Chapter 12: Antidepressants

Introduction Worldwide, depression is a major cause of disability and premature death Depression is the most common of the affective disorders (defined as disorders of mood rather than disturbances of thought or cognition) In addition to the significant suicide risk, depressed individuals are more likely to die from other causes, such as heart disease or cancer

Introduction Depressive symptoms also can occur secondary to other illnesses such as hypothyroidism, Parkinson's disease, and inflammatory conditions For a diagnosis of major depressive disorder to be made, symptoms must be present for at least 2 weeks and must not be precipitated or influenced by a medical illness or medication Depression, in general, is classified as major depression (i.e., unipolar depression) or bipolar depression (i.e., manic depressive illness)

Introduction Individuals must possess at least five symptoms, one of which is either depressed mood OR diminished interest or pleasure in activities Change in appetite Change in sleep Low energy and decreased libido Poor concentration (or difficulty making decisions) Feelings of worthlessness or inappropriate guilt Psychomotor agitation or retardation Recurrent thoughts of suicide

Pathophysiology of Major Depression The neurotrophic hypothesis The monoamine hypothesis

Neurotrophic Hypothesis Depression appears to be associated with a drop in brain-derived neurotrophic factor (BDNF) levels in the cerebrospinal fluid and serum as well as with a decrease in tyrosine kinase receptor B activity BDNF is thought to exert its influence on neuronal survival and growth effects by activating the tyrosine kinase receptor B in both neurons and glia

Neurotrophic Hypothesis Animal and human studies indicate that stress and pain are associated with a drop in BDNF levels and that this loss of neurotrophic support contributes to atrophic structural changes in the hippocampus and perhaps other areas such as the medial frontal cortex and anterior cingulate Studies suggest that major depression is associated with substantial loss of volume in the hippocampus, anterior cingulate and medial orbital frontal cortex

Monoamine hypothesis of depression The monoamine hypothesis grew originally out of associations between the clinical effects of various drugs that cause or alleviate symptoms of depression and their known neurochemical effects on monoaminergic transmission in the brain The monoamine hypothesis of depression suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA)

Monoamine hypothesis of depression The chronic activation of monoamine receptors by antidepressants appears to increase in BDNF transcription One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase immediately with antidepressant use, but maximum beneficial effects of antidepressants are not seen for many weeks The time required to synthesize neurotrophic factors has been proposed as an explanation for this delay of antidepressant effects

Antidpressents Most antidepressants exert important actions on the metabolism of monoamine neurotransmitters and their receptors, particularly norepinephrine and serotonin The pharmacologic effects of any of the antidepressant drugs on neurotransmission occur immediately, whereas the time course for a therapeutic response occurs over several weeks It takes at least 2 weeks to produce significant improvement in mood "therapeutic lag", and maximum benefit may require up to 12 weeks or more

Antidpressents In monoamine systems, reuptake of the transmitter is the main mechanism by which neurotransmission is terminated; thus, inhibition of reuptake can enhance neuro-transmission, presumably by slowing clearance of the transmitter from the synapse and prolonging the dwell-time of the transmitter in the synapse Monoamine oxidase inhibitors (MAOIs) enhances monoaminergic neurotransmission by inhibiting monoamine metabolism and thereby enhancing neurotransmitter storage in secretory granules

Drug Selection: General Considerations Various types of antidepressants are available: Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin norepinephrine reuptake inhibitors (SNRIs) Monoamine oxidase inhibitors (MAOIs) 5-HT2 Antagonists Bupropion

Selective Serotonin Reuptake Inhibitors (SSRIs) They are the most commonly prescribed group of antidepressants They specifically inhibit serotonin reuptake, having 300- to 3000-fold greater selectivity for the serotonin transporter as compared to the norepinephrine transporter Agents: Fluoxetine (Prozac®), paroxetine, sertraline, fluvoxamine, Citalopram, & Escitalopram (s-citalopram)

Selective Serotonin Reuptake Inhibitors (SSRIs) As a class, these medications have little or no affinity for cholinergic, β-adrenergic or histamine receptors and do not interfere with cardiac conduction They are well tolerated by patients who are especially sensitive to the anticholinergic and orthostatic effects of the TCAs and MAOIs SSRI have largely replaced TCAs and MAOIs as the drugs of choice in treating depression

SSRIs- Mechanism of action SSRIs allosterically inhibit the serotonin transporter (SERT) by binding the receptor at a site other than active binding site for serotonin In the serotonin system, 5-HT1A and 5-HT7 autoreceptors on cell bodies in the raphe nucleus and of 5-HT1D autoreceptors on serotonergic terminals suppress neuronal release of serotonin and result in a decrease in neuronal firing Repeated treatment leads to gradual down-regulation and desensitization of autoreceptor mechanisms over several weeks, with a return or increase of presynaptic activity, production, and release of serotonin At therapeutic doses, about 80% of the activity of the transporter is inhibited

SSRIs Stimulation of 5-HT3 receptors is suspected to contribute to common ADRs, including GIT (NV) and sexual effects (delayed or impaired orgasm) Stimulation of 5-HT2C receptors may contribute to the agitation or restlessness sometimes induced by serotonin reuptake inhibitors

SSRIs- Clinical uses Major Depression: the primary indication Obsessive-compulsive disorder (OCD) (fluvoxamine, clomipramine) Panic disorder Generalized anxiety disorder Posttraumatic stress disorder (Sertraline and paroxetine) Social anxiety disorder (SAD): fluvoxamine, venlafaxine Premenstrual dysphoric disorder (fluxetine & sertraline) Bulimia nervosa (only fluoxetine) Premature ejaculation

SSRIs- ADEs GIT: nausea, GIT upset, diarrhea. Sexual dysfunction: loss of libido, delayed orgasm, or diminished arousal. CNS: Sleep disturbances. For this reason, fluoxetine is usually administered in the morning after breakfast Weight gain particularly paroxetine SSRIs have also been associated with extrapyramidal side effects, especially those with Parkinson’s disease There is an association of paroxetine with cardiac septal defects in first trimester exposures

SSRIs- D/D interactions Pharmacokinetic interactions: The SSRIs are potent inhibitors of the CYP450 The potential for drug-drug interactions differs significantly across the SSRIs Paroxetine and fluoxetine are potent CYP2D6 inhibitors responsible for the elimination of TCA drugs, neuroleptic drugs, and some antiarrhythmic and β-adrenergic antagonist drugs

SSRIs- D/D interactions Pharmacokinetic interactions: Fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension Citalopram and escitalopram have the least effect on the cytochrome P450 system & have the most favorable profile regarding D–D interactions

SSRIs- D/D interactions Pharmacodynamic interactions: The most serious interaction with the SSRIs are with MAOIs that produce a serotonin syndrome Fluoxetine* has to be discontinued 4 to 6 weeks before an MAOI can be administered to mitigate the risk of serotonin syndrome * 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 SSRIs

Serotonin-Norepinephrine Reuptake Inhibitors Two classes of antidepressants act as combined serotonin and norepinephrine reuptake inhibitors: Selective serotonin-norepinephrine reuptake inhibitors (SNRIs) Tricyclic antidepressants (TCAs)

a) Selective Serotonin-Norepinephrine Reuptake Inhibitors Agents: venlafaxine, desvenlafaxine, and duloxetine & milnacipran* All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters At dosages <150 mg/day, venlafaxine is a potent inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of norepinephrine re-uptake Duloxetine inhibits serotonin and norepinephrine reuptake at all doses *Milnacipran is not used to treat depression. It is approved for the treatment of fibromyalgia

a) Selective Serotonin-Norepinephrine Reuptake Inhibitors Unlike the TCAs, the SNRIs have little activity at adrenergic, muscarinic, or histamine receptors and, thus, have fewer of these receptor-mediated adverse effects than the TCA

SNRIs- Clinical uses Depression: in patients in whom SSRIs are ineffective chronic joint and muscle pain: duloxetine Fibromyalgia: milnacipran Urinary stress incontinence (duloxetine in Europe) Off-label uses include autism, binge eating disorders, hot flashes (desvenlafaxine), pain syndromes, premenstrual dysphoric disorders, and post-traumatic stress disorders (venlafaxine)

I. SNRIs- ADRs SNRIs have many of the serotonergic adverse effects associated with SSRIs In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation The SNRIs have relatively fewer CYP450 interactions than the SSRIs

II.Tricyclic Antidepressants (TCA) The TCAs were the dominant class of antidepressants until the introduction of SSRIs in the 1980s and 1990s Agents: imipramine (the prototype drug), amitriptyline, clomipramine, doxepin , trimipramine, desipramine, nortriptyline, and protriptyline Maprotiline & amoxapine are not members of the tricyclic family. However, their pharmacology is so similar to that of the TCAs and are commonly included in the general class of TCAs

II.Tricyclic Antidepressants (TCA) The TCAs activity is thought to relate primarily to their inhibition of 5-HT and NE reuptake Within the TCAs, there is considerable variability in affinity for SERT versus NET: Clomipramine has relatively very little affinity for NET but potently binds SERT Desipramine (Imipramine’s metabolite) and nortriptyline, are relatively more selective for NET Imipramine has more serotonin effects initially

II.Tricyclic Antidepressants (TCA) TCAs also block serotonergic, α-adrenergic, histaminic, and muscarinic receptors Actions at these receptors are probably responsible for many of the untoward effects of the TCAs TCAs such as doxepin are sometimes prescribed as hypnotics and used in treatments for pruritus because of their antihistamine properties Amoxapine also blocks the D2 receptor

II. TCA- Clinical uses Depression: that is unresponsive to more commonly used antidepressants )SSRIs or SNRIs) Panic disorder Control bed-wetting in children (older than 6 years) by causing contraction of the internal sphincter of the bladder (Imipramine)1 Treatment of migraine headache and chronic pain syndromes for which the cause of the pain is unclear (Amitriptyline) 1 At present, it is used cautiously because of the inducement of cardiac arrhythmias and other serious cardiovascular problems

II.TCA- ADRs weight gain Sexual dysfunction Antimuscarinic SEs: dry mouth ,constipation, urinary retention, blurred vision, and confusion Life-threatening arrhythmias: The TCAs are class 1A antiarrhythmic agents Sedation (H1 antagonism) weight gain Sexual dysfunction At therapeutic doses, the TCA drugs lower the seizure threshold and at toxic doses can cause life-threatening seizures (especially Maprotiline) Amoxapine has dopamine receptor antagonist properties and can induce EPS, gynecomastia, lactation, and neuroleptic malignant syndrome

TCAs overdoses Acute poisoning with tricyclic antidepressants or MAO inhibitors is potentially life-threatening Compared with TCAs and MAOIs, the other antidepressants are generally much safer in overdose

TCA overdose A 1500 mg dose of imipramine or amitriptyline is enough to be lethal in many patients Symptoms: ventricular tachycardia, fibrillation and seizures are sometimes seen Management: cardiac monitoring, airway support, and gastric lavage. Sodium bicarbonate is often administered to uncouple the TCA from cardiac sodium channels

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

MAO inhibitors Agents: selegline, phenelzine, and tranylcypromine MAO exists in the human body in two molecular forms, known as type A and type B Norepinephrine and serotonin are preferentially metabolized by MAO-A. MAO-B is more likely to be involved in the catabolism of human brain dopamine

MAO inhibitors The MAO inhibitors inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumulate within the presynaptic neuron and leak into the synaptic space Selective MAO-A inhibitors are more effective in treating major depression than type B inhibitors

MAO inhibitors MAOIs are classified by their specificity for MAO-A or -B and whether their effects are reversible or irreversible Phenelzine and tranylcypromine are examples of irreversible, nonselective MAOIs Moclobemide is a reversible and selective inhibitor of MAO-A Selegiline is an irreversible MAO-B–specific agent at low doses, but at higher doses it becomes a nonselective MAOI similar to other agents

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

MAO Inhibitors-Clinical use Depression: Reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants Selegiline is the first antidepressant available in a transdermal delivery system

MAO Inhibitors-ADRs Orthostatic hypotension, weight gain, edema, and sexual dysfunction are common during MAOI therapy Sexual SEs: highest rates are associated with the irreversible nonselective MAOIs (phenelzine and tranylcypromine) Phenelzine tends to be more sedating than either selegiline or tranylcypromine Hepatotoxicity is likely to occur with isocarboxazid or phenelzine

MAO Inhibitors-D-D interactions Pharmacodynamic interaction These combinations of an MAOI with a serotonergic agent (SSRIs, SNRIs, and most TCAs) may result in a life-threatening serotonin syndrome Most case reports of serotonin syndrome (and most fatalities) have occurred with a combination of an MAOI and an SSRI It is caused by overstimulation of 5-HT receptors in the central gray nuclei and the medulla

MAO Inhibitors-D-D interactions Pharmacodynamic interaction Serotonin syndrome consists of a constellation of psychiatric, neurological, and CV symptoms Symptoms range from mild to lethal and include a triad of cognitive (delirium, coma), autonomic (hypertension, tachycardia, diaphoreses) and somatic (myoclonus, hyperreflexia, tremor) effects

MAO Inhibitors-D-D interactions Most serotonergic antidepressants should be discontinued at least 2 weeks before starting a MAOI Fluoxetine, because of its long half-life, should be discontinued for 4–5 weeks before an MAOI is initiated

MAO Inhibitors-D-D interactions Serious interaction with MAOIs occurs when an MAOI is combined with tyramine in the diet (e.g. smoked, aged, or pickled meat or fish, aged cheeses, etc) MAOIs prevent the breakdown of tyramine in the gut resulting in high serum levels that enhance peripheral noradrenergic effects, including raising BP dramatically (Hypertensive crisis) Can be minimized with a low-tyramine diet that begins several days before starting the MAOI & continues for 3-4 weeks after stopping the MAOI

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

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

5-HT2 antagonists Agents: Nefazodone, Trazodone, mirtazapine and mianserin (not marketed in the U.S.) Inhibition of 5-HT2A receptors in both animal and human studies is associated with substantial antianxiety, antipsychotic, and antidepressant effects Nefazodone is a weak inhibitor of both SERT and NET, whereas trazodone is also a weak but selective inhibitor of SERT

5-HT2 antagonists Trazodone’s primary metabolite, m-cpp, is a potent 5-HT2A antagonist, and much of trazodone's benefits as an antidepressant might be attributed to this effect Trazodone also has weak-to-moderate presynaptic α-adrenergic–blocking properties and is a modest antagonist of the H1 receptor

5-HT2 antagonists Mirtazapine has a complex pharmacology: It is an antagonist of 5-HT2 and 5-HT3 receptors By blocking presynaptic α2-adrenoceptors and enhances the release of both norepinephrine and 5-HT Mirtazapine is a potent H1 antagonist, which is associated with the drug's sedative effects

5-HT2 antagonists- Clinical uses Depression: Mirtazapine can be advantagous in patients with depression having sleep difficulties Low doses of trazodone (50-100 mg) have been used widely both alone and concurrently with SSRIs or SNRIs to treat insomnia

I.5-HT2 antagonists- ADRs Sedation (trazodone & mirtazapine): probably because of their potent H1-blocking activity. Sedation necessitates dosing at bedtime Dose-related GIT SEs Priapism: uncommon but serious side effect requiring surgical intervention in one-third of the cases reported weight gain (mirtazapine) Nefazodone has been associated with hepatotoxicity, including rare fatalities and cases of hepatic failure requiring transplantation

II. Bupropion It acts as a weak dopamine and norepinephrine reuptake inhibitor to alleviate the symptoms of depression Bupropion has virtually no direct effects on the serotonin system Unlike the SSRIs, bupropion does not cause sexual side effects It does not block muscarinic, histaminergic, or adrenergic receptors

Bupropion- Clinical uses Depression Bupropion is approved as a treatment for smoking 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

Bupropion & Mirtazapine- SEs Bupropion is occasionally associated with CNS stimulations (agitation, insomnia, and anorexia)

Bupropion- D/D interactions Bupropion is metabolized primarily by CYP2B6, and its metabolism may be altered by drugs such as cyclophosphamide