1 Chapter 12: Antidepressants. 2 Introduction Worldwide, depression is a major cause of disability...

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Chapter 12:Chapter 12:AntidepressantsAntidepressants

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IntroductionIntroduction

• Worldwide, depression is a major cause of Worldwide, depression is a major cause of disability and premature deathdisability and premature death

• Depression is the most common of the affective Depression is the most common of the affective disorders (defined as disorders of mood rather disorders (defined as disorders of mood rather than disturbances of thought or cognition)than disturbances of thought or cognition)

• In addition to the significant suicide risk, In addition to the significant suicide risk, depressed individuals are more likely to die from depressed individuals are more likely to die from other causes, such as heart disease or cancerother causes, such as heart disease or cancer

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• Depressive symptoms also can occur secondary Depressive symptoms also can occur secondary to other illnesses such as hypothyroidism, to other illnesses such as hypothyroidism, Parkinson's disease, and inflammatory conditionsParkinson's disease, and inflammatory conditions

• For a diagnosis of major depressive disorder to be For a diagnosis of major depressive disorder to be made, symptoms must be present for at least 2 made, symptoms must be present for at least 2 weeks and must not be precipitated or influenced weeks and must not be precipitated or influenced by a medical illness or medicationby a medical illness or medication

• Depression, in general, is classified as major Depression, in general, is classified as major depression (i.e., unipolar depression) or bipolar depression (i.e., unipolar depression) or bipolar depression (i.e., manic depressive illness)depression (i.e., manic depressive illness)

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• Individuals must possess at least five symptoms, Individuals must possess at least five symptoms, one of which is either depressed mood OR one of which is either depressed mood OR diminished interest or pleasure in activitiesdiminished interest or pleasure in activitiesa)a) Change in appetiteChange in appetiteb)b) Change in sleepChange in sleepc)c) Low energy and decreased libidoLow energy and decreased libidod)d) Poor concentration (or difficulty making Poor concentration (or difficulty making

decisions)decisions)e)e) Feelings of worthlessness or inappropriate Feelings of worthlessness or inappropriate

guiltguiltf)f) Psychomotor agitation or retardationPsychomotor agitation or retardationg)g) Recurrent thoughts of suicideRecurrent thoughts of suicide

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I.I. The neurotrophic hypothesisThe neurotrophic hypothesis

II.II. The monoamine hypothesisThe monoamine hypothesis

Pathophysiology of Major DepressionPathophysiology of Major Depression

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Neurotrophic HypothesisNeurotrophic Hypothesis

• Depression appears to be associated with a drop Depression appears to be associated with a drop in brain-derived neurotrophic factor (BDNF) levels in brain-derived neurotrophic factor (BDNF) levels in the cerebrospinal fluid and serum as well as in the cerebrospinal fluid and serum as well as with a decrease in tyrosine kinase receptor B with a decrease in tyrosine kinase receptor B activityactivity

• BDNF is thought to exert its influence on neuronal BDNF is thought to exert its influence on neuronal survival and growth effects by activating the survival and growth effects by activating the tyrosine kinase receptor B in both neurons and tyrosine kinase receptor B in both neurons and gliaglia

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Neurotrophic HypothesisNeurotrophic Hypothesis

• Animal and human studies indicate that stress Animal and human studies indicate that stress and pain are associated with a drop in BDNF and pain are associated with a drop in BDNF levels and that this loss of neurotrophic support levels and that this loss of neurotrophic support contributes to atrophic structural changes in the contributes to atrophic structural changes in the hippocampus and perhaps other areas such as hippocampus and perhaps other areas such as the medial frontal cortex and anterior cingulatethe medial frontal cortex and anterior cingulate

• Studies suggest that major depression is Studies suggest that major depression is associated with substantial loss of volume in the associated with substantial loss of volume in the hippocampus, anterior cingulate and medial hippocampus, anterior cingulate and medial orbital frontal cortexorbital frontal cortex

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Monoamine hypothesis of depressionMonoamine hypothesis of depression

• The monoamine hypothesis grew originally out of The monoamine hypothesis grew originally out of associations between the clinical effects of associations between the clinical effects of various drugs that cause or alleviate symptoms of various drugs that cause or alleviate symptoms of depression and their known neurochemical effects depression and their known neurochemical effects on monoaminergic transmission in the brainon monoaminergic transmission in the brain

• The monoamine hypothesis of depression The monoamine hypothesis of depression suggests that depression is related to a deficiency suggests that depression is related to a deficiency in the amount or function of cortical and limbic in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and serotonin (5-HT), norepinephrine (NE), and dopamine (DA)dopamine (DA)

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Monoamine hypothesis of depressionMonoamine hypothesis of depression

• The chronic activation of monoamine receptors by The chronic activation of monoamine receptors by antidepressants appears to increase in BDNF antidepressants appears to increase in BDNF transcriptiontranscription

• One of the weaknesses of the monoamine One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase hypothesis is the fact that amine levels increase immediately with antidepressant use, but immediately with antidepressant use, but maximum beneficial effects of antidepressants are maximum beneficial effects of antidepressants are not seen for many weeksnot seen for many weeks

• The time required to synthesize neurotrophic The time required to synthesize neurotrophic factors has been proposed as an explanation for factors has been proposed as an explanation for this delay of antidepressant effectsthis delay of antidepressant effects

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AntidpressentsAntidpressents

• Most antidepressants exert important actions on Most antidepressants exert important actions on the metabolism of monoamine neurotransmitters the metabolism of monoamine neurotransmitters and their receptors, particularly norepinephrine and their receptors, particularly norepinephrine and serotoninand serotonin

• The pharmacologic effects of any of the The pharmacologic effects of any of the antidepressant drugs on neurotransmission occur antidepressant drugs on neurotransmission occur immediately, whereas the time course for a immediately, whereas the time course for a therapeutic response occurs over several weekstherapeutic response occurs over several weeks

• It takes at least 2 weeks to produce significant It takes at least 2 weeks to produce significant improvement in mood "therapeutic lag", and improvement in mood "therapeutic lag", and maximum benefit may require up to 12 weeks or maximum benefit may require up to 12 weeks or moremore

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AntidpressentsAntidpressents

• In monoamine systems, reuptake of the In monoamine systems, reuptake of the transmitter is the main mechanism by which transmitter is the main mechanism by which neurotransmission is terminated; thus, inhibition of neurotransmission is terminated; thus, inhibition of reuptake can enhance neuro-transmission, reuptake can enhance neuro-transmission, presumably by slowing clearance of the presumably by slowing clearance of the transmitter from the synapse and prolonging the transmitter from the synapse and prolonging the dwell-time of the transmitter in the synapsedwell-time of the transmitter in the synapse

• Monoamine oxidase inhibitors (MAOIs) enhances Monoamine oxidase inhibitors (MAOIs) enhances monoaminergic neurotransmission by inhibiting monoaminergic neurotransmission by inhibiting monoamine metabolism and thereby enhancing monoamine metabolism and thereby enhancing neurotransmitter storage in secretory granulesneurotransmitter storage in secretory granules

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Drug Selection: General ConsiderationsDrug Selection: General Considerations

• VVarious types of antidepressantsarious types of antidepressants are available: are available:

1.1. Selective Serotonin Reuptake Inhibitors Selective Serotonin Reuptake Inhibitors

(SSRIs)(SSRIs)

2.2. Serotonin norepinephrine reuptake inhibitors Serotonin norepinephrine reuptake inhibitors

(SNRIs)(SNRIs)

3.3. Monoamine oxidase inhibitors (MAOIs)Monoamine oxidase inhibitors (MAOIs)

4.4. 5-HT5-HT22 Antagonists Antagonists

5.5. BupropionBupropion

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Selective Serotonin Reuptake Inhibitors Selective Serotonin Reuptake Inhibitors (SSRIs)(SSRIs)

• They are the most commonly prescribed group of They are the most commonly prescribed group of antidepressantsantidepressants

• TheyThey specifically inhibit serotonin reuptake, having specifically inhibit serotonin reuptake, having 300- to 3000-fold greater selectivity for the 300- to 3000-fold greater selectivity for the serotonin transporter as compared to the serotonin transporter as compared to the norepinephrine transporternorepinephrine transporter

• Agents: Fluoxetine (Prozac®), paroxetine, Agents: Fluoxetine (Prozac®), paroxetine, sertraline, fluvoxamine, Citalopram, & sertraline, fluvoxamine, Citalopram, & Escitalopram (s-citalopram)Escitalopram (s-citalopram)

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Selective Serotonin Reuptake Inhibitors Selective Serotonin Reuptake Inhibitors (SSRIs)(SSRIs)

• As a class, these medications have little or no As a class, these medications have little or no affinity for cholinergic, affinity for cholinergic, ββ-adrenergic or histamine -adrenergic or histamine receptors and do not interfere with cardiac receptors and do not interfere with cardiac conductionconduction

• They are well tolerated by patients who are They are well tolerated by patients who are especially sensitive to the anticholinergic and especially sensitive to the anticholinergic and orthostatic effects of the TCAs and MAOIsorthostatic effects of the TCAs and MAOIs

• SSRI SSRI have largely replaced TCAs and MAOIs as have largely replaced TCAs and MAOIs as the drugs of choice in treating depressionthe drugs of choice in treating depression

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SSRIs-SSRIs- Mechanism of actionMechanism of action

• SSRIs allosterically inhibit the serotonin transporter SSRIs allosterically inhibit the serotonin transporter (SERT) by binding the receptor at a site other than (SERT) by binding the receptor at a site other than active binding site for serotoninactive binding site for serotonin

• In the serotonin system, In the serotonin system, 5-HT5-HT1A1A and 5-HT and 5-HT77

autoreceptors on cell bodies in the raphe nucleus and autoreceptors on cell bodies in the raphe nucleus and of 5-HTof 5-HT1D1D autoreceptors on serotonergic terminals autoreceptors on serotonergic terminals

suppress neuronal release of serotonin and result in a suppress neuronal release of serotonin and result in a decrease in neuronal firingdecrease in neuronal firing

• Repeated treatment leads to gradual down-regulation Repeated treatment leads to gradual down-regulation and desensitization of autoreceptor mechanisms over and desensitization of autoreceptor mechanisms over several weeks, with a return or increase of presynaptic several weeks, with a return or increase of presynaptic activity, production, and release of serotonin activity, production, and release of serotonin

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SSRIsSSRIs

• Stimulation of 5-HTStimulation of 5-HT33 receptors is suspected to receptors is suspected to

contribute to common ADRs, including GIT (contribute to common ADRs, including GIT (NVNV) ) and sexual effects (delayed or impaired orgasm)and sexual effects (delayed or impaired orgasm)

• Stimulation of 5-HTStimulation of 5-HT2C2C receptors may contribute to receptors may contribute to

the agitation or restlessness sometimes induced the agitation or restlessness sometimes induced by serotonin reuptake inhibitorsby serotonin reuptake inhibitors

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SSSRIs- SRIs- Clinical usesClinical uses

1. Major Depression: the primary indication Obsessive-compulsive disorder (OCD) (fluvoxamine, clomipramine)

2. Panic disorder3. Generalized anxiety disorder4. Posttraumatic stress disorder (Sertraline and

paroxetine)5. Social anxiety disorder (SAD): fluvoxamine,

venlafaxine6. Premenstrual dysphoric disorder (fluxetine &

sertraline)7. Bulimia nervosa (only fluoxetine)8. Premature ejaculation

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SSRIs- SSRIs- ADEsADEs

1)1) GIT:GIT: nausea, GIT upset, diarrhea. nausea, GIT upset, diarrhea.

2)2) Sexual dysfunction:Sexual dysfunction: loss of libido, delayed loss of libido, delayed orgasm, or diminished arousal. orgasm, or diminished arousal.

3)3) CNS: Sleep disturbances. For this reason, CNS: Sleep disturbances. For this reason, fluoxetine is usually administered in the morning fluoxetine is usually administered in the morning after breakfast after breakfast

4)4) Weight gain particularly paroxetineWeight gain particularly paroxetine5)5) SSRIs have also been associated with SSRIs have also been associated with

extrapyramidal side effects, especially those with extrapyramidal side effects, especially those with Parkinson’s diseaseParkinson’s disease

6)6) There is an association of paroxetine with cardiac There is an association of paroxetine with cardiac septal defects in first trimester exposuresseptal defects in first trimester exposures

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SSRIs- SSRIs- D/D interactionsD/D interactions

A.A. Pharmacokinetic interactions:Pharmacokinetic interactions:

• The SSRIs are potent inhibitors of the The SSRIs are potent inhibitors of the CYCYP450 P450

• The potential for drug-drug interactions differs The potential for drug-drug interactions differs significantly across the SSRIssignificantly across the SSRIs

• Paroxetine and fluoxetine are potent CYP2D6 Paroxetine and fluoxetine are potent CYP2D6 inhibitors responsible for the elimination of inhibitors responsible for the elimination of TCA TCA drugs, neuroleptic drugs, and some drugs, neuroleptic drugs, and some antiarrhythmic and antiarrhythmic and ββ-adrenergic antagonist drugs-adrenergic antagonist drugs

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A.A. Pharmacokinetic interactions:Pharmacokinetic interactions:

• Fluvoxamine, a CYP3A4 inhibitor, may elevate Fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered the levels of concurrently administered substrates for this enzyme such as diltiazem and substrates for this enzyme such as diltiazem and induce bradycardia or hypotensioninduce bradycardia or hypotension

• Citalopram and escitalopram have the least Citalopram and escitalopram have the least effect on the cytochrome P450 system & have effect on the cytochrome P450 system & have the most favorable profile regarding D–D the most favorable profile regarding D–D interactionsinteractions

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B.B. Pharmacodynamic interactions:Pharmacodynamic interactions:

• The most serious interaction with the SSRIs are The most serious interaction with the SSRIs are with MAOIs that produce a with MAOIs that produce a serotonin syndromeserotonin syndrome

• Fluoxetine* has to be discontinued 4 to 6 weeks Fluoxetine* has to be discontinued 4 to 6 weeks before an MAOI can be administered to mitigate before an MAOI can be administered to mitigate the risk of serotonin syndromethe risk of serotonin syndrome

* Fluoxetine is metabolized to an active product, norfluoxetine. The elimination half-life of norfluoxetine is * Fluoxetine is metabolized to an active product, norfluoxetine. The elimination half-life of norfluoxetine is about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIsabout three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs

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Serotonin-Norepinephrine Reuptake Serotonin-Norepinephrine Reuptake InhibitorsInhibitors

• Two classes of antidepressants act as combined Two classes of antidepressants act as combined serotonin and norepinephrine reuptake inhibitors: serotonin and norepinephrine reuptake inhibitors:

a)a) Selective serotonin-norepinephrine reuptake Selective serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibitors (SNRIs)

b)b) Tricyclic antidepressants (TCAs)Tricyclic antidepressants (TCAs)

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a) Selective Serotonin-Norepinephrine Reuptake a) Selective Serotonin-Norepinephrine Reuptake InhibitorsInhibitors

• Agents:Agents: venlafaxine, desvenlafaxine, and venlafaxine, desvenlafaxine, and duloxetine & milnacipran*duloxetine & milnacipran*

• All SNRIs bind the serotonin (SERT) and All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transportersnorepinephrine (NET) transporters

• At dosages <150 mg/day, venlafaxine is a potent venlafaxine is a potent inhibitor of serotonin reuptake and, at medium to inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of norepinephrine re-higher doses, is an inhibitor of norepinephrine re-uptakeuptake

• Duloxetine inhibits serotonin and norepinephrine Duloxetine inhibits serotonin and norepinephrine reuptake at all dosesreuptake at all doses

*Milnacipran is not used to treat depression. It is approved for the treatment of fibromyalgia*Milnacipran is not used to treat depression. It is approved for the treatment of fibromyalgia

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a) Selective Serotonin-Norepinephrine Reuptake a) Selective Serotonin-Norepinephrine Reuptake InhibitorsInhibitors

• Unlike the TCAs, the SNRIs have little activity at Unlike the TCAs, the SNRIs have little activity at adrenergic, muscarinic, or histamine receptors adrenergic, muscarinic, or histamine receptors and, thus, have fewer of these receptor-mediated and, thus, have fewer of these receptor-mediated adverse effects than the adverse effects than the TCATCA

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SNRIs-SNRIs- Clinical usesClinical uses

1.1. DepressionDepression:: in patients in whom SSRIs are in patients in whom SSRIs are ineffectiveineffective

2.2. chronic joint and muscle pain: chronic joint and muscle pain: duloxetineduloxetine3.3. Fibromyalgia: Fibromyalgia: milnacipranmilnacipran4.4. Urinary stress incontinence Urinary stress incontinence (duloxetine in (duloxetine in

Europe)Europe)

• Off-label uses include autism, binge eating disorders, Off-label uses include autism, binge eating disorders, hot flashes (desvenlafaxine), pain syndromes, hot flashes (desvenlafaxine), pain syndromes, premenstrual dysphoric disorders, and post-traumatic premenstrual dysphoric disorders, and post-traumatic stress disorders (venlafaxine)stress disorders (venlafaxine)

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I. SNRIs- ADRsI. SNRIs- ADRs

• SNRIs have many of the serotonergic adverse SNRIs have many of the serotonergic adverse effects associated with SSRIseffects associated with SSRIs

• In addition, SNRIs may also have noradrenergic In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, heart rate, and CNS activation, such as insomnia, anxiety, and agitationanxiety, and agitation

• All the SNRIs have been associated with a All the SNRIs have been associated with a discontinuation syndrome resembling that seen discontinuation syndrome resembling that seen with SSRI discontinuationwith SSRI discontinuation

• The SNRIs have relatively fewer CYP450 The SNRIs have relatively fewer CYP450 interactions than the SSRIsinteractions than the SSRIs

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II.Tricyclic Antidepressants (TCA)II.Tricyclic Antidepressants (TCA)

• The TCAs were the dominant class of The TCAs were the dominant class of antidepressants until the introduction of SSRIs in antidepressants until the introduction of SSRIs in the 1980s and 1990sthe 1980s and 1990s

• Agents: imipramine (the prototype drug), Agents: imipramine (the prototype drug), amitriptyline, clomipramine, doxepin , amitriptyline, clomipramine, doxepin , trimipramine, desipramine, nortriptyline,trimipramine, desipramine, nortriptyline, and and protriptylineprotriptyline

• Maprotiline & amoxapine are not members of the Maprotiline & amoxapine are not members of the tricyclic familytricyclic family. . However, their pharmacology is so However, their pharmacology is so similar to that of the TCAs and are commonly similar to that of the TCAs and are commonly included in the general class of TCAsincluded in the general class of TCAs

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• The TCAs activity is thought to relate primarily to The TCAs activity is thought to relate primarily to their inhibition of 5-HT and their inhibition of 5-HT and NENE reuptake reuptake

• Within the TCAs, there is considerable variability Within the TCAs, there is considerable variability in affinity for SERT versus NET:in affinity for SERT versus NET:o Clomipramine has relatively very little affinity for Clomipramine has relatively very little affinity for

NET but potently binds SERTNET but potently binds SERTo Desipramine (Imipramine’s metabolite) and Desipramine (Imipramine’s metabolite) and

nortriptyline, are relatively more selective for NETnortriptyline, are relatively more selective for NETo Imipramine has more serotonin effects initiallyImipramine has more serotonin effects initially

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• TCAs also block serotonergic, TCAs also block serotonergic, αα--adrenergic, adrenergic, histaminic, and muscarinic receptorshistaminic, and muscarinic receptors

• Actions at these receptors are probably Actions at these receptors are probably responsible for many of the untoward effects of responsible for many of the untoward effects of the TCAsthe TCAs

• TCAs such as doxepin are sometimes prescribed TCAs such as doxepin are sometimes prescribed as hypnotics and used in treatments for pruritus as hypnotics and used in treatments for pruritus because of their antihistamine propertiesbecause of their antihistamine properties

• Amoxapine also blocks the DAmoxapine also blocks the D22 receptor receptor

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II. TCA- II. TCA- Clinical usesClinical uses

1.1. Depression: that is unresponsive to more Depression: that is unresponsive to more commonly used antidepressants commonly used antidepressants ))SSRIs or SSRIs or SNRIs)SNRIs)

2.2. Panic disorder Panic disorder

3.3. Control bed-wetting in children (older than 6 Control bed-wetting in children (older than 6 years) by causing contraction of the internal years) by causing contraction of the internal sphincter of the bladder (Imipramine)sphincter of the bladder (Imipramine)11

4.4. Treatment of migraine headache and chronic Treatment of migraine headache and chronic pain syndromes for which the cause of the pain is pain syndromes for which the cause of the pain is unclearunclear (Amitriptyline)(Amitriptyline)

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II.TCA- II.TCA- ADRsADRs

1.1. Antimuscarinic SEs: Antimuscarinic SEs: dry mouth ,constipation, dry mouth ,constipation, urinary retention, blurred vision, and confusionurinary retention, blurred vision, and confusion

2.2. Life-threatening arrhythmias: The TCAs are Life-threatening arrhythmias: The TCAs are class 1A antiarrhythmic agentsclass 1A antiarrhythmic agents

3.3. SedationSedation (H(H11 antagonism) antagonism)

4.4. weight gainweight gain5.5. Sexual dysfunctionSexual dysfunction6.6. At therapeutic doses, the TCA drugs lower the At therapeutic doses, the TCA drugs lower the

seizure threshold and at toxic doses can cause seizure threshold and at toxic doses can cause life-threatening seizures (especially Maprotiline)life-threatening seizures (especially Maprotiline)

7.7. Amoxapine has dopamine receptor antagonist Amoxapine has dopamine receptor antagonist properties and can induce properties and can induce EPSEPS, gynecomastia, , gynecomastia, lactation, and neuroleptic malignant syndromelactation, and neuroleptic malignant syndrome

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TCAs overdosesTCAs overdoses

• Acute poisoning with tricyclic antidepressants Acute poisoning with tricyclic antidepressants or MAO inhibitors is potentially life-threateningor MAO inhibitors is potentially life-threatening

• Compared with TCAs and MAOIs, the other Compared with TCAs and MAOIs, the other antidepressants are generally much safer in antidepressants are generally much safer in overdoseoverdose

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TCA overdoseTCA overdose

• A 1500 mg dose of imipramine or amitriptyline A 1500 mg dose of imipramine or amitriptyline is enough to be lethal in many patientsis enough to be lethal in many patients

• Symptoms:Symptoms: ventricular tachycardia, fibrillation ventricular tachycardia, fibrillation and seizures are sometimes seenand seizures are sometimes seen

• Management: Management: cardiac monitoring, airway cardiac monitoring, airway support, and gastric lavage. Sodium support, and gastric lavage. Sodium bicarbonate is often administered to uncouple bicarbonate is often administered to uncouple the TCA from cardiac sodium channelsthe TCA from cardiac sodium channels

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TCA overdoseTCA overdose

• If a patient is severely depressed, potentially If a patient is severely depressed, potentially suicidal, impulsive, or has a history of suicidal, impulsive, or has a history of substance abuse, prescribing a relatively safe substance abuse, prescribing a relatively safe antidepressant agent with close clinical follow-antidepressant agent with close clinical follow-up is appropriateup is appropriate

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MAO inhibitorsMAO inhibitors

• Agents: selegline, phenelzine, and Agents: selegline, phenelzine, and tranylcyprominetranylcypromine

• MAO exists in the human body in two MAO exists in the human body in two molecular forms, known as type A and type Bmolecular forms, known as type A and type B

• Norepinephrine and serotonin are Norepinephrine and serotonin are preferentially metabolized by MAO-A. MAO-B preferentially metabolized by MAO-A. MAO-B is more likely to be involved in the catabolism is more likely to be involved in the catabolism of human brain dopamineof human brain dopamine

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• The MAO inhibitors inactivate the enzyme, The MAO inhibitors inactivate the enzyme, permitting neurotransmitter molecules to permitting neurotransmitter molecules to escape degradation and, therefore, to both escape degradation and, therefore, to both accumulate within the presynaptic neuron accumulate within the presynaptic neuron and leak into the synaptic spaceand leak into the synaptic space

• Selective MAO-A inhibitors are more Selective MAO-A inhibitors are more effective in treating major depression than effective in treating major depression than type B inhibitorstype B inhibitors

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• MAOIs are classified by their specificity for MAO-MAOIs are classified by their specificity for MAO-A or -B and whether their effects are reversible or A or -B and whether their effects are reversible or irreversibleirreversible

• Phenelzine and tranylcypromine are examples of Phenelzine and tranylcypromine are examples of irreversible, nonselective MAOIsirreversible, nonselective MAOIs

• Moclobemide is a reversible and selective inhibitor Moclobemide is a reversible and selective inhibitor of MAO-A of MAO-A

• Selegiline is an irreversible MAO-B–specific agent Selegiline is an irreversible MAO-B–specific agent at low doses, but at higher doses it becomes a at low doses, but at higher doses it becomes a nonselective MAOI similar to other agentsnonselective MAOI similar to other agents

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• Despite their efficacy in treating depression, Despite their efficacy in treating depression, because of their risk for drug-drug and drug-because of their risk for drug-drug and drug-food interactions, the MAO inhibitors are food interactions, the MAO inhibitors are considered to be last-line agents in many considered to be last-line agents in many treatment venuestreatment venues

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MAO Inhibitors-MAO Inhibitors-Clinical useClinical use

• Depression: Depression:

– Reserved for treatment of depressions that Reserved for treatment of depressions that resist therapeutic trials of the newer, safer resist therapeutic trials of the newer, safer antidepressantsantidepressants

– Selegiline is the first antidepressant available Selegiline is the first antidepressant available in a transdermal delivery systemin a transdermal delivery system

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MAO Inhibitors-MAO Inhibitors-ADRsADRs

• Orthostatic hypotension, weight gain, edema, and Orthostatic hypotension, weight gain, edema, and sexual dysfunction are common during MAOI sexual dysfunction are common during MAOI therapytherapy

• Sexual SEs: highest rates are associated with the Sexual SEs: highest rates are associated with the irreversible nonselective MAOIs (phenelzine and irreversible nonselective MAOIs (phenelzine and tranylcypromine) tranylcypromine)

• Phenelzine tends to be more sedating than either Phenelzine tends to be more sedating than either selegiline or tranylcypromineselegiline or tranylcypromine

• Hepatotoxicity is likely to occur with isocarboxazid Hepatotoxicity is likely to occur with isocarboxazid or phenelzineor phenelzine

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MAO Inhibitors-MAO Inhibitors-D-D interactionsD-D interactions

1)1) Pharmacodynamic interaction Pharmacodynamic interaction • These combinations of an MAOI with a These combinations of an MAOI with a

serotonergic agent (serotonergic agent (SSRIs, SNRIs, and most SSRIs, SNRIs, and most TCAs) TCAs) may result in a life-threatening may result in a life-threatening serotonin serotonin syndromesyndrome

• Most case reports of serotonin syndrome (and Most case reports of serotonin syndrome (and most fatalities) have occurred with a combination most fatalities) have occurred with a combination of an MAOI and an SSRIof an MAOI and an SSRI

• It is caused by overstimulation of 5-HT receptors It is caused by overstimulation of 5-HT receptors in the central gray nuclei and the medullain the central gray nuclei and the medulla

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1)1) Pharmacodynamic interaction Pharmacodynamic interaction • Serotonin syndrome consists of a constellation of Serotonin syndrome consists of a constellation of

psychiatric, neurological, and CV symptomspsychiatric, neurological, and CV symptoms

• Symptoms range from mild to lethal and include Symptoms range from mild to lethal and include a triad of cognitive (delirium, coma), autonomic a triad of cognitive (delirium, coma), autonomic (hypertension, tachycardia, diaphoreses) and (hypertension, tachycardia, diaphoreses) and somatic (myoclonus, hyperreflexia, tremor) somatic (myoclonus, hyperreflexia, tremor) effectseffects

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• Most serotonergic antidepressants should be Most serotonergic antidepressants should be discontinued at least 2 weeks before starting a discontinued at least 2 weeks before starting a MAOIMAOI

• Fluoxetine, because of its long half-life, should be Fluoxetine, because of its long half-life, should be discontinued for 4–5 weeks before an MAOI is discontinued for 4–5 weeks before an MAOI is initiatedinitiated

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• Serious interaction with MAOIs occurs when an Serious interaction with MAOIs occurs when an MAOI is combined with tyramine in the diet MAOI is combined with tyramine in the diet (e.g. (e.g. smoked, aged, or pickled meat or fish, aged smoked, aged, or pickled meat or fish, aged cheeses, etc)cheeses, etc)

• MAOIs prevent the breakdown of tyramine in the MAOIs prevent the breakdown of tyramine in the gut resulting in high serum levels that enhance gut resulting in high serum levels that enhance peripheral noradrenergic effects, including raising peripheral noradrenergic effects, including raising BP dramatically (Hypertensive crisis)BP dramatically (Hypertensive crisis)

• Can be minimized with a low-tyramine diet that Can be minimized with a low-tyramine diet that begins several days before starting the MAOI & begins several days before starting the MAOI & continues for 3-4 weeks after stopping the MAOIcontinues for 3-4 weeks after stopping the MAOI

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Youdim et al. Nature Reviews Neuroscience 7, 295–309 (April 2006) | doi:10.1038/nrn1883

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• Serious hypertension can occur with concomitant Serious hypertension can occur with concomitant administration of OTC cough and cold administration of OTC cough and cold medications containing sympathomimetic amines medications containing sympathomimetic amines (pseudoephedrine and phenylpropanolamine)- (pseudoephedrine and phenylpropanolamine)- CONTRAINDICATIONS CONTRAINDICATIONS

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55--HTHT22 antagonists antagonists

• Agents: Nefazodone, Trazodone, Agents: Nefazodone, Trazodone, mirtazapine and mirtazapine and mianserin (not marketed in the U.S.)mianserin (not marketed in the U.S.)

• Inhibition of 5-HTInhibition of 5-HT2A2A receptors in both animal and receptors in both animal and

human studies is associated with substantial human studies is associated with substantial antianxiety, antipsychotic, and antidepressant antianxiety, antipsychotic, and antidepressant effectseffects

• Nefazodone is a weak inhibitor of both SERT and Nefazodone is a weak inhibitor of both SERT and NET, whereas trazodone is also a weak but NET, whereas trazodone is also a weak but selective inhibitor of SERT selective inhibitor of SERT

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55--HTHT22 antagonists antagonists

• Trazodone’s primary metabolite, m-cpp, is a Trazodone’s primary metabolite, m-cpp, is a potent 5-HTpotent 5-HT2A2A antagonist, and much of antagonist, and much of

trazodone's benefits as an antidepressant might trazodone's benefits as an antidepressant might be attributed to this effectbe attributed to this effect

• Trazodone also has weak-to-moderate Trazodone also has weak-to-moderate presynaptic presynaptic αα-adrenergic–blocking properties and -adrenergic–blocking properties and is a modest antagonist of the H1 receptoris a modest antagonist of the H1 receptor

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55--HT2 antagonistsHT2 antagonists

• Mirtazapine has a complex pharmacology:Mirtazapine has a complex pharmacology:

1)1) It is an antagonist of 5-HTIt is an antagonist of 5-HT22 and 5-HT and 5-HT33

receptorsreceptors

2)2) By blocking presynaptic By blocking presynaptic αα22-adrenoceptors -adrenoceptors and and

enhances the release of both norepinephrine enhances the release of both norepinephrine and 5-HTand 5-HT

• Mirtazapine is a potent H1 antagonist, which is associated with the drug's sedative effects

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55--HT2 antagonists- HT2 antagonists- Clinical usesClinical uses

• Depression: Depression: Mirtazapine can be advantagous Mirtazapine can be advantagous in patients with depression having sleep in patients with depression having sleep difficultiesdifficulties

• Low doses of trazodone (50-100 mg) have Low doses of trazodone (50-100 mg) have been used widely both alone and concurrently been used widely both alone and concurrently with SSRIs or SNRIs to treat insomniawith SSRIs or SNRIs to treat insomnia

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I.5-HTI.5-HT22 antagonists- antagonists- ADRsADRs

1)1) Sedation (trazodone & mirtazapine): probably Sedation (trazodone & mirtazapine): probably because of their potent Hbecause of their potent H11-blocking activity. -blocking activity.

Sedation necessitates dosing at bedtimeSedation necessitates dosing at bedtime

2)2) Dose-related GIT SEsDose-related GIT SEs

3)3) Priapism: uncommon but serious side effect Priapism: uncommon but serious side effect requiring surgical intervention in one-third of the requiring surgical intervention in one-third of the cases reportedcases reported

4)4) weight gain (mirtazapine)weight gain (mirtazapine)

5)5) Nefazodone has been associated with Nefazodone has been associated with hepatotoxicity, including rare fatalities and cases hepatotoxicity, including rare fatalities and cases of hepatic failure requiring transplantationof hepatic failure requiring transplantation

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II. BupropionII. Bupropion

• It acts as a weak dopamine and norepinephrine It acts as a weak dopamine and norepinephrine reuptake inhibitor to alleviate the symptoms of reuptake inhibitor to alleviate the symptoms of depression depression

• Bupropion has virtually no direct effects on the Bupropion has virtually no direct effects on the serotonin systemserotonin system

• Unlike the SSRIs, bupropion does not cause Unlike the SSRIs, bupropion does not cause sexual side effectssexual side effects

• It does not block muscarinic, histaminergic, or It does not block muscarinic, histaminergic, or adrenergic receptorsadrenergic receptors

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Bupropion- Bupropion- Clinical usesClinical uses

1)1) DepressionDepression

2)2) Bupropion is approved as a treatment for Bupropion is approved as a treatment for smoking cessationsmoking cessation

• The mechanism by which bupropion is helpful in this application is unknown, but the drug may mimic nicotine's effects on dopamine and norepinephrine and may antagonize nicotinic receptors

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Bupropion & Mirtazapine- Bupropion & Mirtazapine- SEsSEs

• BupropionBupropion is occasionally associated with is occasionally associated with CNS stimulations (agitation, insomnia, and CNS stimulations (agitation, insomnia, and anorexia)anorexia)

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Bupropion- Bupropion- D/D interactionsD/D interactions

• Bupropion is metabolized primarily by Bupropion is metabolized primarily by CYP2B6, and its metabolism may be altered CYP2B6, and its metabolism may be altered by drugs such as cyclophosphamideby drugs such as cyclophosphamide

1 Chapter 12: Antidepressants. 2 Introduction Worldwide, depression is a major cause of disability...

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