.

11. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human

monoamine transporter binding profile of escitalopram and Rfluoxetine.

Biol Psychiatry 2001; 50:345350.

12. Stahl SM, Grady MM. Differences in mechanism of action between cur-

rent and future antidepressants. J Clin Psychiatry 2003; 64(suppl 13):1317.

13. Clayton AH, Pradko AF, Croft HA, et al. Prevalence of sexual dysfunction

among newer antidepressants. J Clin Psychiatry 2002; 63:357366.

14. Masand PS, Gupta S. Long-term side effects of newer-generation antide-

pressants: SSRIs, venlafaxine, nefazodone, bupropion, and mirtazapine.

Ann Clin Psychiatry 2002; 14:175182.

15. Kaplan and Sadocks Synopsis of Psychiatry Behavioral Sciences/Clinical

Psychiatry. Philadelphia, PA. Lippincott Williams and Wilkins. 9th edition;

2003:534590.


need for better recognition and adequatetreatment of patients at risk.

It is important to educate patients abouttheir illness and available treatment options.

They should be informed about the currentcontroversy regarding the use of serotoninreuptake inhibitors as a part of the process ofobtaining informed consent. They need to beinstructed to watch for any signs of activation,agitation, or suicidal ideation, and inform theprescribing physician immediately.

It is also reasonable to schedule more fre-quent follow-up visits at the beginning oftreatment to monitor more closely for emer-gence of these side effects. Patients at higherrisk for suicide may be given limited amounts

of the medication, just enough until the nextfollow-up visit. Any reports of suicidalideation need to be taken seriously, and hospi-talization should be considered.

Patients need to be referred for psychiatricconsultation if one or more antidepressants failor produce only a partial response, or if theyhave major depression with psychotic features.

ANTIDEPRESSANTS IN THE ELDERLY

Medication dosages need to be altered in older

age because of physiological changes. Aging andconcomitant medical problems affect the phar-macodynamics and pharmacokinetics of med-ications. In addition, many elderly patients use anumber of medications, and caution should begiven to potential drug interactions.40

No important differences in efficacy havebeen found between classes of antidepressants

in the elderly. The choice of antidepressant inthe elderly should be based on its side effectprofile and drug interactions.41

Serotonin reuptake inhibitors appear to

be safer and better tolerated than tricyclicantidepressants. Common side effects of sero-tonin reuptake inhibitors in the elderly arenausea, insomnia, and sedation. Citalopramand sertraline have the fewest, if any, druginteractions. Paroxetine can cause more seda-tion and anticholinergic side effects.

Tricyclic antidepressants should be start-ed with very low doses. Alpha-1 adrenergicblockade leads to orthostatic hypotension,which can cause dizziness and falls in theelderly. Histaminic effects can cause sedation

and weight gain. Blood levels of tricyclic anti-depressants should be monitored, as shouldtheir electroencephalographic, blood pressure,and cardiac effects.

Mirtazapine may be a useful alternative totricyclic antidepressants in the elderly because itpromotes sleep and causes minimal orthostasis.

IMPORTANCE OF PATIENT EDUCATION

Education and reassurance of patients about sideeffects will enhance compliance and improve

treatment outcome. Providing patients withcontact information might decrease their anxi-ety and help in reporting any adverse event. It isalso very helpful to provide patients with litera-ture explaining the potential side effects.Patients should be encouraged to contact theirprovider about any troublesome side effect thatdoes not resolve.


The risk of

suicide duringantidepressant

therapy

remains a topic

of debate


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16. Rosenstein DL, Nelson JC, Jacobs SC. Seizures associated with antidepres-

sants. J Clin Psychiatry 1993; 54:289299.

17. Dalton SO, Johansen C, Mellemkjar L, et al. Use of selective serotonin

reuptake inhibitors and risk of upper gastrointestinal tract bleeding. Arch

Intern Med 2003; 163:5964.

18. Bourgeois JA, Barbine SE, Bahadur N. A case of SIADH and hyponatremia

associated with citalopram. Psychosomatics 2002; 43:241242.19. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 148:705713.

20. Zajecka J, Tracy KA, Mitchell S. Discontinuation symptoms after treatment

with serotonin reuptake inhibitors: a literature review. J Clin Psychiatry

1997; 58:291297.

21. Fava M, Mulroy R, Alpert J, et al. Emergence of adverse events following

discontinuation of treatment with extended release venlafaxine. Am J

Psychiatry 1997; 154:17601762.

22. Effexor XR (package insert). Collegeville, PA: Wyeth Pharmaceuticals; 2004.

23. Stimmel GL, Dolheide JA, Stahl SM. Mirtazapine: an antidepressant with

noradrenergic and specific serotonergic effects. Pharmacotherapy 1997;

17:1021.

24. Schatzberg AF. Efficacy and tolerability of duloxetine, a novel dual reup-

take inhibitor, in the treatment of major depression disorder. J Clin

Psychiatry 2003; 64(suppl 13):1037.

25. Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. Duloxetine in the treat-

ment of major depressive disorder: double blind clinical trial. J ClinPsychiatry 2002; 63:225231.

26. Cymbalta (package insert). Indianapolis, Ind: Elli Lilly and Company; 2004.

27. Roose SP, Glassman AH. Cardiovascular effects of tricyclic antidepressants

in depressed patients with and without heart disease. J Clin Psychiatry

1989; 7:118.

28. Zajecka JM, Tummala R. Tricyclics: still solid performers for the savvy psychi-

atrist. Curr Psychiatry 2002; 1(6):3139.

29. Janicak PG, Davis JM, Preskorn SH, Ayd FJ. Principles and Practice of

Psychopharmacology. Baltimore, Maryland. Lippincott Williams and

Wilkins. Second edition; 1997.

30. Mendelson WB. A review of the evidence for the efficacy and safety of

trazodone in insomnia. J Clin Psychiatry 2005; 66:469476.

31. Jick H, Kaye J, Jick S. Antidepressants and the risk of suicidal behaviors.

JAMA 2004; 292:338343.

32. US Food and Drug Administration Public Health Advisory. Suicidality in

children and adolescents being treated with antidepressant medications.www.fda.gov/cder/drug/antidepressants/

SSRIPHA200410.htm

33. Wesseley S, Kerwin R. Suicide risk and SSRIs. JAMA 2004; 292:379381.

34. Sadock BJ, Sadock VA. Kaplan & Sadocks Synopsis of Psychiatry. 9th ed.

Philadelphia: Lippincott Williams and Wilkins; 2003:913.

35. Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE. Reducing suicide: A

national imperative. Washington, DC: National Academies Press;

2002:1516.

36. Perlis RH, Stern TA. Suicide. In: Stern TA, Herman JB. Psychiatry Update

and Board Preparation. McGraw Hill; 2000:409.

37. Grunebaum MF, Ellis SP, Li S, Oquendo MA, Mann JJ. Antidepressants and

suicide risk in the United States, 19851999. J Clin Psychiatry 2004;

65:14561462.

38. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between anti-

depressant medication use and rate of suicide. Arch Gen Psychiatry 2005;

62:165172.39. Hampton T. Suicide caution stamped on antidepressants. JAMA 2004;

291:20602061.

40. Baldwin R, Wild R. Management of depression in later life. Adv Psych

Treatment 2004; 10:131139.

41. Dunner D. Treatment considerations for depression in the elderly. CNS

Spectrum 2003; 8:1419.

ADDRESS: Donald Malone, Jr., MD, Department of Psychiatry andPsychology, P57, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH44195; e-mail [email protected].


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