1. Chapter 12: Antidepressants

2. 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

3. 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)

4. 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

5. Pathophysiology of Major Depression
The neurotrophic hypothesis
The monoamine hypothesis

6. 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

7. 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

8. 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)

9. 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

10. 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

11. 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

12. 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

13. 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)

14. 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

15. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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)

24. 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

26. 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

27. 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)

28. 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

29. 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

30. 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

31. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

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

50. 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

51. 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

52. 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

53. 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

54. 5-HT2 antagonists- Clinical uses
Depression: Mirtazapine can be advantagous in patients with depression having sleep difficulties
Low doses of trazodone ( mg) have been used widely both alone and concurrently with SSRIs or SNRIs to treat insomnia

55. 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

56. 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

57. 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

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

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